bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving Methodological System for the Development of Managerial Competence of Heads of Higher Educational Institutions
Authors: Otamurodov G. , Matnazarov A. , Japakov A.
Published: October 2020

This article discusses about the development of management skills and leadership potential of the higher education institutions and these establishments play an important role in improving the quality of education, effective organization of scientific and innovative activities in the country. Priorities have been identified for the development of proposals and recommendations on the meaningful and targeted organization of work on training, retraining, advanced training and development of scientific and innovative activities of teachers in the higher education system.
Relations of Sovereign Kyrgyzstan in the Economic and Social Spheres
Authors: Tobakalov Ch.
Published: October 2020

Kyrgyzstan strives to strengthen and deepen mutually beneficial cooperation in all sectors of the national economy. When forming economic and social ties, the Kyrgyz Republic also primarily paid attention to the development of relations with the CIS countries, especially with Central Asia and Kazakhstan. 90’s. in the first half of the year, Kyrgyzstan’s export-import relations were Russia, Kazakhstan, Uzbekistan, Ukraine, Turkmenistan, Tajikistan, and Belarus, followed by Kazakhstan.
Ethno-territorial Location of the Population of the Surkhan Oasis (on the Example of Farming)
Authors: Eshkurbonov S.
Published: October 2020

The article is devoted to the study of the development of economic and ethno-territorial characteristics of the population engaged in agriculture in the Surkhan oasis. The territory is located in the southern part of Uzbekistan. On the basis of archival sources and literature, the authors analyzed the natural and geographical conditions of agriculture and the location of ethnographic groups living in the Surkhan oasis, such as the Chagatai, who are mainly engaged in agriculture.
From James Legge to Evangeline Edwards: The Role of Scottish and Other Missionaries in the Formation of Sinology in Britain
Authors: Stanley Brian
Published: October 2020

Over the last half-century, the foreign missionary movement from the West has attracted much academic scrutiny from historians of imperial encounters with indigenous peoples. More recently, scholars have also begun to draw attention to the significance of missionaries, former missionaries or their progeny, as repositories of specialist linguistic and cultural knowledge of Asia and Africa who were indispensable to Western governments and universities and whose influence was sometimes formative in shaping conceptions of the non-European world.1This article addresses one aspect of this broader theme, namely the leading role played by missionaries or former missionaries in the development of the academic discipline of sinology in Britain. Particular emphasis is placed on the contributions of two missionaries with strong connections to Scotland. One of these, James Legge, is well known. The other, Evangeline (‘Eve’) Dora Edwards, has been almost entirely forgotten.
CYK Parsing over Distributed Representations
Authors: Zanzotto Fabio Massimo , Satta Giorgio , Cristini Giordano
Published: October 2020

Parsing is a key task in computer science, with applications in compilers, natural language processing, syntactic pattern matching, and formal language theory. With the recent development of deep learning techniques, several artificial intelligence applications, especially in natural language processing, have combined traditional parsing methods with neural networks to drive the search in the parsing space, resulting in hybrid architectures using both symbolic and distributed representations. In this article, we show that existing symbolic parsing algorithms for context-free languages can cross the border and be entirely formulated over distributed representations. To this end, we introduce a version of the traditional Cocke–Younger–Kasami (CYK) algorithm, called distributed (D)-CYK, which is entirely defined over distributed representations. D-CYK uses matrix multiplication on real number matrices of a size independent of the length of the input string. These operations are compatible with recurrent neural networks. Preliminary experiments show that D-CYK approximates the original CYK algorithm. By showing that CYK can be entirely performed on distributed representations, we open the way to the definition of recurrent layer neural networks that can process general context-free languages.
Regulation of Reactive Oxygen Species-Mediated Damage in the Pathogenesis of Schizophrenia
Authors: Madireddy Samskruthi , Madireddy Sahithi
Published: October 2020

The biochemical integrity of the brain is paramount to the function of the central nervous system, and oxidative stress is a key contributor to cerebral biochemical impairment. Oxidative stress, which occurs when an imbalance arises between the production of reactive oxygen species (ROS) and the efficacy of the antioxidant defense mechanism, is believed to play a role in the pathophysiology of various brain disorders. One such disorder, schizophrenia, not only causes lifelong disability but also induces severe emotional distress; however, because of its onset in early adolescence or adulthood and its progressive development, consuming natural antioxidant products may help regulate the pathogenesis of schizophrenia. Therefore, elucidating the functions of ROS and dietary antioxidants in the pathogenesis of schizophrenia could help formulate improved therapeutic strategies for its prevention and treatment. This review focuses specifically on the roles of ROS and oxidative damage in the pathophysiology of schizophrenia, as well as the effects of nutrition, antipsychotic use, cognitive therapies, and quality of life on patients with schizophrenia. By improving our understanding of the effects of various nutrients on schizophrenia, it may become possible to develop nutritional strategies and supplements to treat the disorder, alleviate its symptoms, and facilitate long-term recovery.
Non-Coding and Regulatory RNAs as Epigenetic Remodelers of Fatty Acid Homeostasis in Cancer
Authors: Cruz-Gil Silvia , Fernández Lara P. , Sánchez-Martínez Ruth , Gómez de Cedrón Marta , Ramírez de Molina Ana
Published: October 2020

Cancer cells commonly display metabolic fluctuations. Together with the Warburg effect and the increased glutaminolysis, alterations in lipid metabolism homeostasis have been recognized as a hallmark of cancer. Highly proliferative cancer cells upregulate de novo synthesis of fatty acids (FAs) which are required to support tumor progression by exerting multiple roles including structural cell membrane composition, regulators of the intracellular redox homeostasis, ATP synthesis, intracellular cell signaling molecules, and extracellular mediators of the tumor microenvironment. Epigenetic modifications have been shown to play a crucial role in human development, but also in the initiation and progression of complex diseases. The study of epigenetic processes could help to design new integral strategies for the prevention and treatment of metabolic disorders including cancer. Herein, we first describe the main altered intracellular fatty acid processes to support cancer initiation and progression. Next, we focus on the most important regulatory and non-coding RNAs (small noncoding RNA—sncRNAs—long non-coding RNAs—lncRNAs—and other regulatory RNAs) which may target the altered fatty acids pathway in cancer.
Aggressive NK Cell Leukemia: Current State of the Art
Authors: El Hussein Siba , Medeiros L. , Khoury Joseph
Published: October 2020

Aggressive natural killer (NK) cell leukemia (ANKL) is a rare disease with a grave prognosis. Patients commonly present acutely with fever, constitutional symptoms, hepatosplenomegaly, and often disseminated intravascular coagulation or hemophagocytic syndrome. This acute clinical presentation and the variable pathologic and immunophenotypic features of ANKL overlap with other diagnostic entities, making it challenging to establish a timely and accurate diagnosis of ANKL. Since its original recognition in 1986, substantial progress in understanding this disease using traditional pathologic approaches has improved diagnostic accuracy. This progress, in turn, has facilitated the performance of recent high-throughput studies that have yielded insights into pathogenesis. Molecular abnormalities that occur in ANKL can be divided into three major groups: JAK/STAT pathway activation, epigenetic dysregulation, and impairment of TP53 and DNA repair. These high-throughput data also have provided potential therapeutic targets that promise to improve therapy and outcomes for patients with ANKL. In this review, we provide a historical context of the conception and evolution of ANKL as a disease entity, we highlight advances in diagnostic criteria to recognize this disease, and we review recent understanding of pathogenesis as well as biomarker discoveries that are providing groundwork for innovative therapies.
Dexamethasone Inhibits TRAIL-Induced Apoptosis through c-FLIP(L) Upregulation and DR5 Downregulation by GSK3β Activation in Cancer Cells
Authors: Jeon Mi-Yeon , Woo Seon Min , Seo Seung Un , Kim Sang Hyun , Nam Ju-Ock , Kim Shin , Park Jong-Wook , Kubatka Peter , Min Kyoung-jin , Kwon Taeg Kyu
Published: October 2020

Dexamethasone (DEX), a synthetic glucocorticoid, is commonly used as immunosuppressive and chemotherapeutic agent. This study was undertaken to investigate the effects of DEX on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in cancer cells. We found that upregulation of c-FLIP(L) and downregulation of death receptor 5 (DR5; receptor for TRAIL ligand) contribute to the anti-apoptotic effect of DEX on TRAIL-induced apoptosis. DEX increased c-FLIP(L) expression at the transcriptional levels through the GSK-3β signaling pathway. The pharmacological inhibitor and catalytic mutant of GSK-3β suppressed DEX-induced upregulation of c-FLIP(L) expression. Furthermore, GSK-3β specific inhibitor markedly abolished DEX-mediated reduction of TRAIL-induced apoptosis in human renal cancer cells (Caki-1 and A498), human lung cancer cells (A549), and human breast cancer cells (MDA-MB361). In addition, DEX decreased protein stability of DR5 via GSK-3β-mediated upregulation of Cbl, an E3 ligase of DR5. Knockdown of Cbl by siRNA markedly inhibited DEX-induced DR5 downregulation. Taken together, these results suggest that DEX inhibits TRAIL-mediated apoptosis via GSK-3β-mediated DR5 downregulation and c-FLIP(L) upregulation in cancer cells.
Immuno-Interface Score to Predict Outcome in Colorectal Cancer Independent of Microsatellite Instability Status
Authors: Nestarenkaite Ausrine , Fadhil Wakkas , Rasmusson Allan , Susanti Susanti , Hadjimichael Efthymios , Laurinaviciene Aida , Ilyas Mohammad , Laurinavicius Arvydas
Published: October 2020

Tumor-associated immune cells have been shown to predict patient outcome in colorectal (CRC) and other cancers. Spatial digital image analysis-based cell quantification increases the informative power delivered by tumor microenvironment features and leads to new prognostic scoring systems. In this study we evaluated the intratumoral density of immunohistochemically stained CD8, CD20 and CD68 cells in 87 cases of CRC (48 were microsatellite stable, MSS, and 39 had microsatellite instability, MSI) in both the intratumoral tumor tissue and within the tumor-stroma interface zone (IZ) which was extracted by a previously developed unbiased hexagonal grid analytics method. Indicators of immune-cell gradients across the extracted IZ were computed and explored along with absolute cell densities, clinicopathological and molecular data, including gene mutation (BRAF, KRAS, PIK3CA) and MSI status. Multiple regression modeling identified (p < 0.0001) three independent prognostic factors: CD8+ and CD20+ Immunogradient indicators, that reflect cell migration towards the tumor, were associated with improved patient survival, while the infiltrative tumor growth pattern was linked to worse patient outcome. These features were combined into CD8-CD20 Immunogradient and immuno-interface scores which outperformed both tumor-node-metastasis (TNM) staging and molecular characteristics, and importantly, revealed high prognostic value both in MSS and MSI CRCs.
Potential Molecular Players of the Tumor Microenvironment in Extracranial Pediatric Solid Tumors
Authors: Noguera Rosa , Álvaro Naranjo Tomás
Published: October 2020

Pediatric cancers are rare malignancies worldwide and represent around 1% of all new cancer diagnoses [...]
PARP1 Deficiency Reduces Tumour Growth by Decreasing E2F1 Hyperactivation: A Novel Mechanism in the Treatment of Cancer
Authors: Iglesias Pablo , Seoane Marcos , Golán Irene , Castro-Piedras Isabel , Fraga Máximo , Arce Víctor M. , Costoya Jose A.
Published: October 2020

In recent years, poly (ADP-ribose) polymerase (PARP) inhibitors have been evaluated for treating homologous recombination-deficient tumours, taking advantage of synthetic lethality. However, increasing evidence indicates that PARP1 exert several cellular functions unrelated with their role on DNA repair, including function as a co-activator of transcription through protein-protein interaction with E2F1. Since the RB/E2F1 pathway is among the most frequently mutated in many tumour types, we investigated whether the absence of PARP activity could counteract the consequences of E2F1 hyperactivation. Our results demonstrate that genetic ablation of Parp1 extends the survival of Rb-null embryos, while genetic inactivation of Parp1 results in reduced development of pRb-dependent tumours. Our results demonstrate that PARP1 plays a key role as a transcriptional co-activator of the transcription factor E2F1, an important component of the cell cycle regulation. Considering that most oncogenic processes are associated with cell cycle deregulation, the disruption of this PARP1-E2F1 interaction could provide a new therapeutic target of great interest and a wide spectrum of indications.
Female Malignancies and Immunotherapy: What’s New?
Authors: Pesce Silvia , Vellone Valerio Gaetano , Marcenaro Emanuela
Published: October 2020

For many years, the therapeutic advances in gynecological neoplasms have remained steady, however, in recent years, the application of the most modern “-omics” sciences has shed light on the pathogenesis and on neoplastic progression, with important implications in the introduction of targeted treatments that are more effective and less toxic [...]
Sphingolipid Pathway as a Source of Vulnerability in IDH1mut Glioma
Authors: Dowdy Tyrone , Zhang Lumin , Celiku Orieta , Movva Sriya , Lita Adrian , Ruiz-Rodado Victor , Gilbert Mark R. , Larion Mioara
Published: October 2020

In addition to providing integrity to cellular structure, the various classes of lipids participate in a multitude of functions including secondary messengers, receptor stimulation, lymphocyte trafficking, inflammation, angiogenesis, cell migration, proliferation, necrosis and apoptosis, thus highlighting the importance of understanding their role in the tumor phenotype. In the context of IDH1mut glioma, investigations focused on metabolic alterations involving lipidomics’ present potential to uncover novel vulnerabilities. Herein, a detailed lipidomic analysis of the sphingolipid metabolism was conducted in patient-derived IDH1mut glioma cell lines, as well as model systems, with the of identifying points of metabolic vulnerability. We probed the effect of decreasing D-2HG levels on the sphingolipid pathway, by treating these cell lines with an IDH1mut inhibitor, AGI5198. The results revealed that N,N-dimethylsphingosine (NDMS), sphingosine C17 and sphinganine C18 were significantly downregulated, while sphingosine-1-phosphate (S1P) was significantly upregulated in glioma cultures following suppression of IDH1mut activity. We exploited the pathway using a small-scale, rational drug screen and identified a combination that was lethal to IDHmut cells. Our work revealed that further addition of N,N-dimethylsphingosine in combination with sphingosine C17 triggered a dose-dependent biostatic and apoptotic response in a panel of IDH1mut glioma cell lines specifically, while it had little effect on the IDHWT cells probed here. To our knowledge, this is the first study that shows how altering the sphingolipid pathway in IDH1mut gliomas elucidates susceptibility that can arrest proliferation and initiate subsequent cellular death.
Tumor Microenvironment as a Regulator of Radiation Therapy: New Insights into Stromal-Mediated Radioresistance
Authors: Krisnawan Varintra E. , Stanley Jennifer A. , Schwarz Julie K. , DeNardo David G.
Published: October 2020

A tumor is a complex “organ” composed of malignant cancer cells harboring genetic aberrations surrounded by a stroma comprised of non-malignant cells and an extracellular matrix. Considerable evidence has demonstrated that components of the genetically “normal” tumor stroma contribute to tumor progression and resistance to a wide array of treatment modalities, including radiotherapy. Cancer-associated fibroblasts can promote radioresistance through their secreted factors, contact-mediated signaling, downstream pro-survival signaling pathways, immunomodulatory effects, and cancer stem cell-generating role. The extracellular matrix can govern radiation responsiveness by influencing oxygen availability and controlling the stability and bioavailability of growth factors and cytokines. Immune status regarding the presence of pro- and anti-tumor immune cells can regulate how tumors respond to radiation therapy. Furthermore, stromal cells including endothelial cells and adipocytes can modulate radiosensitivity through their roles in angiogenesis and vasculogenesis, and their secreted adipokines, respectively. Thus, to successfully eradicate cancers, it is important to consider how tumor stroma components interact with and regulate the response to radiation. Detailed knowledge of these interactions will help build a preclinical rationale to support the use of stromal-targeting agents in combination with radiotherapy to increase radiosensitivity.
Microenvironmental Hypoxia Induces Dynamic Changes in Lung Cancer Synthesis and Secretion of Extracellular Vesicles
Authors: Tse Shun Wilford , Tan Chee Fan , Park Jung Eun , Gnanasekaran JebaMercy , Gupta Nikhil , Low Jee Keem , Yeoh Kheng Wei , Chng Wee Joo , Tay Chor Yong , McCarthy Neil E. , Lim Sai Kiang , Sze Siu Kwan
Published: October 2020

Extracellular vesicles (EVs) mediate critical intercellular communication within healthy tissues, but are also exploited by tumour cells to promote angiogenesis, metastasis, and host immunosuppression under hypoxic stress. We hypothesize that hypoxic tumours synthesize hypoxia-sensitive proteins for packing into EVs to modulate their microenvironment for cancer progression. In the current report, we employed a heavy isotope pulse/trace quantitative proteomic approach to study hypoxia sensitive proteins in tumour-derived EVs protein. The results revealed that hypoxia stimulated cells to synthesize EVs proteins involved in enhancing tumour cell proliferation (NRSN2, WISP2, SPRX1, LCK), metastasis (GOLM1, STC1, MGAT5B), stemness (STC1, TMEM59), angiogenesis (ANGPTL4), and suppressing host immunity (CD70). In addition, functional clustering analyses revealed that tumour hypoxia was strongly associated with rapid synthesis and EV loading of lysosome-related hydrolases and membrane-trafficking proteins to enhance EVs secretion. Moreover, lung cancer-derived EVs were also enriched in signalling molecules capable of inducing epithelial-mesenchymal transition in recipient cancer cells to promote their migration and invasion. Together, these data indicate that lung-cancer-derived EVs can act as paracrine/autocrine mediators of tumorigenesis and metastasis in hypoxic microenvironments. Tumour EVs may, therefore, offer novel opportunities for useful biomarkers discovery and therapeutic targeting of different cancer types and at different stages according to microenvironmental conditions.
Time-Resolved Profiling Reveals ATF3 as a Novel Mediator of Endocrine Resistance in Breast Cancer
Authors: Borgoni Simone , Sofyalı Emre , Soleimani Maryam , Wilhelm Heike , Müller-Decker Karin , Will Rainer , Noronha Ashish , Beumers Lukas , Verschure Pernette J. , Yarden Yosef , Magnani Luca , van Kampen Antoine H.C. , Moerland Perry D. , Wiemann Stefan
Published: October 2020

Breast cancer is one of the leading causes of death for women worldwide. Patients whose tumors express Estrogen Receptor α account for around 70% of cases and are mostly treated with targeted endocrine therapy. However, depending on the degree of severity of the disease at diagnosis, 10 to 40% of these tumors eventually relapse due to resistance development. Even though recent novel approaches as the combination with CDK4/6 inhibitors increased the overall survival of relapsing patients, this remains relatively short and there is a urgent need to find alternative targetable pathways. In this study we profiled the early phases of the resistance development process to uncover drivers of this phenomenon. Time-resolved analysis revealed that ATF3, a member of the ATF/CREB family of transcription factors, acts as a novel regulator of the response to therapy via rewiring of central signaling processes towards the adaptation to endocrine treatment. ATF3 was found to be essential in controlling crucial processes such as proliferation, cell cycle, and apoptosis during the early response to treatment through the regulation of MAPK/AKT signaling pathways. Its essential role was confirmed in vivo in a mouse model, and elevated expression of ATF3 was verified in patient datasets, adding clinical relevance to our findings. This study proposes ATF3 as a novel mediator of endocrine resistance development in breast cancer and elucidates its role in the regulation of downstream pathways activities.
E-Cadherin (CDH1 Gene) Germline Mutations in Gastric Cancer: Evolutions and Innovations
Authors: Corso Giovanni , Bonanni Bernardo
Published: October 2020

Family history has contributed greatly to understanding inherited diseases throughout the centuries, in particular familial and hereditary cancer syndromes [...]
The Roles of ceRNAs-Mediated Autophagy in Cancer Chemoresistance and Metastasis
Authors: Zhang Huilin , Lu Bingjian
Published: October 2020

Chemoresistance and metastasis are the main causes of treatment failure and unfavorable outcome in cancers. There is a pressing need to reveal their mechanisms and to discover novel therapy targets. Autophagy is composed of a cascade of steps controlled by different autophagy-related genes (ATGs). Accumulating evidence suggests that dysregulated autophagy contributes to chemoresistance and metastasis via competing endogenous RNA (ceRNA) networks including lncRNAs and circRNAs. ceRNAs sequester the targeted miRNA expression to indirectly upregulate ATGs expression, and thereof participate in autophagy-mediated chemoresistance and metastasis. Here, we attempt to summarize the roles of ceRNAs in cancer chemoresistance and metastasis through autophagy regulation.
Primary Ewing Sarcoma/Primitive Neuroectodermal Tumor of the Kidney: The MD Anderson Cancer Center Experience
Authors: Tarek Nidale , Said Rabih , Andersen Clark R. , Suki Tina S. , Foglesong Jessica , Herzog Cynthia E. , Tannir Nizar M. , Patel Shreyaskumar , Ratan Ravin , Ludwig Joseph A. , Daw Najat C.
Published: October 2020

Limited information exists on the clinical behavior of the Ewing sarcoma family of tumors (ESFT) of the kidney. We reviewed the records of 30 patients (aged 8–69 years) with ESFT of the kidney seen at our institution between 1990 and 2013. We analyzed the event-free survival (EFS) and overall survival (OS) for associations with patient demographics, disease group, tumor size, tumor thrombus, and treatment. Six patients (20%) had tumors confined to the kidney (Group I), seven (23.3%) had local tumor extension beyond the kidney (Group II), and 17 (56.7%) had distant metastasis at diagnosis (Group III). Twenty-five (83.3%) patients underwent radical (19 upfront, five delayed) or partial (one upfront) nephrectomy, 25 (83.3%) chemotherapy and four (13.3%) radiotherapy. The 4-year EFS and OS were 43% (95% CI, 26–61%) and 63% (95% CI, 46–81%), respectively. EFS and OS were significantly associated with disease group and chemotherapy (p < 0.039). The presence of tumor thrombus in renal vein and/or inferior vena cava was associated with worse EFS (p = 0.053). Patients with disease confined to the kidney treated with nephrectomy and adjuvant chemotherapy have favorable outcomes. Local tumor extension beyond the kidney, tumor thrombus, and distant metastasis are unfavorable factors that warrant intensification or novel approaches of therapy.
The Impact of Next Generation Sequencing in Cancer Research
Authors: Nones Katia , Patch Ann-Marie
Published: October 2020

Next generation sequencing (NGS) describes the technical revolution that enabled massively parallel sequencing of fragmented nucleic acids, thus making possible our current genomic understanding of cancers [...]
Current and Future Treatment Strategies for Esophageal Adenocarcinoma
Authors: Quaas Alexander
Published: October 2020

The incidence of adenocarcinoma of the esophagus (EAC) is increasing worldwide [...]
Clonal Evolution and Timing of Metastatic Colorectal Cancer
Authors: Siraj Sarah , Masoodi Tariq , Siraj Abdul K. , Azam Saud , Qadri Zeeshan , Ahmed Saeeda O. , AlBalawy Wafaa N. , Al-Obaisi Khadija A. , Parvathareddy Sandeep K. , AlManea Hadeel M. , AlHussaini Hussah F. , Abduljabbar Alaa , Alhomoud Samar , Al-Dayel Fouad H. , Alkuraya Fowzan S. , Al-Kuraya Khawla S.
Published: October 2020

Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide, where ~50% of patients develop metastasis, despite current improved management. Genomic characterisation of metastatic CRC, and elucidating the effects of therapy on the metastatic process, are essential to help guide precision medicine. Multi-region whole-exome sequencing was performed on 191 sampled tumour regions of patient-matched therapy-naïve and treated CRC primary tumours (n = 92 tumour regions) and metastases (n = 99 tumour regions), in 30 patients. Somatic variants were analysed to define the origin, composition, and timing of seeding in the metastatic progression of therapy-naïve and treated metastatic CRC. High concordance, with few genomic differences, was observed between primary CRC and metastases. Most cases supported a late dissemination model, via either monoclonal or polyclonal seeding. Polyclonal seeding appeared more common in therapy-naïve metastases than in treated metastases. Whereby, treatment prompted for the selection of distinct resistant clones, through monoclonal seeding to distant metastatic sites. Overall, this study reinforces the importance of early clinical detection and surgical excision of the CRC tumour, whilst further highlighting the clinical challenges for metastatic CRC with increased intratumour heterogeneity (either due to early dissemination or polyclonal metastatic spread) and the underlying risk of future therapeutic resistance in treated patients.
Identification of High-Risk Atypical Meningiomas According to Semantic and Radiomic Features
Authors: Kalasauskas Darius , Kronfeld Andrea , Renovanz Mirjam , Kurz Elena , Leukel Petra , Krenzlin Harald , Brockmann Marc A. , Sommer Clemens J. , Ringel Florian , Keric Naureen
Published: October 2020

Up to 60% of atypical meningiomas (World Health Organization (WHO) grade II) reoccur within 5 years after resection. However, no clear radiological criteria exist to identify tumors with higher risk of relapse. In this study, we aimed to assess the association of certain radiomic and semantic features of atypical meningiomas in MRI with tumor recurrence. We identified patients operated on primary atypical meningiomas in our department from 2007 to 2017. An analysis of 13 quantitatively defined radiomic and 11 qualitatively defined semantic criteria was performed based on preoperative MRI scans. Imaging characteristics were assessed along with clinical and survival data. The analysis included 76 patients (59% women, mean age 59 years). Complete tumor resection was achieved in 65 (86%) cases, and tumor relapse occurred in 17 (22%) cases. Mean follow-up time was 41.6 (range 3–168) months. Cystic component was significantly associated with tumor recurrence (odds ratio (OR) 21.7, 95% confidence interval (CI) 3.8–124.5) and shorter progression-free survival (33.2 vs. 80.7 months, p < 0.001), whereas radiomic characteristics had no predictive value in univariate analysis. However, multivariate analysis demonstrated significant predictive value of high cluster prominence (hazard ratio (HR) 5.89 (1.03–33.73) and cystic component (HR 20.21 (2.46–166.02)) for tumor recurrence. The combination of radiomic and semantic features might be an effective tool for identifying patients with high-risk atypical meningiomas. The presence of a cystic component in these tumors is associated with a high risk of tumor recurrence.
The Role of Non-Coding RNAs in Uveal Melanoma
Authors: Bande Manuel , Fernandez-Diaz Daniel , Fernandez-Marta Beatriz , Rodriguez-Vidal Cristina , Lago-Baameiro Nerea , Silva-Rodríguez Paula , Paniagua Laura , Blanco-Teijeiro María José , Pardo María , Piñeiro Antonio
Published: October 2020

Uveal melanoma (UM) is the most common primary intraocular tumor in adulthood. Approximately 50% of patients develop metastatic disease, which typically affects the liver and is usually fatal within one year. This type of cancer is heterogeneous in nature and is divided into two broad groups of tumors according to their susceptibility to develop metastasis. In the last decade, chromosomal abnormalities and the aberrant expression of several signaling pathways and oncogenes in uveal melanomas have been described. Recently, importance has been given to the association of the mentioned deregulation with the expression of non-coding RNAs (ncRNAs). Here, we review the different classes of ncRNAs—such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs)—and their contribution to the development of UM. Special attention is given to miRNAs and their regulatory role in physiopathology and their potential as biomarkers. As important agents in gene regulation, ncRNAs have a huge potential for opening up therapeutic pathways, predicting response to treatment, and anticipating patient outcome for UM.
High Levels of miR-7-5p Potentiate Crizotinib-Induced Cytokilling and Autophagic Flux by Targeting RAF1 in NPM-ALK Positive Lymphoma Cells
Authors: Sorrentino Domenico , Frentzel Julie , Mitou Géraldine , Blasco Rafael B. , Torossian Avédis , Hoareau-Aveilla Coralie , Pighi Chiara , Farcé Manon , Meggetto Fabienne , Manenti Stéphane , Espinos Estelle , Chiarle Roberto , Giuriato Sylvie
Published: October 2020

Anaplastic lymphoma kinase positive anaplastic large cell lymphomas (ALK+ ALCL) are an aggressive pediatric disease. The therapeutic options comprise chemotherapy, which is efficient in approximately 70% of patients, and targeted therapies, such as crizotinib (an ALK tyrosine kinase inhibitor (TKI)), used in refractory/relapsed cases. Research efforts have also converged toward the development of combined therapies to improve treatment. In this context, we studied whether autophagy could be modulated to improve crizotinib therapy. Autophagy is a vesicular recycling pathway, known to be associated with either cell survival or cell death depending on the cancer and therapy. We previously demonstrated that crizotinib induced cytoprotective autophagy in ALK+ lymphoma cells and that its further intensification was associated with cell death. In line with these results, we show here that combined ALK and Rapidly Accelerated Fibrosarcoma 1 (RAF1) inhibition, using pharmacological (vemurafenib) or molecular (small interfering RNA targeting RAF1 (siRAF1) or microRNA-7-5p (miR-7-5p) mimics) strategies, also triggered autophagy and potentiated the toxicity of TKI. Mechanistically, we found that this combined therapy resulted in the decrease of the inhibitory phosphorylation on Unc-51-like kinase-1 (ULK1) (a key protein in autophagy initiation), which may account for the enforced autophagy and cytokilling effect. Altogether, our results support the development of ALK and RAF1 combined inhibition as a new therapeutic approach in ALK+ ALCL.
The CINs of Polo-Like Kinase 1 in Cancer
Authors: Cunningham Chelsea E. , MacAuley Mackenzie J. , Vizeacoumar Frederick S. , Abuhussein Omar , Freywald Andrew , Vizeacoumar Franco J.
Published: October 2020

Polo-like kinase 1 (PLK1) is overexpressed near ubiquitously across all cancer types and dysregulation of this enzyme is closely tied to increased chromosomal instability and tumor heterogeneity. PLK1 is a mitotic kinase with a critical role in maintaining chromosomal integrity through its function in processes ranging from the mitotic checkpoint, centrosome biogenesis, bipolar spindle formation, chromosome segregation, DNA replication licensing, DNA damage repair, and cytokinesis. The relation between dysregulated PLK1 and chromosomal instability (CIN) makes it an attractive target for cancer therapy. However, clinical trials with PLK1 inhibitors as cancer drugs have generally displayed poor responses or adverse side-effects. This is in part because targeting CIN regulators, including PLK1, can elevate CIN to lethal levels in normal cells, affecting normal physiology. Nevertheless, aiming at related genetic interactions, such as synthetic dosage lethal (SDL) interactions of PLK1 instead of PLK1 itself, can help to avoid the detrimental side effects associated with increased levels of CIN. Since PLK1 overexpression contributes to tumor heterogeneity, targeting SDL interactions may also provide an effective strategy to suppressing this malignant phenotype in a personalized fashion.
Quantification of Receptor Occupancy by Ligand—An Understudied Class of Potential Biomarkers
Authors: Veeramani Suresh , Weiner George J.
Published: October 2020

Molecular complexes, such as ligand–receptor complexes, are vital for both health and disease and can be shed into the circulation in soluble form. Relatively little is known about the biology of soluble ligand–receptor complexes. The functional importance of such complexes and their potential use as clinical biomarkers in diagnosis and therapy remains underappreciated. Most traditional technologies used to study ligand–receptor complexes measure the individual levels of soluble ligands or receptors rather than the complexes themselves. The fraction of receptors occupied by ligand, and the potential clinical relevance of such information, has been largely overlooked. Here, we review the biological significance of soluble ligand–receptor complexes with a specific focus on their potential as biomarkers of cancer and other inflammatory diseases. In addition, we discuss a novel RNA aptamer-based technology, designated ligand–receptor complex-binding aptamers (LIRECAP), that can provide precise measurement of the fraction of a soluble receptor occupied by its ligand. The potential applicability of the LIRECAP technology as a biomarker discovery platform is also described.
An In Vitro Evaluation of the Molecular Mechanisms of Action of Medical Plants from the Lamiaceae Family as Effective Sources of Active Compounds against Human Cancer Cell Lines
Authors: Sitarek Przemysław , Merecz-Sadowska Anna , Śliwiński Tomasz , Zajdel Radosław , Kowalczyk Tomasz
Published: October 2020

It is predicted that 1.8 million new cancer cases will be diagnosed worldwide in 2020; of these, the incidence of lung, colon, breast, and prostate cancers will be 22%, 9%, 7%, and 5%, respectively according to the National Cancer Institute. As the global medical cost of cancer in 2020 will exceed about $150 billion, new approaches and novel alternative chemoprevention molecules are needed. Research indicates that the plants of the Lamiaceae family may offer such potential. The present study reviews selected species from the Lamiaceae and their active compounds that may have the potential to inhibit the growth of lung, breast, prostate, and colon cancer cells; it examines the effects of whole extracts, individual compounds, and essential oils, and it discusses their underlying molecular mechanisms of action. The studied members of the Lamiaceae are sources of crucial phytochemicals that may be important modulators of cancer-related molecular targets and can be used as effective factors to support anti-tumor treatment.
Baseline MRI-Radiomics Can Predict Overall Survival in Non-Endemic EBV-Related Nasopharyngeal Carcinoma Patients
Authors: Bologna Marco , Corino Valentina , Calareso Giuseppina , Tenconi Chiara , Alfieri Salvatore , Iacovelli Nicola Alessandro , Cavallo Anna , Cavalieri Stefano , Locati Laura , Bossi Paolo , Romanello Domenico Attilio , Ingargiola Rossana , Rancati Tiziana , Pignoli Emanuele , Sdao Silvana , Pecorilla Mattia , Facchinetti Nadia , Trama Annalisa , Licitra Lisa , Mainardi Luca , Orlandi Ester
Published: October 2020

Advanced stage nasopharyngeal cancer (NPC) shows highly variable treatment outcomes, suggesting the need for independent prognostic factors. This study aims at developing a magnetic resonance imaging (MRI)-based radiomic signature as a prognostic marker for different clinical endpoints in NPC patients from non-endemic areas. A total 136 patients with advanced NPC and available MRI imaging (T1-weighted and T2-weighted) were selected. For each patient, 2144 radiomic features were extracted from the main tumor and largest lymph node. A multivariate Cox regression model was trained on a subset of features to obtain a radiomic signature for overall survival (OS), which was also applied for the prognosis of other clinical endpoints. Validation was performed using 10-fold cross-validation. The added prognostic value of the radiomic features to clinical features and volume was also evaluated. The radiomics-based signature had good prognostic power for OS and loco-regional recurrence-free survival (LRFS), with C-index of 0.68 and 0.72, respectively. In all the cases, the addition of radiomics to clinical features improved the prognostic performance. Radiomic features can provide independent prognostic information in NPC patients from non-endemic areas.
Heterogeneity Matters: Different Regions of Glioblastoma Are Characterized by Distinctive Tumor-Supporting Pathways
Authors: Manini Ivana , Caponnetto Federica , Dalla Emiliano , Ius Tamara , Pepa Giuseppe Maria Della , Pegolo Enrico , Bartolini Anna , Rocca Giuseppe La , Menna Grazia , Loreto Carla Di , Olivi Alessandro , Skrap Miran , Sabatino Giovanni , Cesselli Daniela
Published: October 2020

The glioblastoma microenvironment plays a substantial role in glioma biology. However, few studies have investigated its spatial heterogeneity. Exploiting 5-ALA Fluorescence Guided Surgery (FGS), we were able to distinguish between the tumor core (ALA+), infiltrating area (ALA-PALE) and healthy tissue (ALA−) of the glioblastoma, based on the level of accumulated fluorescence. The aim of this study was to investigate the properties of the microenvironments associated with these regions. For this purpose, we isolated glioma-associated stem cells (GASC), resident in the glioma microenvironment, from ALA+, ALA-PALE and ALA− samples and compared them in terms of growth kinetic, phenotype and for the expression of 84 genes associated with cancer inflammation and immunity. Differentially expressed genes were correlated with transcriptomic datasets from TCGA/GTEX. Our results show that GASC derived from the three distinct regions, despite a similar phenotype, were characterized by different transcriptomic profiles. Moreover, we identified a GASC-based genetic signature predictive of overall survival and disease-free survival. This signature, highly expressed in ALA+ GASC, was also well represented in ALA PALE GASC. 5-ALA FGS allowed to underline the heterogeneity of the glioma microenvironments. Deepening knowledge of these differences can contribute to develop new adjuvant therapies targeting the crosstalk between tumor and its supporting microenvironment.
Vascular Complications in Patients with Hepatocellular Carcinoma Treated with Sorafenib
Authors: Pomej Katharina , Scheiner Bernhard , Park Dabin , Bauer David , Balcar Lorenz , Meischl Tobias , Mandorfer Mattias , Reiberger Thomas , Müller Christian , Trauner Michael , Pinter Matthias
Published: October 2020

VEGF(R)-targeted therapies are associated with an increased risk of thromboembolism and bleeding, which might be pronounced in patients with increased cardiovascular risk. Nevertheless, sorafenib represents an important treatment option in patients with hepatocellular carcinoma (HCC). We retrospectively investigated the risk of arterial/venous thromboembolic and bleeding events in 252 patients treated with sorafenib for HCC between 05/2006 and 03/2020 at the Medical University of Vienna. Cardiovascular risk was assessed using Framingham score. Eight patients (3.2%) experienced 11 arterial/venous thromboembolic events. Only two patients (0.8%) developed arterial thromboembolism even though cardiovascular risk was low, intermediate, and high in 15 (8.7%), 104 (60%), and 54 (31.2%) of 173 assessable patients. Median overall survival (OS) was shorter in the high risk vs. low/intermediate risk group 7.4 (95% CI: 3.4–11.3) vs. 10.0 (95% CI: 6.8–13.2 months) and independently associated with OS in multivariable analysis HR: 1.53 (95% CI: 1.07–2.19; p = 0.019). Forty-eight (19%) patients experienced a bleeding, most commonly gastrointestinal bleeding (14%) followed by epistaxis (4.7%). Advanced liver dysfunction was not associated with an increased incidence of bleeding/venous thromboembolism. Sorafenib represents a safe treatment option even in patients with increased cardiovascular risk. Bleeding complications were comparable with previous reports, even though patients with more advanced liver disease were included.
GATA2 Related Conditions and Predisposition to Pediatric Myelodysplastic Syndromes
Authors: Bruzzese Antonella , Leardini Davide , Masetti Riccardo , Strocchio Luisa , Girardi Katia , Algeri Mattia , Del Baldo Giada , Locatelli Franco , Mastronuzzi Angela
Published: October 2020

Myelodysplastic syndromes (MDS) are hematopoietic disorders rare in childhood, often occurring in patients with inherited bone marrow failure syndromes or germinal predisposition syndromes. Among the latter, one of the most frequent involves the gene GATA binding protein 2 (GATA2), coding for a transcriptional regulator of hematopoiesis. The genetic lesion as well as the clinical phenotype are extremely variable; many patients present hematological malignancies, especially MDS with the possibility to evolve into acute myeloid leukemia. Variable immune dysfunction, especially resulting in B- and NK-cell lymphopenia, lead to severe infections, including generalized warts and mycobacterial infection. Defects of alveolar macrophages lead to pulmonary alveolar proteinosis through inadequate clearance of surfactant proteins. Currently, there are no clear guidelines for the monitoring and treatment of patients with GATA2 mutations. In patients with MDS, the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT) that restores normal hematopoiesis preventing the progression to acute myeloid leukemia and clears long-standing infections. However, to date, the donor type, conditioning regimen, and the optimal time to proceed to HSCT, as well as the level of chimerism needed to reverse the phenotype, remain unclear highlighting the need for consensus guidelines.
High PD-L1/CD274 Expression of Monocytes and Blood Dendritic Cells Is a Risk Factor in Lung Cancer Patients Undergoing Treatment with PD1 Inhibitor Therapy
Authors: Riemann Dagmar , Schütte Wolfgang , Turzer Steffi , Seliger Barbara , Möller Miriam
Published: October 2020

The aim of this study was to investigate the expression of the coinhibitory molecule PD-L1/CD274 in monocytes and dendritic cells (DC) in the blood of lung cancer patients undergoing PD1 inhibitor therapy and to correlate data with patient’s outcome. PD-L1/CD274 expression of monocytes, CD1c+ myeloid DC (mDC) and CD303+ plasmacytoid DC (pDC) was determined by flow cytometry in peripheral blood at immunotherapy onset. The predictive value of the PD-L1/CD274-expression data was determined by patients’ survival analysis. Patients with a high PD-L1/CD274 expression of monocytes and blood DC subpopulations rarely responded to PD1 inhibitor therapy. Low PD-L1/CD274 expression of monocytes and DC correlated with prolonged progression-free survival (PFS) as well as overall survival (OS). The highest PD-L1/CD274 expression was found in CD14+HLA-DR++CD16+ intermediate monocytes. Whereas the PD-L1/CD274 expression of monocytes and DC showed a strong positive correlation, only the PD-L1/CD274 expression of DC inversely correlated with DC amounts and lymphocyte counts in peripheral blood. Our results implicate that a high PD-L1/CD274 expression of blood monocytes and DC subtypes is a risk factor for therapy response and for the survival of lung cancer patients undergoing PD1 inhibitor therapy.
Chemerin Is Induced in Non-Alcoholic Fatty Liver Disease and Hepatitis B-Related Hepatocellular Carcinoma
Authors: Haberl Elisabeth M. , Feder Susanne , Pohl Rebekka , Rein-Fischboeck Lisa , Dürholz Kerstin , Eichelberger Laura , Wanninger Josef , Weiss Thomas S. , Buechler Christa
Published: October 2020

Chemerin is protective in experimental models of hepatocellular carcinoma (HCC). Noteworthy, chemerin mRNA and protein were reduced in HCC tissues of Asian patients with mostly hepatitis B disease etiology. The current study nevertheless showed that chemerin protein was induced in tumor tissues of European HCC patients with non-alcoholic fatty liver disease (NAFLD) and patients with unclear disease etiology. A similar regulation was observed in hepatitis B virus (HBV), but not in hepatitis C virus (HCV), related HCC. The apparent discrepancy between the regulation of chemerin in HBV-HCC obtained from our study and recent reports led us to use the chemerin antibodies applied in the previous assays. These antibodies could not equally detect different chemerin isoforms, which were overexpressed in HepG2 cells. Higher chemerin protein in HCC was nevertheless confirmed by the use of all antibodies. Chemerin protein was low in Huh7 and PLC/PRF/5 cells whereas HepG2 and Hep3B cells had chemerin protein similar as primary human hepatocytes. Besides, the anti-tumor effects of retinoids in hepatocyte cell lines did not enclose upregulation of chemerin, which was initially discovered as a tazarotene induced protein in the skin. Finally, protein levels of the chemerin receptor, chemokine-like receptor 1 (CMKLR1), declined in non-viral, and tended to be lower in HBV-HCC tissues suggesting reduced chemerin activity in the tumors. To sum up, our work showed an opposite regulation of chemerin and CMKLR1 in NAFLD and HBV associated HCC. In HCV-HCC neither chemerin nor its receptor were changed in the tumor tissues. Current findings do not support a critical role of total chemerin protein levels in HCC of non-viral and viral etiology. Accordingly, tumor-localized chemerin protein was not associated with tumor-node-metastasis classification.
Erratum: Mapelli, S.N., et al. A Novel Prostate Cell Type-Specific Gene Signature to Interrogate Prostate Tumor Differentiation Status and Monitor Therapeutic Response (Running Title: Phenotypic Classification of Prostate Tumors). Cancers 2020, 12, 176
Authors: Mapelli Sarah , Albino Domenico , Mello-Grand Maurizia , Shinde Dheeraj , Scimeca Manuel , Bonfiglio Rita , Bonanno Elena , Chiorino Giovanna , Garcia-Escudero Ramon , Catapano Carlo , Carbone Giuseppina
Published: October 2020

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