bluuebunny/crossref_metadata_2025 huggingface dataset:
Post-Translational Modifications That Drive Prostate Cancer Progression
Authors: Samaržija Ivana
Published: February 2021

While a protein primary structure is determined by genetic code, its specific functional form is mostly achieved in a dynamic interplay that includes actions of many enzymes involved in post-translational modifications. This versatile repertoire is widely used by cells to direct their response to external stimuli, regulate transcription and protein localization and to keep proteostasis. Herein, post-translational modifications with evident potency to drive prostate cancer are explored. A comprehensive list of proteome-wide and single protein post-translational modifications and their involvement in phenotypic outcomes is presented. Specifically, the data on phosphorylation, glycosylation, ubiquitination, SUMOylation, acetylation, and lipidation in prostate cancer and the enzymes involved are collected. This type of knowledge is especially valuable in cases when cancer cells do not differ in the expression or mutational status of a protein, but its differential activity is regulated on the level of post-translational modifications. Since their driving roles in prostate cancer, post-translational modifications are widely studied in attempts to advance prostate cancer treatment. Current strategies that exploit the potential of post-translational modifications in prostate cancer therapy are presented.
Control of Gene Expression by Exosome-Derived Non-Coding RNAs in Cancer Angiogenesis and Lymphangiogenesis
Authors: Arcucci Valeria , Stacker Steven A. , Achen Marc G.
Published: February 2021

Tumour angiogenesis and lymphangiogenesis are hallmarks of cancer and have been associated with tumour progression, tumour metastasis and poor patient prognosis. Many factors regulate angiogenesis and lymphangiogenesis in cancer including non-coding RNAs which are a category of RNAs that do not encode proteins and have important regulatory functions at transcriptional and post-transcriptional levels. Non-coding RNAs can be encapsulated in extracellular vesicles called exosomes which are secreted by tumour cells or other cells in the tumour microenvironment and can then be taken up by the endothelial cells of blood vessels and lymphatic vessels. The “delivery” of these non-coding RNAs to endothelial cells in tumours can facilitate tumour angiogenesis and lymphangiogenesis. Here we review recent findings about exosomal non-coding RNAs, specifically microRNAs and long non-coding RNAs, which regulate tumour angiogenesis and lymphangiogenesis in cancer. We then focus on the potential use of these molecules as cancer biomarkers and opportunities for exploiting ncRNAs for the treatment of cancer.
An Evaluation Methodology for Interactive Reinforcement Learning with Simulated Users
Authors: Bignold Adam , Cruz Francisco , Dazeley Richard , Vamplew Peter , Foale Cameron
Published: February 2021

Interactive reinforcement learning methods utilise an external information source to evaluate decisions and accelerate learning. Previous work has shown that human advice could significantly improve learning agents’ performance. When evaluating reinforcement learning algorithms, it is common to repeat experiments as parameters are altered or to gain a sufficient sample size. In this regard, to require human interaction every time an experiment is restarted is undesirable, particularly when the expense in doing so can be considerable. Additionally, reusing the same people for the experiment introduces bias, as they will learn the behaviour of the agent and the dynamics of the environment. This paper presents a methodology for evaluating interactive reinforcement learning agents by employing simulated users. Simulated users allow human knowledge, bias, and interaction to be simulated. The use of simulated users allows the development and testing of reinforcement learning agents, and can provide indicative results of agent performance under defined human constraints. While simulated users are no replacement for actual humans, they do offer an affordable and fast alternative for evaluative assisted agents. We introduce a method for performing a preliminary evaluation utilising simulated users to show how performance changes depending on the type of user assisting the agent. Moreover, we describe how human interaction may be simulated, and present an experiment illustrating the applicability of simulating users in evaluating agent performance when assisted by different types of trainers. Experimental results show that the use of this methodology allows for greater insight into the performance of interactive reinforcement learning agents when advised by different users. The use of simulated users with varying characteristics allows for evaluation of the impact of those characteristics on the behaviour of the learning agent.
Visual Attention-Related Processing: Perspectives from Ageing, Cognitive Decline and Dementia
Authors: Hanley Claire J. , Tales Andrea
Published: February 2021

Regarded as a defining factor in resource management, it is widely accepted that visual attention and related processing will deteriorate, in a global fashion, across the lifespan and produce detrimental consequences for environmental interactions [...]
Cathodal Transcranial Direct Current Stimulation (tDCS) Applied to the Left Premotor Cortex Interferes with Explicit Reproduction of a Motor Sequence
Authors: Pollok Bettina , Schmitz-Justen Claire , Krause Vanessa
Published: February 2021

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that allows the modulation of cortical excitability. TDCS effects can outlast the stimulation period presumably due to changes of GABA concentration which play a critical role in use-dependent plasticity. Consequently, tDCS and learning-related synaptic plasticity are assumed to share common mechanisms. Motor sequence learning has been related to activation changes within a cortico-subcortical network and findings from a meta-analysis point towards a core network comprising the cerebellum as well as the primary motor (M1) and the dorsolateral premotor cortex (dPMC). The latter has been particularly related to explicit motor learning by means of brain imaging techniques. We here test whether tDCS applied to the left dPMC affects the acquisition and reproduction of an explicitly learned motor sequence. To this end, 18 healthy volunteers received anodal, cathodal and sham tDCS to the left dPMC and were then trained on a serial reaction time task (SRTT) with their right hand. Immediately after the training and after overnight sleep, reproduction of the learned sequence was tested by means of reaction times as well as explicit recall. Regression analyses suggest that following cathodal tDCS reaction times at the end of the SRTT training-block explained a significant proportion of the number of correctly reported sequence items after overnight sleep. The present data suggest the left premotor cortex as one possible target for the application of non-invasive brain stimulation techniques in explicit motor sequence learning with the right hand.
Generation of the Human Pluripotent Stem-Cell-Derived Astrocyte Model with Forebrain Identity
Authors: Peteri Ulla-Kaisa , Pitkonen Juho , Utami Kagistia Hana , Paavola Jere , Roybon Laurent , Pouladi Mahmoud A. , Castrén Maija L.
Published: February 2021

Astrocytes form functionally and morphologically distinct populations of cells with brain-region-specific properties. Human pluripotent stem cells (hPSCs) offer possibilities to generate astroglia for studies investigating mechanisms governing the emergence of astrocytic diversity. We established a method to generate human astrocytes from hPSCs with forebrain patterning and final specification with ciliary neurotrophic factor (CNTF). Transcriptome profiling and gene enrichment analysis monitored the sequential expression of genes determining astrocyte differentiation and confirmed activation of forebrain differentiation pathways at Day 30 (D30) and D60 of differentiation in vitro. More than 90% of astrocytes aged D95 in vitro co-expressed the astrocytic markers glial fibrillary acidic protein (GFAP) and S100β. Intracellular calcium responses to ATP indicated differentiation of the functional astrocyte population with constitutive monocyte chemoattractant protein-1 (MCP-1/CCL2) and tissue inhibitor of metalloproteinases-2 (TIMP-2) expression. The method was reproducible across several hPSC lines, and the data demonstrated the usefulness of forebrain astrocyte modeling in research investigating forebrain pathology.
Interpretable Machine Learning Models for Three-Way Classification of Cognitive Workload Levels for Eye-Tracking Features
Authors: Kaczorowska Monika , Plechawska-Wójcik Małgorzata , Tokovarov Mikhail
Published: February 2021

The paper is focussed on the assessment of cognitive workload level using selected machine learning models. In the study, eye-tracking data were gathered from 29 healthy volunteers during examination with three versions of the computerised version of the digit symbol substitution test (DSST). Understanding cognitive workload is of great importance in analysing human mental fatigue and the performance of intellectual tasks. It is also essential in the context of explanation of the brain cognitive process. Eight three-class classification machine learning models were constructed and analysed. Furthermore, the technique of interpretable machine learning model was applied to obtain the measures of feature importance and its contribution to the brain cognitive functions. The measures allowed improving the quality of classification, simultaneously lowering the number of applied features to six or eight, depending on the model. Moreover, the applied method of explainable machine learning provided valuable insights into understanding the process accompanying various levels of cognitive workload. The main classification performance metrics, such as F1, recall, precision, accuracy, and the area under the Receiver operating characteristic curve (ROC AUC) were used in order to assess the quality of classification quantitatively. The best result obtained on the complete feature set was as high as 0.95 (F1); however, feature importance interpretation allowed increasing the result up to 0.97 with only seven of 20 features applied.
Energy Rating of Buildings to Promote Energy-Conscious Design in Israel
Authors: Yezioro Abraham , Capeluto Isaac Guedi
Published: February 2021

Improving the energy efficiency of existing and new buildings is an important step towards achieving more sustainable environments. There are various methods for grading buildings that are required according to regulations in different places for green building certification. However, in new buildings, these rating systems are usually implemented at late design stages due to their complexity and lack of integration in the architectural design process, thus limiting the available options for improving their performance. In this paper, the model ENERGYui used for design and rating buildings in Israel is presented. One of its main advantages is that it can be used at any design stage, including the early ones. It requires information that is available at each stage only, as the additional necessary information is supplemented by the model. In this way, architects can design buildings in a way where they are aware of each design decision and its impact on their energy performance, while testing different design directions. ENERGYui rates the energy performance of each basic unit, as well as the entire building. The use of the model is demonstrated in two different scenarios: an office building in which basic architectural features such as form and orientation are tested from the very beginning, and a residential building in which the intervention focuses on its envelope, highlighting the possibilities of improving their design during the whole design process.
Serum Concentrations of KL-6 in Patients with IPF and Lung Cancer and Serial Measurements of KL-6 in IPF Patients Treated with Antifibrotic Therapy
Authors: d’Alessandro Miriana , Bergantini Laura , Cameli Paolo , Pieroni Maria , Refini Rosa Metella , Sestini Piersante , Bargagli Elena
Published: February 2021

Background: Krebs von den Lungen-6 (KL-6) was suggested as ILD biomarker including idiopathic pulmonary fibrosis (IPF). Lung cancer is one of the most severe comorbidity of IPF patients. This study aims to serially analyze KL-6 in IPF patients after 24 months of Nintedanib and to first investigate the biomarker behavior in IPF associated with adenocarcinoma. Materials and methods: One hundred and forty-two ILD patients (median (IQR), 69 (63–75) years; 86 males) were retrospectively enrolled. Serial serum samples were collected from IPF patients before starting antifibrotic therapy and after 12 months. Serum KL-6 levels were measured by KL-6 reagent assay (Fujirebio Europe, UK). Results: Increased KL-6 concentrations were identified in IPF-LC patients than IPF, fibrotic hypersensitivity pneumonitis, and pulmonary fibrosis associated with autoimmune disease groups. A cut-off value was calculated to distinguish IPF and IPF-LC patients. IPF patients monitored for 24 months with Nintedanib showed persisted increased levels of KL-6 with a progressive decline of FVC percentages. Conclusion: This preliminary study offers a first demonstration that very high serum concentrations of KL-6 in IPF-LC patients are associated with poor prognosis. Moreover, serial evaluation of serum KL-6 in IPF patients over 24 months of Nintedanib treatment revealed that most patients experienced a stabilization of lung function parameters and of serum concentrations of KL-6.
Why Target Innate Immune Cells in Cancers?
Authors: Poupot Mary
Published: February 2021

The immune system is a smart way to fight cancer, with its precise targeting of cancer cells sparing healthy cells [...]
Lights and Shadows in Immuno-Oncology Drug Development
Authors: Bergamino Sirvén Milana , Pernas Sonia , Cheang Maggie C. U.
Published: February 2021

The rapidly evolving landscape of immuno-oncology (IO) is redefining the treatment of a number of cancer types. IO treatments are becoming increasingly complex, with different types of drugs emerging beyond checkpoint inhibitors. However, many of the new drugs either do not progress from phase I-II clinical trials or even fail in late-phase trials. We have identified at least five areas in the development of promising IO treatments that should be redefined for more efficient designs and accelerated approvals. Here we review those critical aspects of IO drug development that could be optimized for more successful outcome rates in all cancer types. It is important to focus our efforts on the mechanisms of action, types of response and adverse events of these novel agents. The use of appropriate clinical trial designs with robust biomarkers of response and surrogate endpoints will undoubtedly facilitate the development and subsequent approval of these drugs. Further research is also needed to establish biomarker-driven strategies to select which patients may benefit from immunotherapy and identify potential mechanisms of resistance.
Molecular and Functional Links between Neurodevelopmental Processes and Treatment-Induced Neuroendocrine Plasticity in Prostate Cancer Progression
Authors: Kaarijärvi Roosa , Kaljunen Heidi , Ketola Kirsi
Published: February 2021

Neuroendocrine plasticity and treatment-induced neuroendocrine phenotypes have recently been proposed as important resistance mechanisms underlying prostate cancer progression. Treatment-induced neuroendocrine prostate cancer (t-NEPC) is highly aggressive subtype of castration-resistant prostate cancer which develops for one fifth of patients under prolonged androgen deprivation. In recent years, understanding of molecular features and phenotypic changes in neuroendocrine plasticity has been grown. However, there are still fundamental questions to be answered in this emerging research field, for example, why and how do the prostate cancer treatment-resistant cells acquire neuron-like phenotype. The advantages of the phenotypic change and the role of tumor microenvironment in controlling cellular plasticity and in the emergence of treatment-resistant aggressive forms of prostate cancer is mostly unknown. Here, we discuss the molecular and functional links between neurodevelopmental processes and treatment-induced neuroendocrine plasticity in prostate cancer progression and treatment resistance. We provide an overview of the emergence of neurite-like cells in neuroendocrine prostate cancer cells and whether the reported t-NEPC pathways and proteins relate to neurodevelopmental processes like neurogenesis and axonogenesis during the development of treatment resistance. We also discuss emerging novel therapeutic targets modulating neuroendocrine plasticity.
Optimizing Dose and Timing in Magnetic Tracer Techniques for Sentinel Lymph Node Detection in Early Breast Cancers: The Prospective Multicenter SentiDose Trial
Authors: Hersi Abdi-Fatah , Pistiolis Lida , Dussan Luberth Carlos , Vikhe-Patil Eva , Nilsson Fredrik , Mohammed Imad , Olofsson Bagge Roger , Wärnberg Fredrik , Eriksson Staffan , Karakatsanis Andreas
Published: February 2021

Superparamagnetic iron oxide nanoparticles (SPIO) are non-inferior to radioisotope and blue dye (RI + BD) for sentinel lymph node (SLN) detection. Previously, 2 mL SPIO (Sienna+®) in 3 mL NaCl was used. In this dose-optimizing study, lower doses of a new refined SPIO solution (Magtrace®) (1.5 vs. 1.0 mL) were tested in different timeframes (0–24 h perioperative vs. 1–7 days preoperative) and injections sites (subareolar vs. peritumoral). Two consecutive breast cancer cohorts (n = 328) scheduled for SLN-biopsy were included from 2017 to 2019. All patients received isotope ± blue dye as back-up. SLNs were identified primarily with the SentiMag® probe and thereafter a gamma-probe. The primary endpoint was SLN detection rate with SPIO. Analyses were performed as a one-step individual patient-level meta-analysis using patient-level data from the previously published Nordic Trial (n = 206) as a third, reference cohort. In 534 patients, the SPIO SLN detection rates were similar (97.5% vs. 100% vs. 97.6%, p = 0.11) and non-inferior to the dual technique. Significantly more SLNs were retrieved in the preoperative 1.0 mL cohort compared with 1.5 and the 2.0 mL cohorts (2.18 vs. 1.85 vs. 1.83, p = 0.003). Lower SPIO volumes injected up to 7 days before the operation have comparable efficacy to standard SPIO dose and RI + BD for SLN detection.
Dual Targeting Oncoproteins MYC and HIF1α Regresses Tumor Growth of Lung Cancer and Lymphoma
Authors: Huang Xiaohu , Liu Yan , Wang Yin , Bailey Christopher , Zheng Pan , Liu Yang
Published: February 2021

MYC and HIF1α are among the most important oncoproteins whose pharmacologic inhibition has been challenging for the diverse mechanisms driving their abnormal expression and because of the challenge in blocking protein-DNA interactions. Surprisingly, we found that MYC and HIF1α proteins in echinomycin-treated cells were degraded through proteasome dependent pathways, respectively by the β-TrCP- or VHL-dependent mechanisms. The degradation is induced in a variety of cancer types, including those with mutations in the p53 tumor and LKB tumor suppressors and the KRAS oncogene. Consistent with inhibition of MYC and HIF1α, administration of echinomycin inhibited growth of lung adenocarcinoma xenograft and a syngeneic lymphoma model in mice. Furthermore, echinomycin efficiently induced regression of syngeneic mouse lymphoma driven by MYC over-expression. Our data demonstrated a new mechanism by which echinomycin simultaneously targets MYC and HIF1α for degradation to inhibit growth of lung cancer and lymphoma. Given the broad impact of β-TrCP or VHL in stability of oncogenic proteins, echinomycin may emerge as a non-PROTAC (proteolysis targeting chimera) degrader of oncogenic proteins.
Long-Term Survival Outcomes of Cytoreductive Nephrectomy Combined with Targeted Therapy for Metastatic Renal Cell Carcinoma: A Systematic Review and Individual Patient Data Meta-Analysis
Authors: Esagian Stepan M. , Ziogas Ioannis A. , Kosmidis Dimitrios , Hossain Mohammad D. , Tannir Nizar M. , Msaouel Pavlos
Published: February 2021

The role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) remains controversial during the targeted therapy era. To reconcile the current literature, we analyzed the reported survival data at the individual patient level and compared the long-term survival outcomes of CN combined with targeted therapy vs. targeted therapy alone in patients with mRCC. We performed a systematic review of the literature using the MEDLINE, Scopus, and Cochrane Library databases (end-of-search date: 21 July 2020). We recuperated individual patient data from the Kaplan–Meier curves for overall (OS), progression-free (PFS), and cancer-specific survival (CSS) from each study. We subsequently performed one-stage frequentist and Bayesian random-effects meta-analyses using both Cox proportional hazards and restricted mean survival time (RMST) models. Two-stage random-effects meta-analyses were also performed as sensitivity analyses. A subgroup analysis was also performed to determine the effect of CN timing. Fifteen studies fulfilling our inclusion criteria were identified, including fourteen retrospective cohort studies and one randomized controlled trial. In the one-stage frequentist meta-analysis, the CN group had superior OS (hazard ratio [HR]: 0.58, 95% confidence interval [CI]: 0.54–0.62, p < 0.0001) and CSS (HR: 0.63, 95% CI: 0.53–0.75, p < 0.0001). No meaningful clinical difference was observed in PFS (HR: 0.90, 95% CI: 0.80–1.02, p = 0.09). One-stage Bayesian meta-analysis also revealed superior OS (HR: 0.59, 95% credibility interval [CrI]: 0.55–0.63) and CSS (HR: 0.63, 95% CrI: 0.53–0.75) in the CN group, while no meaningful clinical difference was detected in PFS (HR: 0.91, 95% CrI: 0.80–1.02). Similar results were obtained with the RMST models. The OS benefit was also noted in the two-stage meta-analyses models, and in the subgroup of patients who received upfront CN. The combination of CN and targeted therapy for mRCC may lead to superior long-term survival outcomes compared to targeted therapy alone. Careful patient selection based on prognostic factors is required to optimize outcomes.
Current Knowledge about Mechanisms of Drug Resistance against ALK Inhibitors in Non-Small Cell Lung Cancer
Authors: Smolle Elisabeth , Taucher Valentin , Lindenmann Joerg , Jost Philipp J. , Pichler Martin
Published: February 2021

Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer subtypes. Two to seven percent of NSCLC patients harbor gene rearrangements of the anaplastic lymphoma kinase (ALK) gene or, alternatively, harbor chromosomal fusions of ALK with echinoderm microtubule-associated protein-like 4 (EML4). The availability of tyrosine kinase inhibitors targeting ALK (ALK-TKIs) has significantly improved the progression-free and overall survival of NSCLC patients carrying the respective genetic aberrations. Yet, increasing evidence shows that primary or secondary resistance to ALK-inhibitors during the course of treatment represents a relevant clinical problem. This necessitates a switch to second- or third-generation ALK-TKIs and a close observation of NSCLC patients on ALK-TKIs during the course of treatment by repetitive molecular testing. With this review of the literature, we aim at providing an overview of current knowledge about resistance mechanisms to ALK-TKIs in NSCLC.
Feasibility of Continual Deep Learning-Based Segmentation for Personalized Adaptive Radiation Therapy in Head and Neck Area
Authors: Kim Nalee , Chun Jaehee , Chang Jee Suk , Lee Chang Geol , Keum Ki Chang , Kim Jin Sung
Published: February 2021

This study investigated the feasibility of deep learning-based segmentation (DLS) and continual training for adaptive radiotherapy (RT) of head and neck (H&N) cancer. One-hundred patients treated with definitive RT were included. Based on 23 organs-at-risk (OARs) manually segmented in initial planning computed tomography (CT), modified FC-DenseNet was trained for DLS: (i) using data obtained from 60 patients, with 20 matched patients in the test set (DLSm); (ii) using data obtained from 60 identical patients with 20 unmatched patients in the test set (DLSu). Manually contoured OARs in adaptive planning CT for independent 20 patients were provided as test sets. Deformable image registration (DIR) was also performed. All 23 OARs were compared using quantitative measurements, and nine OARs were also evaluated via subjective assessment from 26 observers using the Turing test. DLSm achieved better performance than both DLSu and DIR (mean Dice similarity coefficient; 0.83 vs. 0.80 vs. 0.70), mainly for glandular structures, whose volume significantly reduced during RT. Based on subjective measurements, DLS is often perceived as a human (49.2%). Furthermore, DLSm is preferred over DLSu (67.2%) and DIR (96.7%), with a similar rate of required revision to that of manual segmentation (28.0% vs. 29.7%). In conclusion, DLS was effective and preferred over DIR. Additionally, continual DLS training is required for an effective optimization and robustness in personalized adaptive RT.
Dual-Target CAR-Ts with On- and Off-Tumour Activity May Override Immune Suppression in Solid Cancers: A Mathematical Proof of Concept
Authors: León-Triana Odelaisy , Pérez-Martínez Antonio , Ramírez-Orellana Manuel , Pérez-García Víctor M.
Published: February 2021

Chimeric antigen receptor (CAR)-T cell-based therapies have achieved substantial success against B-cell malignancies, which has led to a growing scientific and clinical interest in extending their use to solid cancers. However, results for solid tumours have been limited up to now, in part due to the immunosuppressive tumour microenvironment, which is able to inactivate CAR-T cell clones. In this paper we put forward a mathematical model describing the competition of CAR-T and tumour cells, taking into account their immunosuppressive capacity. Using the mathematical model, we show that the use of large numbers of CAR-T cells targetting the solid tumour antigens could overcome the immunosuppressive potential of cancer. To achieve such high levels of CAR-T cells we propose, and study computationally, the manufacture and injection of CAR-T cells targetting two antigens: CD19 and a tumour-associated antigen. We study in silico the resulting dynamics of the disease after the injection of this product and find that the expansion of the CAR-T cell population in the blood and lymphopoietic organs could lead to the massive production of an army of CAR-T cells targetting the solid tumour, and potentially overcoming its immune suppression capabilities. This strategy could benefit from the combination with PD-1 inhibitors and low tumour loads. Our computational results provide theoretical support for the treatment of different types of solid tumours using T cells engineered with combination treatments of dual CARs with on- and off-tumour activity and anti-PD-1 drugs after completion of classical cytoreductive treatments.
Melanotic Neuroectodermal Tumor of Infancy (MNTI) and Pineal Anlage Tumor (PAT) Harbor A Medulloblastoma Signature by DNA Methylation Profiling
Authors: Lopez-Nunez Oscar , Alaggio Rita , John Ivy , Ciolfi Andrea , Pedace Lucia , Mastronuzzi Angela , Gianno Francesca , Giangaspero Felice , Rossi Sabrina , Donofrio Vittoria , Cinalli Giuseppe , Surrey Lea F. , Tartaglia Marco , Locatelli Franco , Miele Evelina
Published: February 2021

MNTI is a rare tumor of indeterminate histogenesis and molecular signature. We performed methylation and copy number variation (CNV) profiles in patients with MNTI (n = 7) and PAT (n = 1) compared to the methylation brain tumor classifier v11b4 (BT-C) and the medulloblastoma (MB) classifier group 3/4 v1.0 (MB3/4-C). The patients’ mean age was 8 months (range: 4–48). The BT-C classified five MNTIs and one PAT (relapse) as class family MB-G3/G4, subclass group 3 (score: >0.9). The remaining two MNTIs and PAT (primary) were classified as class family plexus tumor, subclass pediatric (scores: >0.45). The MB3/4-C classified all MNTIs as high-risk MB-G3, Subtype II (score: >0.45). The primary PAT was classified as subtype III (score: 0.99) and its relapse as subtype II/III. MNTI and PAT clustered close to MB-G3. CNV analysis showed multiple rearrangements in one PAT and two MNTIs. The median follow-up was 54 months (four MNTIs in remission, one PAT died). In conclusion, we demonstrated that MNTI shares a homogenous methylation profile with MB-G3, and possibly with PAT. The role of a multipotent progenitor cell (i.e., early cranial neural crest cell) in their histogenesis and the influence of the anatomical site, tumor microenvironment, and other cytogenetic events in their divergent biologic behavior deserve further investigation.
The Vault Nanoparticle: A Gigantic Ribonucleoprotein Assembly Involved in Diverse Physiological and Pathological Phenomena and an Ideal Nanovector for Drug Delivery and Therapy
Authors: Frascotti Gianni , Galbiati Elisabetta , Mazzucchelli Matteo , Pozzi Maria , Salvioni Lucia , Vertemara Jacopo , Tortora Paolo
Published: February 2021

The vault nanoparticle is a eukaryotic ribonucleoprotein complex consisting of 78 individual 97 kDa-“major vault protein” (MVP) molecules that form two symmetrical, cup-shaped, hollow halves. It has a huge size (72.5 × 41 × 41 nm) and an internal cavity, wherein the vault poly(ADP-ribose) polymerase (vPARP), telomerase-associated protein-1 (TEP1), and some small untranslated RNAs are accommodated. Plenty of literature reports on the biological role(s) of this nanocomplex, as well as its involvement in diseases, mostly oncological ones. Nevertheless, much has still to be understood as to how vault participates in normal and pathological mechanisms. In this comprehensive review, current understanding of its biological roles is discussed. By different mechanisms, vault’s individual components are involved in major cellular phenomena, which result in protection against cellular stresses, such as DNA-damaging agents, irradiation, hypoxia, hyperosmotic, and oxidative conditions. These diverse cellular functions are accomplished by different mechanisms, mainly gene expression reprogramming, activation of proliferative/prosurvival signaling pathways, export from the nucleus of DNA-damaging drugs, and import of specific proteins. The cellular functions of this nanocomplex may also result in the onset of pathological conditions, mainly (but not exclusively) tumor proliferation and multidrug resistance. The current understanding of its biological roles in physiological and pathological processes should also provide new hints to extend the scope of its exploitation as a nanocarrier for drug delivery.
Epigenetic Alterations in Triple-Negative Breast Cancer—The Critical Role of Extracellular Matrix
Authors: Zolota Vasiliki , Tzelepi Vasiliki , Piperigkou Zoi , Kourea Helen , Papakonstantinou Efthymia , Argentou Maria-Ioanna , Karamanos Nikos K.
Published: February 2021

Triple-negative breast cancer (TNBC) is an aggressive subgroup of breast cancer characterized by genomic complexity and therapeutic options limited to only standard chemotherapy. Although it has been suggested that stratifying TNBC patients by pathway-specific molecular alterations may predict benefit from specific therapeutic agents, application in routine clinical practice has not yet been established. There is a growing body of the literature supporting that epigenetic modifications comprised by DNA methylation, chromatin remodeling and non-coding RNAs play a fundamental role in TNBC pathogenesis. Extracellular matrix (ECM) is a highly dynamic 3D network of macromolecules with structural and cellular regulatory roles. Alterations in the expression of ECM components result in uncontrolled matrix remodeling, thus affecting its ability to regulate vital functions of cancer cells, including proliferation, migration, adhesion, invasion and epithelial-to-mesenchymal transition (EMT). Recent molecular data highlight the major role of tumor microenvironment and ECM alterations in TNBC and approaches for targeting tumor microenvironment have recently been recognized as potential therapeutic strategies. Notably, many of the ECM/EMT modifications in cancer are largely driven by epigenetic events, highlighting the pleiotropic effects of the epigenetic network in TNBC. This article presents and critically discusses the current knowledge on the epigenetic alterations correlated with TNBC pathogenesis, with emphasis on those associated with ECM/EMT modifications, their prognostic and predictive value and their use as therapeutic targets.
Combinations of Radiotherapy with Vaccination and Immune Checkpoint Inhibition Differently Affect Primary and Abscopal Tumor Growth and the Tumor Microenvironment
Authors: Rückert Michael , Deloch Lisa , Frey Benjamin , Schlücker Eberhard , Fietkau Rainer , Gaipl Udo S.
Published: February 2021

Radiotherapy (RT) is known to have immune-modulatory properties. We hypothesized that RT and inactivated whole tumor cell vaccines generated with high hydrostatic pressure (HHP) synergize to retard the tumor growth which can be additionally improved with anti-PD-1 treatment. In abscopal tumor models, we injected mice with B16-F10 melanoma or TS/A mammary tumors. To evaluate the efficiency of RT in combination with HHP vaccines, we locally irradiated only one tumor with 2 × 8 Gy or 3 × 8 Gy. HHP vaccines further retarded the growth of locally irradiated (2 × 8 Gy) tumors. However, HHP vaccination combined with RT failed to induce abscopal anti-tumor immune responses, namely those to non-irradiated tumors, and even partly abrogated those which were induced with RT plus anti-PD-1. In the latter group, the abscopal effects were accompanied by an elevated infiltration of CD8+ T cells, monocytes/macrophages, and dendritic cells. 3 × 8 Gy failed to induce abscopal effects in association with increased expression of immunosuppressive checkpoint molecules compared to 2 × 8 Gy. We conclude that HHP vaccines induce anti-tumor effects, but only if the tumor microenvironment was previously modulated by hypofractionated RT with not too many fractions, but failed to improve RT plus anti-PD-induced abscopal responses that are characterized by distinct immune alterations.
A Stereoselective, Multicomponent Catalytic Carbonylative Approach to a New Class of α,β-Unsaturated γ-Lactam Derivatives
Authors: Mancuso Raffaella , Ziccarelli Ida , Brindisi Matteo , Altomare Cosimo D. , Frattaruolo Luca , Falcicchio Aurelia , Della Ca’ Nicola , Cappello Anna Rita , Gabriele Bartolo
Published: February 2021

We report a stereoselective, multicomponent catalytic carbonylative approach to a new class of α,β-unsaturated γ-lactam derivatives with potential biological activity, that are, alkyl (Z)-2-(2-oxopyrrolidin-3-ylidene)acetates. Our method is based on the catalytic assembly of readily available building blocks, namely, homopropargylic amines, carbon monoxide, an alcohol, and oxygen (from air). These simple substrates are efficiently activated in ordered sequence under the action of a very simple catalytic system, consisting of PdI2 in conjunction with KI to give the γ-lactam products in 47–85% yields. Carbonylation reactions are carried out at 100 °C for 2–5 h under 40 atm of a 4:1 mixture of CO‒air, with 0.5–5 mol% of PdI2 and 5–50 mol% of KI.
Review on Alternative Route to Acrolein through Oxidative Coupling of Alcohols
Authors: Folliard Vincent , Tommaso Jacopo de , Dubois Jean-Luc
Published: February 2021

Oxidative coupling of alcohols using methanol and ethanol, which can both be made renewable, is an attractive route to produce acrolein (propenaldehyde) in a single-step process. Currently acrolein is produced by direct oxidation of fossil propylene, and catalytic double dehydration of glycerol has been also investigated up to pilot scale. Although glycerol is an attractive feedstock, it suffers of several drawbacks. Addressing the limitations of both routes, the oxidative coupling of alcohols combines an exothermic oxidation and cross-aldolization. The best performing catalysts so far combine redox and acid/base sites. Reviewing the academic and patent literature, the present paper also addresses the economic analysis, to highlight the potential of this reaction at a yield from 70%, and at two different plant scales. The analysis has been made to guide further research, with the remaining technical problems to solve. Improved selectivity contributing to reduce the amount of equipment and the investment cost should be the prime target.
Easily Recycled CuMgFe Catalysts Derived from Layered Double Hydroxides for Hydrogenolysis of Glycerol
Authors: Yu Xiaopeng , Zhang Fubao , Wang Yi , Cheng Dejun
Published: February 2021

A series of CuMgFe catalysts with different (Cu + Mg)/Fe molar ratios derived from hydrotalcites were prepared by coprecipitation for the hydrogenolysis of glycerol to 1,2-propanediol (1,2-PDO). X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectra (XPS), vibrating sample magnetometer (VSM), hydrogen temperature-programmed reduction (H2-TPR), CO2-TPD, and H2-TPD (temperature-programmed desorption of CO2 and H2) were used to investigate the physicochemical properties of the catalysts. The CuMgFe-layered double oxides (CuMgFe-4LDO) catalyst with (Cu + Mg)/Fe molar ratio of 4 exhibited superior activity and stability. The high glycerol conversion and 1,2-propanediol selectivity over CuMgFe-4LDO catalyst were attributed to its strong basicity, excellent H2 activation ability, and an increase in the surface Cu content. The CuMgFe catalysts could be easily recycled with the assistance of an external magnetic field due to their magnetism.
Green Synthesis of 2-Oxazolidinones by an Efficient and Recyclable CuBr/Ionic Liquid System via CO2, Propargylic Alcohols, and 2-Aminoethanols
Authors: Bu Chao , Gong Yanyan , Du Minchen , Chen Cheng , Chaemchuen Somboon , Hu Jia , Zhang Yongxing , Díaz Velázquez Heriberto , Yuan Ye , Verpoort Francis
Published: February 2021

With the aim of profitable conversion of carbon dioxide (CO2) in an efficient, economical, and sustainable manner, we developed a CuBr/ionic liquid (1-butyl-3-methylimidazolium acetate) catalytic system that could efficiently catalyze the three-component reactions of propargylic alcohols, 2-aminoethanols, and CO2 to produce 2-oxazolidinones and α-hydroxy ketones. Remarkably, this catalytic system employed lower metal loading (0.0125–0.5 mol%) but exhibited the highest turnover number (2960) ever reported, demonstrating its excellent activity and sustainability. Moreover, our catalytic system could efficiently work under 1 atm of CO2 pressure and recycle among the metal-catalyzed systems.
Regulatory T Cells Inhibit T Cell Activity by Downregulating CD137 Ligand via CD137 Trogocytosis
Authors: Luu Khang , Patwardhan Mugdha Vijay , Zeng Qun , Wickström Stina L. , Lundqvist Andreas , Schwarz Herbert
Published: February 2021

CD137 is a costimulatory molecule expressed on activated T cells. CD137 ligand (CD137L) is expressed by antigen presenting cells (APC), which use the CD137—CD137L system to enhance immune responses. It was, therefore, surprising to discover CD137 expression on regulatory T cells (Treg). The function of CD137 in Treg are controversial. While some studies report that CD137 signalling converts Treg to effector T cells (Teff), other studies find that CD137-expressing Treg display a stronger inhibitory activity than CD137- Treg. Here, we describe that CD137 on Treg binds to CD137L on APC, upon which one of the two molecules is transferred via trogocytosis to the other cell, where CD137—CD137L forms a complex that is internalized and deprives APC of the immune-stimulatory CD137L. Truncated forms of CD137 that lack the cytoplasmic domain of CD137 are also able to downregulate CD137L, demonstrating that CD137 signalling is not required. Comparable data have been obtained with human and murine cells, indicating that this mechanism is evolutionarily conserved. These data describe trogocytosis of CD137 and CD137L as a new mechanism employed by Treg to control immune responses by downregulating the immunostimulatory CD137L on APC.
NF-κB in Cancer Immunity: Friend or Foe?
Authors: Lalle Guilhem , Twardowski Julie , Grinberg-Bleyer Yenkel
Published: February 2021

The emergence of immunotherapies has definitely proven the tight relationship between malignant and immune cells, its impact on cancer outcome and its therapeutic potential. In this context, it is undoubtedly critical to decipher the transcriptional regulation of these complex interactions. Following early observations demonstrating the roles of NF-κB in cancer initiation and progression, a series of studies converge to establish NF-κB as a master regulator of immune responses to cancer. Importantly, NF-κB is a family of transcriptional activators and repressors that can act at different stages of cancer immunity. In this review, we provide an overview of the selective cell-intrinsic contributions of NF-κB to the distinct cell types that compose the tumor immune environment. We also propose a new view of NF-κB targeting drugs as a new class of immunotherapies for cancer.
Social Defeat Stress during Early Adolescence Confers Resilience against a Single Episode of Prolonged Stress in Adult Rats
Authors: Mancini Giulia Federica , Marchetta Enrico , Pignani Irene , Trezza Viviana , Campolongo Patrizia
Published: February 2021

Early-life adverse experiences (first hit) lead to coping strategies that may confer resilience or vulnerability to later experienced stressful events (second hit) and the subsequent development of stress-related psychopathologies. Here, we investigated whether exposure to two stressors at different stages in life has long-term effects on emotional and cognitive capabilities, and whether the interaction between the two stressors influences stress resilience. Male rats were subjected to social defeat stress (SDS, first hit) in adolescence and to a single episode of prolonged stress (SPS, second hit) in adulthood. Behavioral outcomes, hippocampal expression of brain-derived neurotrophic factor, and plasma corticosterone levels were tested in adulthood. Rats exposed to both stressors exhibited resilience against the development of stress-induced alterations in emotional behaviors and spatial memory, but vulnerability to cued fear memory dysfunction. Rats subjected to both stressors demonstrated resilience against the SDS-induced alterations in hippocampal brain-derived neurotrophic factor expression and plasma corticosterone levels. SPS alone altered locomotion and spatial memory retention; these effects were absent in SDS-exposed rats later exposed to SPS. Our findings reveal that exposure to social stress during early adolescence influences the ability to cope with a second challenge experienced later in life.
A New Instrument to Assess Children’s Understanding of Death: Psychometrical Properties of the EsCoMu Scale in a Sample of Spanish Children
Authors: Fernández-Alcántara Manuel , de los Santos-Roig Macarena , Pérez-Marfil María Nieves , Cruz-Quintana Francisco , Vázquez-Sánchez Juan Manuel , Montoya-Juárez Rafael
Published: February 2021

The acquisition of the death concept in children may influence how these children cope with the losses that they will confront throughout their lives. At the present time, there is a lack of psychometric instruments in Spanish-speaking countries in order to evaluate the components of the death concept in children. The aim of this study was to create and validate a scale (EsCoMu-Escala sobre el Concepto de Muerte) in order to provide insight about the concept of death in children. The sample was formed by 358 children from ages 6 to 13 years. The final EsCoMu version has 27 items which serve to evaluate universality, irreversibility, non-functionality and causality. The results of the confirmatory factor analysis show an adequate fit index for the four dimensions model, reliability (α = 83) and validity evidence, specifically based on the children’s age. In conclusion, EsCoMu is an instrument that shows adequate reliability and validity indices in order to assess the concept of death and its four components among children. Due to its simplicity, this instrument can be very useful if applied to the field of neurodevelopmental disorders.
Influence of Substrate Temperature on Electrical and Optical Properties of Hydrogenated Boron Carbide Thin Films Deposited by RF Sputtering
Authors: Nehate Shraddha Dhanraj , Saikumar Ashwin Kumar , Sundaram Kalpathy B.
Published: February 2021

Amorphous hydrogenated boron carbide films were deposited on silicon and glass substrates using radio frequency sputtering. The substrate temperature was varied from room temperature to 300 °C. The substrate temperature during deposition was found to have significant effects on the electrical and optical properties of the deposited films. X-ray photoelectron spectroscopy (XPS) revealed an increase in sp2-bonded carbon in the films with increasing substrate temperature. Reflection electron energy loss spectroscopy (REELS) was performed in order to detect the presence of hydrogen in the films. Metal-insulator-metal (MIM) structure was developed using Al and hydrogenated boron carbide to measure dielectric value and resistivity. Deposited films exhibited lower dielectric values than pure boron carbide films. With higher substrate deposition temperature, a decreasing trend in dielectric value and resistivity of the films was observed. For different substrate temperatures, the dielectric value of films ranged from 6.5–3.5, and optical bandgap values were between 2.25–2.6 eV.
Diagnosing Burn Wounds Infection: The Practice Gap & Advances with MolecuLight Bacterial Imaging
Authors: Farhan Nawras , Jeffery Steven
Published: February 2021

Burn injuries constitute a critical economic burden on healthcare infrastructures worldwide. They are often associated with high mortality rates due to severe complications. Infection is the most common complication, highlighting the importance of prompt and precise diagnosis in order to prevent detrimental consequences and to optimize patient outcomes. Here we examine the current standard of care for diagnosing infection in both burn and chronic wounds followed by an investigation into the research surrounding a relatively new technique for bacterial detection, fluorescence imaging. With five years of published research on bacterial fluorescence imaging (MolecuLight i:X device), we have summarized and analysed the validity of the procedure and compared it to the current standard of care; clinical assessment and microbiological analysis. We highlight the benefits that could be obtained through the use of this technology as well as the limitations and the feasibility of incorporating this novel procedure into the standard of care.