bluuebunny/crossref_metadata_2025 huggingface dataset:
Using Google Community Mobility Reports to investigate the incidence of COVID-19 in the United States
Authors: Paez Antonio
Published: May 2020

In 2020 Google released a set of Community Mobility Reports (GCMR). These reports are based on the company’s location-tracking capabilities and measure changes in mobility with respect to a baseline. This novel source of data offers an opportunity to investigate potential correlations between mobility and incidence of COVID-19. Using data from the New York Times on COVID-19 cases and GCMR, this paper presents an analysis of mobility levels and incidence of COVID-19 by state in the US. The results provide insights about the utility and interpretability of GCMR for COVID-19 research and decision-making.
Arkeologinen näkökulma alakoulun oppikirjojen kuvauksiin Suomen esihistoriasta
Authors: Aalto Ilari , Kemppinen Lauri
Published: May 2020

Useimmille suomalaisille alakoulun historianopetus on koulupolun ainoa vaihe, jossa voidaan käsitellä Suomen esihistoriaa (8850 eaa.–1200 jaa.) ja sen arkeologista kulttuuriperintöä. Koulukirjoilla on keskeinen osa esihistoriasisällön opettamisessa. Tutkimme artikkelissa, miten Suomen esihistoria esitetään tällä hetkellä käytössä olevissa oppikirjoissa. Aineistomme koostuu seitsemästä, vuosina 2003–2019 julkaistusta historian oppikirjasta. Oppikirjojen esihistoriasisällöt koodattiin ja teemoiteltiin NVIVO 11 -ohjelmiston avulla 50:een sisältöalueeseen. Muodostetun tietokannan avulla pystyttiin havaitsemaan historian oppikirjojen sisällöllisiä eroja ja muodostamaan tilastointiin pohjautuva kokonaiskäsitys oppikirjojen tavasta lähestyä esihistoriaa. Sisältöanalyysin perusteella uusimman opetussuunnitelman aikana julkaistuissa kirjoissa on tapahtunut selvä muutos sisältötiedossa: kirjoissa painotetaan historian taitoja tietosisällön kustannuksella. Uusimmissa oppikirjoissa on luovuttu esihistoriallisen aineellisen kulttuurin esittelystä, mutta sen sijaan kirjat painottavat muinaista uskomusmaailmaa. Oppikirjojen tietosisältö vastaa monilta osin 1980- ja 1990-lukujen tutkimustilannetta. Uudemmissa oppikirjoissa etnisyyttä on käsitelty aiempaa kyseenlaistavammin, mutta kaikissa oppikirjoissa etenkin saamelaisten osuus Suomen esihistoriasta jää epäselväksi. Ehdotamme, että opetussuunnitelmaa täsmennettäisiin siten, että se ohjaisi nykyistä selvemmin esihistorian yhtämittaiseen käsittelyyn. Vallitseva opetussuunnitelma tuottaa oppikirjoja, joiden esihistoriaa käsittelevä tietosisältö ei vaikuta arkeologisesta näkökulmasta mielekkäältä.
Struggles and Strategies in Constructing Professional Identity: The First-Year Teaching Experiences of Indonesian EFL Novice Teachers
Authors: Ke Lomi Aplonia Nelci , Mbato Concilianus Laos
Published: May 2020

Several studies have recorded the increasing number of teachers who left the profession in the first year of teaching in recent years. The main cause is the difficulties over the first year of teaching and the unsatisfactory construction and growth of professional identity. This qualitative study attempted to reveal the struggles faced during their first year of teaching by EFL novice teachers working in Nusa Tenggara Timur, Indonesia and how they coped with those struggles regarding their development of professional identity. The struggles are split into internal and external struggles based on the result. The internal struggles are linked to how teachers controlled their emotions self-efficacy, and ability to teach, their jobs and their personal opinions. The external challenges related to the management of the classroom, the abilities, and attitudes of the students, the lack of resources and facilities in the school, the relationships with their colleagues and their salaries. This research is intended to provide more insight into the realities of teachers working in an underdeveloped province like East Nusa Tenggara, in particular how they establish their professional identity in a lack of facilities and learning resources.Keywords: East Nusa Tenggara; Novice Teachers; Professional Identity; Struggles and Strategies
Sosialisasi Pentingnya Kesadaran Masyarakat Terhadap Lingkungan Melalui Kegiatan Netralisasi Sungai
Authors: Anggraheni Ika , Mukarromah Lailatul , Triani Novi , Mathari Mathari , Aziizi Ainun Nur , Afifah Lu'luul Millati , Rahmawati Refika , Ismail Aldian Fajar , Khoiruddin M. Yusuf Alfan , Bessy Baharudin , Adelia Adelia , Mufarokhah Zulfa , Abrory Muhammad Nizar
Published: May 2020

Pemahaman sampah pada masyarakat masih sangat rendah. Hal ini seperti yang terjadi di desa Dadapan, Kecamatan Wajak, Kabupaten Malang. Persoalan pembuangan sampah yang tidak pada tempatnya sehingga menganggu kebersihan lingkungan terutama di Sungai Desa Dadapan. Secara umum kondisi alam desa Dadapan adalah perumahan yang penuh dengan bangunan rumah warga. Minimnya tempat pembuangan sampah membuat warga membuang sampah di sungai. Dalam permasalahan ini kami mengadakan program penetralisasi sungai. Kegitatan itu berupa pembersihan sungai yang telah tercemar oleh sampah masyarakat. Solusi dari pencemaran lingkungan tersebut diadakan program kelompok meliputi Pengadaan Tempat Sampah Untuk RT 015 RW 005 Dusun Pagar Gunung, Kerja Bakti, Sosialisasi Program KKN-PPM Tematik, Pendampingan TPA, Administrasi Desa.
Contemporary french comparative studies: issues and methods
Authors: Narivska Valentyna , Pakhsarian Nataliia
Published: May 2020

The paper presents a review of the main issues and methods of studying modern French literature and comparative studies.

The authors outline the diferences between European approaches, now taken with focus rather on all-European common principles than cultural distinctions, and American tendencies that reflect the priority of feminist and post-colonial methods of comparative studies. Attention is paid to the French peculiarities concerning the replacement of the term ‘influence’ by ‘intertextuality’, and to the role of intermedial and interdisciplinary comparative studies.

Among the outlined concepts and issues are research ethics in comparative studies; non-essential writers and genres (F. Lavokat); relation of comparative studies to the concepts of European and world literature (A. Tomiche); the role and place of comparative studies in literature and culture (F. Toudoire-Surlapierre), accuracy and universality of defining the discipline (B. Franco), the study of links between literature and art (G. Steiner).

Attention is also paid to the discussions on the concept of ‘world literature’ (in particular to the views of P. Kazanova) that concern the term ‘world literature’ as it is interpreted by American researchers and ‘European literature’ used by French ones. Other issues are the concept of ‘cultural transfer’; the content of hermeneutic practice in comparison; the role of analysis and ‘defamiliarization’ (introduced by V. Shklovsky); comparison as an object of criticism, a tool of analytics, and methodological necessity; the transversality as the coexistence of diferent comparative methods. The comparative approach has been shown as ontological and culturological vision, a special method of research with a basis in comparison and opposition of the interconnected systems covering translation studies, mythology, imagology, geocriticism, post-colonial and gender studies, research of cultural transfer specified as multicomparativism.
Why is there no just riot theory?
Authors: Havercroft Jonathan
Published: May 2020

Given the prevalence of riots throughout human history, the lack of normative theorizing about riots when compared to other forms of political violence is striking. I hypothesize this lacuna is due to the riot’s extra-institutionality. Riots are extra-public because crowds riot rather than institutionalized groups such as parties or social movements. Riots are extra-state because they violate the state’s monopoly on violence. Riots are extra-legal because they are a form of unlawful assembly. Riots are extra-Parliamentary because they operate outside of the normal legislative process. When political theorists have scrutinized each of these four institutions, they also have identified reasons to resist each of them. By considering the justifiable reasons for resisting each of these foundational institutions I propose some provisional criteria for a justifiable riot and argue that political theorists should pay attention to the normative dimension of riots.
Епіграветт Східного Прикарпаття та епіграветт і східний епіграветт в історичному розвитку
Authors: Olenkovskyi Mykola
Published: May 2020

У статті наводяться узагальнені висновки щодо розвитку культурно-історичних процесів в епіграветті Східної Європи. Аргументується соціально-історична база походження класичного епіграветту Східної Європи у Східному Прикарпатті (на території України та Молдови) та його поширення у межах Правобережної України. Наводяться дані щодо походження й історичного розвитку східного епіграветту. Надається аналіз східного епіграветту Лівобережної України за окремими археологічними культурами. Висловлюється погляд щодо впливу як класичного, так і східного епіграветту на формування фінального палеоліту та початку мезоліту Східної Європи.
SISTEM PRESENSI MENGGUNAKAN NFC SMARTPHONE ANDROID DAN RASPBERRY PI (STUDI KASUS POLITEKNIK NEGERI MALANG)
Authors: Affandi Luqman , Ekojono  , Rizaldi Ahmad
Published: May 2020

Presensi adalah kegiatan pengambilan data untuk mencatat jumlah kehadiran. Ada beberapa metode pengambilan presensi yang sering digunakan, yaitu memanggil nama satu persatu dan memberikan kertas untuk ditanda-tangani satu persatu. Hal tersebut merupakan cara konvensional yang masih diterapkan di Politeknik Negeri Malang (Polinema). Pengambilan data kehadiran secara konvensional kurang efisien  dan memiliki beberapa masalah diantaranya membutuhkan waktu yang lama dalam memanggil mahasiswa satu persatu, membutuhkan biaya untuk mencetak kertas dan kertas presensi sering kali terlambat dicetak dan didistribusikan. Berdasarkan permasalahan tersebut, muncul ide untuk memanfaatkan NFC pada smartphone Android untuk melakukan proses presensi pada setiap mahasiswa. Sistem menggunakan Representational State Transfer (REST) untuk komunikasi data. Sistem presensi Jurusan Teknologi Informasi (JTI) Polinema dengan cara konvensional membutuhkan waktu 1 jam. Dengan memanfaatkan teknologi ini, sistem presensi hanya membutuhkan waktu selama 5 menit. Berdasarkan pengujian alat pembaca NFC  jarak optimal pembacaan tag adalah < 4 cm untuk smartphone dan  < 3 cm untuk sticker NFC dan waktu rata-rata response sampai data terkirim ke database server adalah 0.47541s untuk NFC smartphone dan 0.19975s untuk sticker NFC.
PERBANDINGAN METODE FTS DAN MA PADA PERAMALAN PERSEDIAAN BERAS
Authors: Kusbianto Deddy , Pramudhita Agung , Nurhalimah
Published: May 2020

Dalam memenuhi kebutuhan masyarakat Kabupaten Malang dan menjaga stabilitas ketersediaan beras pemerintah setempat perlu melakukan proses peramalan. Dimana dalam melakukan proses peramalan menggunakan metode peramalan, salah satunya dengan menggunakan metode Fuzzy Time Series dan Moving Average yaitu dengan menangkap pola dari data yang telah lalu kemudian digunakan untuk memproyeksikan data yang akan da¬¬tang. Dari hasil implementasi dua metode tersebut menghasilkan perbandingan jumlah persediaan beras. hasil perbandingan tersebut akan dipakai untuk mengukur tingkat error dari masing – masing metode dengan menggunakan MAD (Mean Absolute Deviation), MSE (Mean Square Error), RMSE ( Root Square Error ) dan MAPE (Mean Absolute Percentage Error). Kesimpulannya adalah metode fuzzy time series cocok digunakan untuk studi kasus peramalan persediaan beras dibandingkan menggunakan metode moving average. Sehingga untuk proses peramalan selanjutnya dan untuk mendapatkan hasil dengan tingkat error sedikit dapat menggunakan metode fuzzy time series.
MEDIA PEMBELAJARAN INTERAKTIF TERHADAP GWK CUTURE PARK MENGGUNAKAN TEKNOLOGI AUGMENTED REALITY
Authors: Nurhasan Usman , Prasetyo Arief , Wardani Efita Tria
Published: May 2020

Garuda Wisnu Kencana Culture Park Bali merupakan salah satu tempat wisata di Bali yang saat ini menjadi tempat wisata non pantai favorit. Di dalamnya terdapat sejarah mengenai kebudayaan Bali dan sejarah patung GWK itu sendiri. Namun belum banyak yag mengetahui akan sejarah tersebut. Salah satu hal menyebabkan ketidaktahuan orang akan sejarah ini adalah belum adanya suatu perangkat yang memadai. Maka dibuatkannya media pembelajaran untuk memudakan mempelajari sejarah GWK. Aplikasi ini menerapkan teknologi Augmented Reality dan game kuis. Aplikasi ini akan dirancang menggunakan metode Simultaneous Markerless dengan library Vuforia SDK untuk pendeteksian gambar agar tampilan visual menjadi lebih menarik. Dan juga menerapkan metode Fisher Yates Shuffle untuk randomisasi soal pada kuis. Teknologi ini akan diimplementasikan pada perangkat smartphone berbasis Android. Hasil akhir yang diharapkan agar dapat menarik minat masyarakat untuk mempelajari budaya Indonesia khususnya budaya Bali dan sejarah patung GWK. Berdasarkan hasil uji coba yang dilakukan, dapat disimpulkan bahwa aplikasi ini berjalan sesuai tujuannya, dan dapat dinyatakan menarik minat belajar siswa dengan hasil presentase 86,3%, sehingga didapatkan hasil responden sangat tertarik denan aplikasi yang dibuat.
Persepsi dan Dukungan Keluarga terhadap Pemberian Imunisasi MR
Authors: Rafidah Rafidah , Yuliastuti Erni
Published: May 2020

Nationally, MR immunization is 51.05% as of September 30, 2018. MR immunization coverage in South Kalimantan Province until October 31, 2018, is 56.58%. The lowest achievement is Banjar Regency, with 36.46%. The study aimed to determine the relationship between perception and family support (husband) with MR immunization. The study design used a cross-sectional study. The study population was mothers who had children aged nine months to 15 years in the working area of the Beruntung Baru Public Health Center, totaling 6,379 people. The sample size was 377 people. This study used accidental sampling. Univariate data analysis and bivariate analysis with Chi-Square statistical test. The results of the study showed a relationship between perceptions (p-value=0,001; OR=24,7) and and family support (p-value=0,001; OR=9,3) with giving MR immunization. This study suggests the Beruntung Baru public health center to improve health promotion on MR immunization by holding counseling so that the public could better understand MR immunization.
Avances frente a la conciliación trabajo-familia en Latinoamérica: una revisión sistemática de la literatura
Authors: Carlosama Rodriguez Diana Milena , Martínez Narvaez Estefany Melissa , Matabanchoy Tulcan Sonia Maritza
Published: May 2020

El presente estudio tiene como objetivo conocer los avances en el tema de conciliación trabajo-familia, que se han presentado entre los años de 2008 a 2018 en Latinoamérica. Para ello se analizaron mediante revisión sistemática 51 estudios en las bases de datos Redalyc, Scielo, Dialnet y EBSCOhost. Los resultados indican que existen avances en cuanto a la comprensión del fenómeno y su relación con otras variables, el desarrollo y validación de instrumentos de medición y evaluación, además de avances en torno a la publicación sobre el tema en los últimos años; se sugiere continuar investigando sobre la temática, con el fin de llenar vacíos, fundamentalmente en cuanto a la implementación de estrategias que aporten tanto a las organizaciones como a los colaboradores.
A Review of Low-Power Electric Propulsion Research at the Space Propulsion Centre Singapore
Authors: Potrivitu George-Cristian , Sun Yufei , Rohaizat Muhammad Wisnuh Aggriawan bin , Cherkun Oleksii , Xu Luxiang , Huang Shiyong , Xu Shuyan
Published: May 2020

The age of space electric propulsion arrived and found the space exploration endeavors at a paradigm shift in the context of new space. Mega-constellations of small satellites on low-Earth orbit (LEO) are proposed by many emerging commercial actors. Naturally, the boom in the small satellite market drives the necessity of propulsion systems that are both power and fuel efficient and accommodate small form-factors. Most of the existing electric propulsion technologies have reached the maturity level and can be the prime choices to enable mission versatility for small satellite platforms in Earth orbit and beyond. At the Plasma Sources and Applications Centre/Space Propulsion Centre (PSAC/SPC) Singapore, a continuous effort was dedicated to the development of low-power electric propulsion systems that can meet the small satellites market requirements. This review presents the recent progress in the field of electric propulsion at PSAC/SPC Singapore, from Hall thrusters and thermionic cathodes research to more ambitious devices such as the rotamak-like plasma thruster. On top of that, a review of the existing vacuum facilities and plasma diagnostics used for electric propulsion testing and characterization is included in the present research.
Mechanical System and Template-Matching-Based Position-Measuring Method for Automatic Spool Positioning and Loading in Welding Wire Winding
Authors: Xu Jie , He Xin , Ji Weixi
Published: May 2020

Welding wire is a major type of welding consumable, which needs to be winded onto spools for sale. Currently, the winding process is accomplished manually due to obstacles such as automatic spool loading and clamping. When loading the spool, the angular position of the spool is a prerequisite for matching the drive rod on the spindle and drive bore on the spool. Therefore, this paper proposes a template-matching method combined with area-based matching and feature-point detection to measure the angular position of the spool, and presents a mechanical system that can rotate the spool to match the drive rod and push the spool onto the spindle. A novel feature-point distribution density (FPDD) method was developed to accelerate the matching process and improve matching reliability by pre-locating the searching area. The robustness and accuracy of the template-matching-based measuring method were validated using a built prototype of the mechanical system. The comparison result shows that the proposed method was superior in robustness, accuracy, and speed, and it was efficient for automatic spool loading in the welding wire winding process.
Modeling and Control of a DC Motor Coupled to a Non-Rigid Joint
Authors: Pinto Vítor , Gonçalves José , Costa Paulo
Published: May 2020

Throughout this paper, the model, its parameter estimation and a controller for a solution using a DC motor with a gearbox worm, coupled to a non-rigid joint, will be presented. First, the modeling of a non-linear system based on a DC Motor with Worm Gearbox coupled to a non-rigid joint is presented. The full system was modeled based on the modeling of two sub-systems that compose it—a non-rigid joint configuration and the DC motor with the worm gearbox configuration. Despite the subsystems are interdependent, its modelling can be performed independently trough a carefully chosen set of experiments. Modeling accurately the system is crucial in order to simulate and know the expected performance. The estimation process and the proposed experimental setup are presented. This setup collects data from an absolute encoder, a load cell, voltage and current sensors. The data obtained from these sensors is presented and used to obtaining some physical parameters from both systems. Finally, through an optimization process, the remaining parameters are estimated, thus obtaining a realistic model of the complete system. Finally, the controller setup is presented and the results obtained are also presented.
Risk of Hepatocellular Carcinoma after HCV Clearance by Direct-Acting Antivirals Treatment Predictive Factors and Role of Epigenetics
Authors: Rinaldi Luca , Nevola Riccardo , Franci Gianluigi , Perrella Alessandro , Corvino Giusy , Marrone Aldo , Berretta Massimiliano , Morone Maria Vittoria , Galdiero Marilena , Giordano Mauro , Adinolfi Luigi Elio , Sasso Ferdinando Carlo
Published: May 2020

Direct-acting antivirals (DAAs) induce a rapid virologic response (SVR) in up to 99% of chronic hepatitis C patients. The role of SVR by DAAs on the incidence or recurrence of hepatocellular carcinoma (HCC) is still a matter of debate, although it is known that SVR does not eliminate the risk of HCC. In this review, we made an updated analysis of the literature data on the impact of SVR by DAAs on the risk of HCC as well as an assessment of risk factors and the role of epigenetics. Data showed that SVR has no impact on the occurrence of HCC in the short–medium term but reduces the risk of HCC in the medium–long term. A direct role of DAAs in the development of HCC has not been demonstrated, while the hypothesis of a reduction in immune surveillance in response to the rapid clearance of HCV and changes in the cytokine pattern influencing early carcinogenesis remains to be further elucidated. HCV induces epigenetic alterations such as modifications of the histone tail and DNA methylation, which are risk factors for HCC, and such changes are maintained after HCV clearance. Future epigenetic studies could lead to identify useful biomarkers and therapeutic targets. Cirrhosis has been identified as a risk factor for HCC, particularly if associated with high liver stiffness and α-fetoprotein values, diabetes and the male sex. Currently, considering the high number and health cost to follow subjects’ post-HCV clearance by DAAs, it is mandatory to identify those at high risk of HCC to optimize management.
Correction: Oh, J.Y., et al. Synergistic Autophagy Effect of miR-212-3p in Zoledronic Acid-Treated In Vitro and Orthotopic In Vivo Models and in Patient-Derived Osteosarcoma Cells, Cancers 2019, 11, 1812
Authors: Oh Ju Yeon , Kim Eun Ho , Lee Yeon-Joo , Sai Sei , Lim Sun Ha , Park Jang Woo , Chung Hye Kyung , Kim Joon , Vares Guillaume , Takahashi Akihisa , Jeong Youn Kyoung , Kim Mi-Sook , Kong Chang-Bae
Published: May 2020

The authors wish to make the following corrections to this paper [...]
ESM-1 Overexpression is Involved in Increased Tumorigenesis of Radiotherapy-Resistant Breast Cancer Cells
Authors: Jin Hana , Rugira Trojan , Ko Young Shin , Park Sang Won , Yun Seung Pil , Kim Hye Jung
Published: May 2020

The key barrier to the effectiveness of radiotherapy remains the radioresistance of breast cancer cells, resulting in increased tumor recurrence and metastasis. Thus, in this study, we aimed to clarify the difference between radiotherapy-resistant (RT-R) breast cancer (BC) and BC, and accordingly, analyzed gene expression levels between radiotherapy-resistant (RT-R) MDA-MB-231 cells and MDA-MB-231 cells. Gene expression array showed that ESM-1 was the most upregulated in RT-R-MDA-MB-231 cells compared to MDA-MB-231 cells. Then, we aimed to investigate the role of ESM-1 in the increased tumorigenesis of RT-R-BC cells. RT-R-MDA-MB-231, which showed an increased expression level of ESM1, exhibited significantly enhanced proliferation, colony forming ability, migration, and invasion compared to MDA-MB-231 cells, and ESM-1 knockdown effectively reversed these effects. In addition, compared to MDA-MB-231 cells, RT-R-MDA-MB-231 cells displayed improved adhesion to endothelial cells (ECs) due to the induction of adhesion molecules and increased MMP-9 activity and VEGF-A production, which were decreased by ESM-1 knockdown. Moreover, the expression of HIF-1α and activation of NF-κB and STAT-3 were increased in RT-R-MDA-MB-231 cells compared to MDA-MB-231 cells, and these effects were abolished by the knockdown of ESM-1. Finally, we confirmed the role of ESM-1 in tumorigenesis in an in vivo mouse model. Tumor volume, lung metastasis, and tumorigenic molecules (VEGF-A, HIF-1α, MMP-9, ICAM-1, VCAM-1, and phospho-NF-κB and phospho-STAT-3) were significantly induced in mice injected with ESM-1-overexpressing 4T1 cells and greatly enhanced in those injected with ESM-1-overexpressing RT-R-4T1 cells. Taken together, these results suggest for the first time that ESM-1 plays a critical role in tumorigenesis of breast cancer cells, especially RT-R-breast cancer cells, through the induction of cell proliferation and invasion.
Bad Neighborhood: Fibrotic Stroma as a New Player in Melanoma Resistance to Targeted Therapies
Authors: Diazzi Serena , Tartare-Deckert Sophie , Deckert Marcel
Published: May 2020

Current treatments for metastatic cutaneous melanoma include immunotherapies and drugs targeting key molecules of the mitogen-activated protein kinase (MAPK) pathway, which is often activated by BRAF driver mutations. Overall responses from patients with metastatic BRAF mutant melanoma are better with therapies combining BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors. However, most patients that initially respond to therapies develop drug resistance within months. Acquired resistance to targeted therapies can be due to additional genetic alterations in melanoma cells and to non-genetic events frequently associated with transcriptional reprogramming and a dedifferentiated cell state. In this second scenario, it is possible to identify pro-fibrotic responses induced by targeted therapies that contribute to the alteration of the melanoma tumor microenvironment. A close interrelationship between chronic fibrosis and cancer has been established for several malignancies including breast and pancreatic cancers. In this context, the contribution of fibrosis to drug adaptation and therapy resistance in melanoma is rapidly emerging. In this review, we summarize recent evidence underlining the hallmarks of fibrotic diseases in drug-exposed and resistant melanoma, including increased remodeling of the extracellular matrix, enhanced actin cytoskeleton plasticity, high sensitivity to mechanical cues, and the establishment of an inflammatory microenvironment. We also discuss several potential therapeutic options for manipulating this fibrotic-like response to combat drug-resistant and invasive melanoma.
Emerging Therapeutic RNAs for the Targeting of Cancer Associated Fibroblasts
Authors: Santana-Viera Laura , Ibba Maria L. , Rotoli Deborah , Catuogno Silvia , Esposito Carla L.
Published: May 2020

Tumor mass consists of a complex ensemble of malignant cancer cells and a wide variety of resident and infiltrating cells, secreted factors, and extracellular matrix proteins that are referred as tumor microenvironment (TME). Cancer associated fibroblasts (CAFs) are key TME components that support tumor growth, generating a physical barrier against drugs and immune infiltration, and contributing to regulate malignant progression. Thus, it is largely accepted that therapeutic approaches aimed at hampering the interactions between tumor cells and CAFs can enhance the effectiveness of anti-cancer treatments. In this view, nucleic acid therapeutics have emerged as promising molecules. Here, we summarize recent knowledge about their role in the regulation of CAF transformation and tumor-promoting functions, highlighting their therapeutic utility and challenges.
PSMA Theranostics: Review of the Current Status of PSMA-Targeted Imaging and Radioligand Therapy
Authors: Jones Wallace , Griffiths Kelly , Barata Pedro C. , Paller Channing J.
Published: May 2020

Prostate-specific membrane antigen (PSMA) has been the subject of extensive investigation in the past two decades as a promising molecular target for prostate cancer (PCa). Its appealing molecular features have enabled the development of a novel diagnostic and therapeutic—thus “theranostic”—approach to PCa. There is now substantial evidence of the high sensitivity of PSMA-targeted imaging for PCa lesions and growing evidence of the therapeutic efficacy of PSMA radioligand therapy for metastatic castration-resistant prostate cancer. This article presents a broad overview of the current status of PSMA theranostics, including current evidence, potential clinical impact, and active areas of research.
Association between Abdominal Obesity and Incident Colorectal Cancer: A Nationwide Cohort Study in Korea
Authors: Nam Ga Eun , Baek Se-Jin , Choi Hong Bae , Han Kyungdo , Kwak Jung-Myun , Kim Jin , Kim Seon-Hahn
Published: May 2020

Background: We investigated the association of w May aist circumference (WC) and abdominal obesity with the incident colorectal cancer risk in Korean adults. Methods: This nationwide population-based cohort study was based on health insurance claims data. We analyzed data from 9,959,605 participants acquired through health check-ups of the Korean National Health Insurance Service in 2009 who were followed up until the end of 2017. We performed multivariable Cox proportional hazards regression analysis. Results: During 8.3 years of follow up, 101,197 cases (1.0%) of colorectal cancer were recorded. After adjusting for potential confounders, there was a positive association between WC and colorectal cancer risk (p for trend <0.001). Abdominal obesity was associated with an increased risk of colorectal (hazard ratio: 1.10, (95% confidence interval: 1.08–1.12)), colon (1.11, 1.09–1.13), and rectal cancer (1.08, 1.05–1.10). These associations were independent of body mass index and were more pronounced in men and elderly individuals. Conclusion: We revealed that higher WC is related to colorectal cancer risk, thus suggesting that abdominal obesity may be a risk factor for colorectal cancer in this East Asian population.
Genetic Target Modulation Employing CRISPR/Cas9 Identifies Glyoxalase 1 as a Novel Molecular Determinant of Invasion and Metastasis in A375 Human Malignant Melanoma Cells In Vitro and In Vivo
Authors: Jandova Jana , Perer Jessica , Hua Anh , Snell Jeremy A. , Wondrak Georg T.
Published: May 2020

Metabolic reprogramming is a molecular hallmark of cancer. Recently, we have reported the overexpression of glyoxalase 1 (encoded by GLO1), a glutathione-dependent enzyme involved in detoxification of the reactive glycolytic byproduct methylglyoxal, in human malignant melanoma cell culture models and clinical samples. However, the specific role of GLO1 in melanomagenesis remains largely unexplored. Here, using genetic target modulation, we report the identification of GLO1 as a novel molecular determinant of invasion and metastasis in malignant melanoma. First, A375 human malignant melanoma cells with GLO1 deletion (A375-GLO1_KO) were engineered using CRISPR/Cas9, and genetic rescue clones were generated by stable transfection of KO clones employing a CMV-driven GLO1 construct (A375-GLO1_R). After confirming GLO1 target modulation at the mRNA and protein levels (RT-qPCR, immunodetection, enzymatic activity), phenotypic characterization indicated that deletion of GLO1 does not impact proliferative capacity while causing significant sensitization to methylglyoxal-, chemotherapy-, and starvation-induced cytotoxic stress. Employing differential gene expression array analysis (A375-GLO1_KO versus A375-GLO1_WT), pronounced modulation of epithelial mesenchymal transition (EMT)-related genes [upregulated: CDH1, OCLN, IL1RN, PDGFRB, SNAI3; (downregulated): BMP1, CDH2, CTNNB1, FN1, FTH1, FZD7, MELTF, MMP2, MMP9, MYC, PTGS2, SNAI2, TFRC, TWIST1, VIM, WNT5A, ZEB1, and ZEB2 (up to tenfold; p < 0.05)] was observed—all of which are consistent with EMT suppression as a result of GLO1 deletion. Importantly, these expression changes were largely reversed upon genetic rescue employing A375-GLO1_R cells. Differential expression of MMP9 as a function of GLO1 status was further substantiated by enzymatic activity and ELISA analysis; phenotypic assessment revealed the pronounced attenuation of morphological potential, transwell migration, and matrigel 3D-invasion capacity displayed by A375-GLO1_KO cells, reversed again in genetic rescue clones. Strikingly, in a SCID mouse metastasis model, lung tumor burden imposed by A375-GLO1_KO cells was strongly attenuated as compared to A375-GLO1_WT cells. Taken together, these prototype data provide evidence in support of a novel function of GLO1 in melanoma cell invasiveness and metastasis, and ongoing investigations explore the function and therapeutic potential of GLO1 as a novel melanoma target.
Management of Oxaliplatin-Induced Peripheral Sensory Neuropathy
Authors: Cavaletti Guido , Marmiroli Paola
Published: May 2020

Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a severe and potentially permanent side effect of cancer treatment affecting the majority of oxaliplatin-treated patients, mostly with the onset of acute symptoms, but also with the establishment of a chronic sensory loss that is supposed to be due to dorsal root ganglia neuron damage. The pathogenesis of acute as well as chronic OIPN is still not completely known, and this is a limitation in the identification of effective strategies to prevent or limit their occurrence. Despite intense investigation at the preclinical and clinical levels, no treatment can be suggested for the prevention of OIPN, and only limited evidence for the efficacy of duloxetine in the treatment setting has been provided. In this review, ongoing neuroprotection clinical trials in oxaliplatin-treated patients will be analyzed with particular attention paid to the hypothesis leading to the study, to the trial strengths and weaknesses, and to the outcome measures proposed to test the efficacy of the therapeutic approach. It can be concluded that (1) prevention and treatment of OIPN still remains an important and unmet clinical need, (2) further, high-quality research is mandatory in order to achieve reliable and effective results, and (3) dose and schedule modification of OHP-based chemotherapy is currently the most effective approach to limit the severity of OIPN.
RNA-Sequencing of Tumor-Educated Platelets, a Novel Biomarker for Blood-Based Sarcoma Diagnostics
Authors: Heinhuis Kimberley M. , In ’t Veld Sjors G. J. G. , Dwarshuis Govert , van den Broek Daan , Sol Nik , Best Myron G. , van Coevorden Frits , Haas Rick L. , Beijnen Jos H. , van Houdt Winan J. , Würdinger Tom , Steeghs Neeltje
Published: May 2020

Sarcoma is a heterogeneous group of rare malignancies arising from mesenchymal tissues. Recurrence rates are high and methods for early detection by blood-based biomarkers do not exist. Hence, development of blood-based liquid biopsies as disease recurrence monitoring biomarkers would be an important step forward. Recently, it has been shown that tumor-educated platelets (TEPs) harbor specific spliced ribonucleic acid(RNA)-profiles. These RNA-repertoires are potentially applicable for cancer diagnostics. We aim to evaluate the potential of TEPs for blood-based diagnostics of sarcoma patients. Fifty-seven sarcoma patients (active disease), 38 former sarcoma patients (cancer free for ≥3 years) and 65 healthy donors were included. RNA was isolated from platelets and sequenced. Quantified read counts were processed with self-learning particle-swarm optimization-enhanced thromboSeq analysis and subjected to analysis of variance (ANOVA) statistics. Highly correlating spliced platelet messenger RNAs (mRNAs) of sarcoma patients were compared to controls (former sarcoma + healthy donors) to identify a quantitative sarcoma-specific signature measure, the TEP-score. ANOVA analysis identified distinctive platelet RNA expression patterns of 2647 genes (false discovery rate <0.05) in sarcoma patients as compared to controls. The self-learning algorithm reached a diagnostic accuracy of 87% (validation set only; n = 53 samples, area under the curve (AUC): 0.93, 95% confidence interval (CI): 0.86–1). Our data indicates that TEP RNA-based liquid biopsies may enable for sarcoma diagnostics.
Soluble PD-L1 in NSCLC Patients Treated with Checkpoint Inhibitors and Its Correlation with Metabolic Parameters
Authors: Castello Angelo , Rossi Sabrina , Toschi Luca , Mansi Luigi , Lopci Egesta
Published: May 2020

We investigated the role of soluble PD-L1 (sPD-L1) in non-small cell lung carcinoma (NSCLC) patients treated with immune checkpoint inhibitors (ICI) and analyzed its association with clinical outcomes and metabolic parameters by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT). Between July 2017 and May 2019, we enrolled 20 candidate patients of ICI therapy who had serum frozen samples and 18F-FDG PET/CT available, both at baseline and at the first response evaluation. This analysis is embedded into a larger prospective study (NCT03563482). Twelve out of 20 patients received nivolumab, one patient received combination of nivolumab and ipilimumab, whereas the others received pembrolizumab. Median sPD-L1 level at baseline was 27.22 pg/mL. We found a significant association between patients with elevated sPD-L1, above the median value, and high metabolic tumor burden, expressed by metabolic tumor volume (MTV, 115.3 vs. 35.5, p = 0.034) and total lesion glycolysis (TLG, 687 vs. 210.1, p = 0.049). At the first restaging after 7–8 weeks, median sPD-L1 levels significantly increased as compared to baseline median value (43.9 pg/mL, p = 0.017). No significant differences in response rates were detected, according to both morphological and metabolic response criteria. Likewise, no difference in survival outcomes were observed between low sPD-L1 and high sPD-L1 patients. The increase of sPD-L1 concentrations during ICI treatment may reflect the expansion of tumor volume and the tumor lysis. Moreover, it is supposed that sPD-L1 has its own biological action, either by reducing membrane PD-1 sites available for nivolumab or by inducing lymphocytes exhaustion after binding their membrane PD-1. Further, larger studies are needed to confirm our preliminary results on the role of sPD-L1 during ICI therapy.
The Tumor Suppressor TGFBR3 Blocks Lymph Node Metastasis in Head and Neck Cancer
Authors: Fang Wei-Yu , Kuo Yi-Zih , Chang Jang-Yang , Hsiao Jenn-Ren , Kao Hung-Ying , Tsai Sen-Tien , Wu Li-Wha
Published: May 2020

The TGF-β type III receptor (TGFBR3) is an essential constituent of the TGF-β signaling. In this study, we observed a down-regulation of TGFBR3 in oral cancer, a subtype of head and neck cancer (HNC), and patients with low TGFBR3 had poor clinical outcomes. Ectopic expression of TGFBR3 decreased migration and invasion of oral cancer cells and lymph node metastasis of tumors, whereas depletion of TGFBR3 had the opposite effect. In SMAD4-positive OC-2 oral cancer cells, TGFBR3-mediated suppression requires both of its cytoplasmic interacting partners ARRB2 and GIPC1. We demonstrated that TGFBR3 induces the abundance of secreted angiogenin (ANG), a known pro-angiogenic factor, and ANG is essential and sufficient to mediate TGFBR3-dependent inhibition of migration and invasion of oral cancer cells. Notably, in SMAD4-deficient CAL-27 oral cancer cells, only GIPC1 is essential for TGFBR3-induced suppressive activity. Accordingly, HNC patients with low expressions of both TGFBR3 and GIPC1 had the poorest overall survival. In summary, we conclude that TGFBR3 is as a tumor suppressor via SMAD4-dependent and -independent manner in both tumor and stromal cells during oral carcinogenesis. Our study should facilitate the possibility of using TGFBR3-mediated tumor suppression for HNC treatment.
Controlled Release of Therapeutics from Thermoresponsive Nanogels: A Thermal Magnetic Resonance Feasibility Study
Authors: Ji Yiyi , Winter Lukas , Navarro Lucila , Ku Min-Chi , Periquito João S. , Pham Michal , Hoffmann Werner , Theune Loryn E. , Calderón Marcelo , Niendorf Thoralf
Published: May 2020

Thermal magnetic resonance (ThermalMR) accommodates radio frequency (RF)-induced temperature modulation, thermometry, anatomic and functional imaging, and (nano)molecular probing in an integrated RF applicator. This study examines the feasibility of ThermalMR for the controlled release of a model therapeutics from thermoresponsive nanogels using a 7.0-tesla whole-body MR scanner en route to local drug-delivery-based anticancer treatments. The capacity of ThermalMR is demonstrated in a model system involving the release of fluorescein-labeled bovine serum albumin (BSA-FITC, a model therapeutic) from nanometer-scale polymeric networks. These networks contain thermoresponsive polymers that bestow environmental responsiveness to physiologically relevant changes in temperature. The release profile obtained for the reference data derived from a water bath setup used for temperature stimulation is in accordance with the release kinetics deduced from the ThermalMR setup. In conclusion, ThermalMR adds a thermal intervention dimension to an MRI device and provides an ideal testbed for the study of the temperature-induced release of drugs, magnetic resonance (MR) probes, and other agents from thermoresponsive carriers. Integrating diagnostic imaging, temperature intervention, and temperature response control, ThermalMR is conceptually appealing for the study of the role of temperature in biology and disease and for the pursuit of personalized therapeutic drug delivery approaches for better patient care.
FDG-PET/CT, a Promising Exam for Detecting High-Risk Myeloma Patients?
Authors: Michaud-Robert Anne-Victoire , Jamet Bastien , Bailly Clément , Carlier Thomas , Moreau Philippe , Touzeau Cyrille , Bourgeois Mickael , Kraeber-Bodere Françoise , Bodet-Milin Caroline
Published: May 2020

Multiple myeloma (MM) is a haematological neoplasm characterized by a clonal proliferation of malignant plasma cells in the bone marrow. MM is associated with high morbidity and mortality and variable survival, which can be very short for some patients but over 10 years for others. These differences in survival are explained by intra- and inter-tumoral heterogeneity and demonstrate the potential benefits of adapting the treatment course for high-risk patients with a poorer prognosis. Indeed, identification of these high-risk patients is necessary and is based on the identification of high-risk biomarkers including clinical variables, genomics and imaging results. Positron emission tomography combined with computed tomography using 18F-deoxyfluoroglucose (FDG-PET/CT) is a reliable technique for the initial staging of patients with symptomatic multiple myeloma (MM), and has been included in the IMWG (International Myeloma Working Group) recommendations in 2019. According to clinical studies, FDG-PET/CT characteristics could be used to define high-risk patients at initial diagnosis of symptomatic MM. The goal of this review is to demonstrate the prognostic value of FDG-PET in symptomatic MM patients, particularly in identifying high-risk patients, and thus, to best adapt therapeutic management in the future.
Serum PD-1/PD-L1 Levels, Tumor Expression and PD-L1 Somatic Mutations in HER2-Positive and Triple Negative Normal-Like Feline Mammary Carcinoma Subtypes
Authors: Nascimento Catarina , Urbano Ana Catarina , Gameiro Andreia , Ferreira João , Correia Jorge , Ferreira Fernando
Published: May 2020

Tumor microenvironment has gained great relevance due to its ability to regulate distinct checkpoints mediators, orchestrating tumor progression. Serum programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) levels were compared with healthy controls and with serum cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and tumor necrosis factor-alpha (TNF-α) levels in order to understand the role of PD-1/PD-L1 axis in cats with mammary carcinoma. PD-1 and PD-L1 expression was evaluated in tumor-infiltrating lymphocytes (TILs) and cancer cells, as the presence of somatic mutations. Results showed that serum PD-1 and PD-L1 levels were significantly higher in cats with HER2-positive (p = 0.017; p = 0.032) and triple negative (TN) normal-like mammary carcinomas (p = 0.004; p = 0.015), showing a strong positive correlation between serum CTLA-4 and TNF-α levels. In tumors, PD-L1 expression in cancer cells was significantly higher in HER2-positive samples than in TN normal-like tumors (p = 0.010), as the percentage of PD-L1-positive TILs (p = 0.037). PD-L1 gene sequencing identified two heterozygous mutations in exon 4 (A245T; V252M) and one in exon 5 (T267S). In summary, results support the use of spontaneous feline mammary carcinoma as a model for human breast cancer and suggest that the development of monoclonal antibodies may be a therapeutic strategy.
Correction: Teeuwssen and Fodde; Colon Cancer Heterogeneity and Phenotypic Plasticity in Metastasis Formation. Cancers 2019, 11(9), 1368
Authors: Teeuwssen Miriam , Fodde Riccardo
Published: May 2020

The authors would like to make a correction to their published paper [...]
Membrane Elastic Properties during Neural Precursor Cell Differentiation
Authors: Soares Juliana , Araujo Glauber R. de S. , Santana Cintia , Matias Diana , Moura-Neto Vivaldo , Farina Marcos , Frases Susana , Viana Nathan B. , Romão Luciana , Nussenzveig H. Moysés , Pontes Bruno
Published: May 2020

Neural precursor cells differentiate into several cell types that display distinct functions. However, little is known about how cell surface mechanics vary during the differentiation process. Here, by precisely measuring membrane tension and bending modulus, we map their variations and correlate them with changes in neural precursor cell morphology along their distinct differentiation fates. Both cells maintained in culture as neural precursors as well as those plated in neurobasal medium reveal a decrease in membrane tension over the first hours of culture followed by stabilization, with no change in bending modulus. During astrocyte differentiation, membrane tension initially decreases and then increases after 72 h, accompanied by consolidation of glial fibrillary acidic protein expression and striking actin reorganization, while bending modulus increases following observed alterations. For oligodendrocytes, the changes in membrane tension are less abrupt over the first hours, but their values subsequently decrease, correlating with a shift from oligodendrocyte marker O4 to myelin basic protein expressions and a remarkable actin reorganization, while bending modulus remains constant. Oligodendrocytes at later differentiation stages show membrane vesicles with similar membrane tension but higher bending modulus as compared to the cell surface. Altogether, our results display an entire spectrum of how membrane elastic properties are varying, thus contributing to a better understanding of neural differentiation from a mechanobiological perspective.
Crucial Role of Lamin A/C in the Migration and Differentiation of MSCs in Bone
Authors: Alcorta-Sevillano Natividad , Macías Iratxe , Rodríguez Clara I. , Infante Arantza
Published: May 2020

Lamin A/C, intermediate filament proteins from the nuclear lamina encoded by the LMNA gene, play a central role in mediating the mechanosignaling of cytoskeletal forces into nucleus. In fact, this mechanotransduction process is essential to ensure the proper functioning of other tasks also mediated by lamin A/C: the structural support of the nucleus and the regulation of gene expression. In this way, lamin A/C is fundamental for the migration and differentiation of mesenchymal stem cells (MSCs), the progenitors of osteoblasts, thus affecting bone homeostasis. Bone formation is a complex process regulated by chemical and mechanical cues, coming from the surrounding extracellular matrix. MSCs respond to signals modulating the expression levels of lamin A/C, and therefore, adapting their nuclear shape and stiffness. To promote cell migration, MSCs need soft nuclei with low lamin A content. Conversely, during osteogenic differentiation, lamin A/C levels are known to be increased. Several LMNA mutations present a negative impact in the migration and osteogenesis of MSCs, affecting bone tissue homeostasis and leading to pathological conditions. This review aims to describe these concepts by discussing the latest state-of-the-art in this exciting area, focusing on the relationship between lamin A/C in MSCs’ function and bone tissue from both, health and pathological points of view.