bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiparametric Circulating Tumor Cell Analysis to Select Targeted Therapies for Breast Cancer Patients
Authors: Franken André , Behrens Bianca , Reinhardt Florian , Yang Liwen , Rivandi Mahdi , Marass Francesco , Jaeger Bernadette , Krawczyk Natalia , Cieslik Jan-Philipp , Honisch Ellen , Asperger Hannah , Jeannot Emmanuelle , Proudhon Charlotte , Beerenwinkel Niko , Schölermann Natali , Esposito Irene , Dietzel Frederic , Stoecklein Nikolas H. , Niederacher Dieter , Fehm Tanja , Neubauer Hans
Published: November 2021

Background: The analysis of liquid biopsies, e.g., circulating tumor cells (CTCs) is an appealing diagnostic concept for targeted therapy selection. In this proof-of-concept study, we aimed to perform multiparametric analyses of CTCs to select targeted therapies for metastatic breast cancer patients. Methods: First, CTCs of five metastatic breast cancer patients were analyzed by whole exome sequencing (WES). Based on the results, one patient was selected and monitored by longitudinal and multiparametric liquid biopsy analyses over more than three years, including WES, RNA profiling, and in vitro drug testing of CTCs. Results: Mutations addressable by targeted therapies were detected in all patients, including mutations that were not detected in biopsies of the primary tumor. For the index patient, the clonal evolution of the tumor cells was retraced and resistance mechanisms were identified. The AKT1 E17K mutation was uncovered as the driver of the metastatic process. Drug testing on the patient’s CTCs confirmed the efficacy of drugs targeting the AKT1 pathway. During a targeted therapy chosen based on the CTC characterization and including the mTOR inhibitor everolimus, CTC numbers dropped by 97.3% and the disease remained stable as determined by computer tomography/magnetic resonance imaging. Conclusion: These results illustrate the strength of a multiparametric CTC analysis to choose and validate targeted therapies to optimize cancer treatment in the future. Furthermore, from a scientific point of view, such studies promote the understanding of the biology of CTCs during different treatment regimens.
Impact of DNA Damage Response—Targeted Therapies on the Immune Response to Tumours
Authors: Lutfi Nura , Galindo-Campos Miguel Alejandro , Yélamos José
Published: November 2021

The DNA damage response (DDR) maintains the stability of a genome faced with genotoxic insults (exogenous or endogenous), and aberrations of the DDR are a hallmark of cancer cells. These cancer-specific DDR defects present new therapeutic opportunities, and different compounds that inhibit key components of DDR have been approved for clinical use or are in various stages of clinical trials. Although the therapeutic rationale of these DDR-targeted agents initially focused on their action against tumour cells themselves, these agents might also impact the crosstalk between tumour cells and the immune system, which can facilitate or impede tumour progression. In this review, we summarise recent data on how DDR-targeted agents can affect the interactions between tumour cells and the components of the immune system, both by acting directly on the immune cells themselves and by altering the expression of different molecules and pathways in tumour cells that are critical for their relationship with the immune system. Obtaining an in-depth understanding of the mechanisms behind how DDR-targeted therapies affect the immune system, and their crosstalk with tumour cells, may provide invaluable clues for the rational development of new therapeutic strategies in cancer.
Molecular and Cellular Mechanisms of Perineural Invasion in Oral Squamous Cell Carcinoma: Potential Targets for Therapeutic Intervention
Authors: Misztal Carly I. , Green Carlos , Mei Christine , Bhatia Rita , Velez Torres Jaylou M. , Kamrava Brandon , Moon Seo , Nicolli Elizabeth , Weed Donald , Sargi Zoukaa , Dinh Christine T.
Published: November 2021

The most common oral cavity cancer is squamous cell carcinoma (SCC), of which perineural invasion (PNI) is a significant prognostic factor associated with decreased survival and an increased rate of locoregional recurrence. In the classical theory of PNI, cancer was believed to invade nerves directly through the path of least resistance in the perineural space; however, more recent evidence suggests that PNI requires reciprocal signaling interactions between tumor cells and nerve components, particularly Schwann cells. Specifically, head and neck SCC can express neurotrophins and neurotrophin receptors that may contribute to cancer migration towards nerves, PNI, and neuritogenesis towards cancer. Through reciprocal signaling, recent studies also suggest that Schwann cells may play an important role in promoting PNI by migrating toward cancer cells, intercalating, and dispersing cancer, and facilitating cancer migration toward nerves. The interactions of neurotrophins with their high affinity receptors is a new area of interest in the development of pharmaceutical therapies for many types of cancer. In this comprehensive review, we discuss diagnosis and treatment of oral cavity SCC, how PNI affects locoregional recurrence and survival, and the impact of adjuvant therapies on tumors with PNI. We also describe the molecular and cellular mechanisms associated with PNI, including the expression of neurotrophins and their receptors, and highlight potential targets for therapeutic intervention for PNI in oral SCC.
The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance
Authors: Retecki Kuba , Seweryn Milena , Graczyk-Jarzynka Agnieszka , Bajor Malgorzata
Published: November 2021

Breast cancer (BC) has traditionally been considered to be not inherently immunogenic and insufficiently represented by immune cell infiltrates. Therefore, for a long time, it was thought that the immunotherapies targeting this type of cancer and its microenvironment were not justified and would not bring benefits for breast cancer patients. Nevertheless, to date, a considerable number of reports have indicated tumor-infiltrating lymphocytes (TILs) as a prognostic and clinically relevant biomarker in breast cancer. A high TILs expression has been demonstrated in primary tumors, of both, HER2-positive BC and triple-negative (TNBC), of patients before treatment, as well as after treatment with adjuvant and neoadjuvant chemotherapy. Another milestone was reached in advanced TNBC immunotherapy with the help of the immune checkpoint inhibitors directed against the PD-L1 molecule. Although those findings, together with the recent developments in chimeric antigen receptor T cell therapies, show immense promise for significant advancements in breast cancer treatments, there are still various obstacles to the optimal activity of immunotherapeutics in BC treatment. Of these, the immunosuppressive tumor microenvironment constitutes a key barrier that greatly hinders the success of immunotherapies in the most aggressive types of breast cancer, HER2-positive and TNBC. Therefore, the improvement of the current and the demand for the development of new immunotherapeutic strategies is strongly warranted.
Her2 Expression in Circulating Tumor Cells Is Associated with Poor Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer
Authors: Maillet Denis , Allioli Nathalie , Péron Julien , Plesa Adriana , Decaussin-Petrucci Myriam , Tartas Sophie , Sajous Christophe , Ruffion Alain , Crouzet Sébastien , Freyer Gilles , Vlaeminck-Guillem Virginie
Published: November 2021

HER2-dependent signaling may support the development of metastatic castration-resistant prostate cancer (mCRPC) by activating androgen receptor signaling through ligand-independent mechanisms. From 41 mCRPC patients (including 31 treated with Androgen Receptor Signaling Inhibitors [ARSI]), Circulating Tumor Cells (CTCs) were prospectively enriched with AdnaTest platform and analyzed with a multiplexed assay for HER2 and AR-V7 mRNA expression. Then, we evaluated the impact of HER2 expression on PSA-response, Progression Free Survival (PFS) and Overall Survival (OS). HER2 expression was detected in CTCs of 26 patients (63%). Although PSA response was similar regardless of HER2 status, patients with HER2 positive CTCs had shorter PSA-PFS (median: 6.2 months versus 13.0 months, p = 0.034) and radiological-PFS (6.8 months versus 25.6 months, p = 0.022) than patients without HER2 expression. HER2 expression was also associated with a shorter OS (22.7 months versus not reached, p = 0.05). In patients treated with ARSI, multivariate analyses revealed that the prognostic impact of HER2 status on PSA-PFS was independent of AR-V7 expression and of the detection of CTCs by an AdnaTest. We showed for the first time the poor prognostic value of HER2 expression in CTCs from patients with mCRPC. The therapeutic interest of targeting this actionable pathway remains to be explored.
Checkpoint Inhibition in Bladder Cancer: Clinical Expectations, Current Evidence, and Proposal of Future Strategies Based on a Tumor-Specific Immunobiological Approach
Authors: Mancini Mariangela , Righetto Marialaura , Noessner Elfriede
Published: November 2021

In contrast with other strategies, immunotherapy is the only treatment aimed at empowering the immune system to increase the response against tumor growth. Immunotherapy has a role in the treatment of bladder cancer (BC) due to these tumors’ high tumor mutational burden (TMB) and mostly prominent immune infiltrate. The therapy or combination has to be adjusted to the tumor’s immunobiology. Recently, a new class of immunotherapeutic agents, immune checkpoint inhibitors (ICI), has shown potential in increasing treatment chances for patients with genitourinary cancers, improving their oncological outcomes. The clinical efficacy of ICI has been shown in both the first-line treatment of cisplatin-ineligible patients, with programmed death ligand 1 (PD-L1)-positive tumors (atezolizumab, pembrolizumab), and in second-line settings, for progression after platinum-based chemotherapy (atezolizumab, pembrolizumab, and nivolumab for FDA and EMA; durvalumab and avelumab for FDA alone). Predicting the response to ICI is important since only a subset of patients undergoing ICI therapy develop a concrete and lasting response. Most of the patients require a different therapy or therapy combination to achieve tumor control. The cancer immunity cycle provides a conceptual framework to assist therapy selection. Biomarkers to predict response to ICI must identify where the cancer immunity cycle is disrupted. We reviewed the current knowledge on ICI treatment in BC, going from basic science to current data and available clinical evidence. Secondly, a critical analysis of published data is provided, and an original panel of biomarkers able to predict response to ICI treatment, based on tumor-specific immune profiling, is proposed.
NTRK1/TrkA Activation Overrides the G2/M-Checkpoint upon Irradiation
Authors: Hassiepen Christina , Soni Aashish , Rudolf Ines , Boron Vivian , Oeck Sebastian , Iliakis George , Schramm Alexander
Published: November 2021

High expression of the receptor tyrosine kinase TrkA/NTRK1 is associated with a favorable outcome in several solid tumors of childhood including neuroblastoma. During development, TrkA/NTRK1 governs migration and differentiation of neuronal precursor cells, while it is associated with mitotic dysfunction and altered DNA damage response, among others, in neuroblastoma. Here, we used human neuroblastoma cell lines with inducible TrkA/NTRK1 expression to mechanistically explore the role of TrkA/NTRK1 signaling in checkpoint activation after DNA damage induced by ionizing radiation (IR). TrkA/NTRK1 activated cells showed increased short-term cell viability upon IR compared to vector control cells. This was accompanied by a deficient G2/M-checkpoint at both low (1 Gy) and high doses (4 Gy) of IR. In a tightly controlled setting, we confirmed that this effect was strictly dependent on activation of TrkA/NTRK1 by its ligand, nerve growth factor (NGF). TrkA/NTRK1-expressing cells displayed impaired ATM and CHK1 phosphorylation, resulting in stabilization of CDC25B. In line with these findings, ATM or ATR inhibition recapitulated the effects of TrkA/NTRK1 activation on the IR-induced G2/M-checkpoint. In conclusion, we here provide first evidence for a previously unrecognized function of NTRK signaling in checkpoint regulation and the response to IR.
Porous Hexacyanometallate(III) Complexes as Catalysts in the Ring-Opening Copolymerization of CO2 and Propylene Oxide
Authors: Penche Guillermo , González-Velasco Juan R. , González-Marcos M. Pilar
Published: November 2021

In this work, six porous hexacyanometallate complexes (Ni3[Co(CN)6]2, Co3[Co(CN)6]2, Fe3[Co(CN)6]2, Ni3[Fe(CN)6]2, Co3[Fe(CN)6]2, Fe4[Fe(CN)6]2) were synthesized by a complexing agent assisted coprecipitation method and thoroughly characterized via X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), in situ high-temperature X-ray diffraction (HT-XRD), elemental analysis (EA), X-ray fluorescence (XRF), scanning electron microscopy (SEM), transmission electron microscopy (TEM), N2 physisorption, and gas–solid phase titration with NH3. The thermal stability, chemical composition, pore size and volume, crystallite size and density of surface acid sites were strongly sensitive to both the transition metal and the cyanometallate anion employed. On that basis, transition metal hexacyanometallates must be perceived as an adaptable class of zeolite-like microporous materials. The catalytic properties of these compounds were tested by copolymerization of propylene oxide and CO2, a green route to obtain biodegradable aliphatic polycarbonates. All compounds under study showed moderate activity in the target reaction. The obtained copolymers were characterized by modest CO2 content (carbonate units ranging from 16 to 33%), random structure (RPEC ≈ 70%), and moderate molecular weight (Mw = 6000–85,400 g/mol) with broad dispersity values (ĐM = 4.1–15.8).
Modification of Cobalt Oxide Electrochemically Deposited on Stainless Steel Meshes with Co-Mn Thin Films Prepared by Magnetron Sputtering: Effect of Preparation Method and Application to Ethanol Oxidation
Authors: Jirátová Květa , Perekrestov Roman , Dvořáková Michaela , Balabánová Jana , Koštejn Martin , Veselý Martin , Čada Martin , Topka Pavel , Pokorná Dana , Hubička Zdeněk , Kovanda František
Published: November 2021

Magnetron sputtering is an advantageous method for preparing catalysts supported on stainless steel meshes. Such catalysts are particularly suitable for processes carried out at high space velocities. One of these is the catalytic total oxidation of volatile organic compounds (VOC), economically feasible and environmentally friendly method of VOC abatement. The reactive radio frequency (RF) magnetron sputtering of Mn and Co + Mn mixtures in an oxidation Ar + O2 atmosphere was applied to form additional thin oxide coatings on cobalt oxide layers prepared by electrochemical deposition and heating on stainless steel meshes. Time of the RF magnetron sputtering was changed to obtain MnOx and CoMnOx coatings of various thickness (0.1–0.3 µm). The properties of the supported CoOx-MnOx and CoOx-CoMnOx catalysts were characterized by scanning electron microscopy (SEM), powder X-ray diffraction (XRD), temperature programmed reduction (H2-TPR), Fourier-transform infrared (FTIR) and Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS). The catalytic activity was investigated in the deep oxidation of ethanol, which was employed as a model VOC. According to the specific activities (amount of ethanol converted per unit mass of metal oxides per hour), the performance of CoOx-MnOx catalysts was higher than that of CoOx-CoMnOx ones. The catalysts with the smallest layer thickness (0.1 µm) showed the highest catalytic activity. Compared to the commercial pelletized Co-Mn-Al mixed oxide catalyst, the sputtered catalysts exhibited considerably higher (23–87 times) catalytic activity despite the more than 360–570 times lower content of the Co and Mn active components in the catalytic bed.
TBO Degradation by Heterogeneous Fenton-like Reaction Using Fe Supported over Activated Carbon
Authors: Samir Brahim , Bakhta Soumia , Bouazizi Nabil , Sadaoui Zahra , Allalou Ouiza , Le Derf Franck , Vieillard Julien
Published: November 2021

This study reports on the synthesis, immobilization, and stabilization of iron (Fe) particles in activated carbon (AC) from date stem material for the heterogeneous Fenton-like removal of hazardous pollutants from water. AC-Fe was synthesized through a simple and sustainable chemical reaction using and resulting in an environmentally friendly material (AC-Fe). X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS) and energy-dispersive X-ray analyses (EDX) were used to characterize the synthesized samples. XRD, FTIR and XPS results showed the successful incorporation of iron particles onto AC. SEM images indicated smooth surfaces with clearly visible Fe particles. Compared to pure AC, AC-Fe showed higher degradation rates of toluidine blue O (TBO) dye. The effects of the initial pH and TBO and H2O2 concentrations on TBO degradation were investigated. The AC-Fe catalyst proved highly efficient in the Fenton-like degradation of TBO (50 ppm), with the removal of up to 99% in 3 min. This catalyst was used efficiently for up to four repeated cycles. The improved catalytic activity of AC-Fe was related to Fe particles for the generation of HO•. These results prove that date stems—a waste product from agriculture—are a suitable precursor for preparing an appropriate AC and catalyst and for eliminating dyes from an aqueous solution by a heterogeneous Fenton-like reaction. The above results open an interesting avenue for the development of functional green catalysts based on AC-Fe for pollution removal.
C-C Motif Chemokine Ligand-17 as a Novel Biomarker and Regulator of Epithelial Mesenchymal Transition in Renal Fibrogenesis
Authors: Hsieh Yi-Hsien , Wang Wen-Chien , Hung Tung-Wei , Lee Chu-Che , Tsai Jen-Pi
Published: November 2021

CCL17, a chemotactic cytokine produced by macrophages, is known to promote inflammatory and fibrotic effects in multiple organs, but its role in mediating renal fibrosis is unclear. In our study cohort of 234 chronic kidney disease (CKD) patients and 65 healthy controls, human cytokine array analysis revealed elevated CCL17 expression in CKD that correlated negatively with renal function. The area under the receiver operating characteristic curve of CCL17 to predict the development of CKD stages 3b–5 was 0.644 (p < 0.001), with the optimal cut-off value of 415.3 ng/mL. In vitro over-expression of CCL17 in HK2 cells had no effect on cell viability, but increased cell motility and the expression of α-SMA, vimentin and collagen I, as shown by western blot analysis. In a unilateral ureteral obstruction (UUO) mouse model, we observed significantly increased interstitial fibrosis and renal tubule dilatation by Masson’s Trichrome and H&E staining, and markedly increased expression of CCL17, vimentin, collagen I, and α-SMA by IHC stain, qRTPCR, and western blotting. CCL17 induced renal fibrosis by promoting the epithelial-mesenchymal transition, resulting in ECM accumulation. CCL17 may be a useful biomarker for predicting the development of advanced CKD.
Alterations in Immune Response Profile of Tumor-Draining Lymph Nodes after High-Intensity Focused Ultrasound Ablation of Breast Cancer Patients
Authors: Zhu Xue-Qiang , Lu Pei , Xu Zhong-Lin , Zhou Qiang , Zhang Jun , Wang Zhi-Biao , Wu Feng
Published: November 2021

Previous studies have revealed that high-intensity focused ultrasound (HIFU) ablation can trigger an antitumor immune response. The aim of this study was to investigate immune response in tumor-draining lymph nodes (TDLNs) after HIFU treatment. Forty-eight female patients with biopsy-confirmed breast cancer were divided into a control group and an HIFU group. In the control group, 25 patients underwent modified radical mastectomy, but 23 patients in the HIFU group received HIFU ablation of primary cancer, followed by the same operation. Using HE and immunohistochemical staining, the immunologic reactivity pattern and immune cell profile were assessed in paraffin-embedded axillary lymph nodes (ALNs) in all patients. The results showed that ALNs presented more evident immune reactions in the HIFU group than in the control group (100% vs. 64%). Among the ALNs, 78.3% had mixed cellular and humoral immune response, whereas 36% in the control group showed cellular immune response. The numbers of CD3+, CD4+, NK cell, and activated CTLs with Fas ligand+, granzyme+ and perforin+ expression were significantly higher in the ALNs in the HIFU group. It was concluded that HIFU could stimulate potent immune response and significantly increase T cell, activated CTLs and NK cell populations in the TDLNs of breast cancer.
Genetic and Epigenetic Targeting Therapy for Pediatric Acute Lymphoblastic Leukemia
Authors: Xu Huan , Yu Hui , Jin Runming , Wu Xiaoyan , Chen Hongbo
Published: November 2021

Acute lymphoblastic leukemia is the most common malignancy in children and is characterized by numerous genetic and epigenetic abnormalities. Epigenetic mechanisms, including DNA methylations and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. Emerging studies are increasing our understanding of the epigenetic role of leukemogenesis and have demonstrated the potential of DNA methylations and histone modifications as a biomarker for lineage and subtypes classification, predicting relapse, and disease progression in acute lymphoblastic leukemia. Epigenetic abnormalities are relatively reversible when treated with some small molecule-based agents compared to genetic alterations. In this review, we conclude the genetic and epigenetic characteristics in ALL and discuss the future role of DNA methylation and histone modifications in predicting relapse, finally focus on the individual and precision therapy targeting epigenetic alterations.
Role of ADGRG1/GPR56 in Tumor Progression
Authors: Ng Kwai-Fong , Chen Tse-Ching , Stacey Martin , Lin Hsi-Hsien
Published: November 2021

Cellular communication plays a critical role in diverse aspects of tumorigenesis including tumor cell growth/death, adhesion/detachment, migration/invasion, angiogenesis, and metastasis. G protein-coupled receptors (GPCRs) which constitute the largest group of cell surface receptors are known to play fundamental roles in all these processes. When considering the importance of GPCRs in tumorigenesis, the adhesion GPCRs (aGPCRs) are unique due to their hybrid structural organization of a long extracellular cell-adhesive domain and a seven-transmembrane signaling domain. Indeed, aGPCRs have been increasingly shown to be associated with tumor development by participating in tumor cell interaction and signaling. ADGRG1/GPR56, a representative tumor-associated aGPCR, is recognized as a potential biomarker/prognostic factor of specific cancer types with both tumor-suppressive and tumor-promoting functions. We summarize herein the latest findings of the role of ADGRG1/GPR56 in tumor progression.
Chimeric Antigen Receptors Expand the Repertoire of Antigenic Macromolecules for Cellular Immunity
Authors: Keane John T. , Posey Avery D.
Published: November 2021

T-cell therapies have made significant improvements in cancer treatment over the last decade. One cellular therapy utilizing T-cells involves the use of a chimeric MHC-independent antigen-recognition receptor, typically referred to as a chimeric antigen receptor (CAR). CAR molecules, while mostly limited to the recognition of antigens on the surface of tumor cells, can also be utilized to exploit the diverse repertoire of macromolecules targetable by antibodies, which are incorporated into the CAR design. Leaning into this expansion of target macromolecules will enhance the diversity of antigens T-cells can target and may improve the tumor-specificity of CAR T-cell therapy. This review explores the types of macromolecules targetable by T-cells through endogenous and synthetic antigen-specific receptors.
Recent Studies on the Fabrication of Multilayer Films by Magnetron Sputtering and Their Irradiation Behaviors
Authors: Ni Jinyang , Li Jin , Jian Jie , He Jianchao , Chen Hongsheng , Leng Xuesong , Liu Xiangli
Published: November 2021

Multilayer films with high-density layer interfaces have been studied widely because of the unique mechanical and functional properties. Magnetron sputtering is widely chosen to fabricate multilayer films because of the convenience in controlling the microstructure. Essentially, the properties of multilayer films are decided by the microstructure, which could be adjusted by manipulating the deposition parameters, such as deposition temperature, rate, bias, and target–substrate distance, during the sputter process. In this review, the influences of the deposition parameters on the microstructure evolution of the multilayer films have been summarized. Additionally, the impacts of individual layer thickness on the microstructure evolution as well as the irradiation behavior of various multilayer films have been discussed.
Linear Electron Beam Assisted Roll-to-Roll in-Vacuum Flexographic Patterning for Flexible Thermoelectric Generators
Authors: Stuart Bryan W. , Morgan Katrina , Tao Xudong , Zeimpekis Ioannis , Feng Zhuo , Gregory Daniel , Assender Hazel E.
Published: November 2021

In this work, we investigated the use of in-line linear electron beam irradiation (LEB) surface treatment integrated into a commercially compatible roll-to-roll (R2R) processing line, as a single fluorocarbon cleaning step, following flexography oil masking used to pattern layers for devices. Thermoelectric generators (TEGs) were selected as the flexible electronic device demonstrator; a green renewable energy harvester ideal for powering wearable technologies. BiTe/BiSbTe-based flexible TEGs (f-TEGs) were fabricated using in-line oil patterned aluminium electrodes, followed by a 600 W LEB cleaning step, in which the duration was optimised. A BiTe/BiSbTe f-TEG using an oil-patterned electrode and a 15 min LEB clean (to remove oil prior to BiTe/BiSbTe deposition) showed similar Seebeck and output power (S ~ 0.19 mV K−1 and p = 0.02 nW at ΔT = 20 K) compared to that of an oil-free reference f-TEG, demonstrating the success of using the LEB as a cleaning step to prevent any remaining oil interfering with the subsequent active material deposition. Device lifetimes were investigated, with electrode/thermoelectric interface degradation attributed to an aluminium/fluorine reaction, originating from the fluorine-rich masking oil. A BiTe/GeTe f-TEG using an oil-patterned/LEB clean, exceeded the lifetime of the comparable BiTe/BiSbTe f-TEG, highlighting the importance of deposited material reactivities with the additives from the masking oil, in this case fluorine. This work therefore demonstrates (i) full device architectures within a R2R system using vacuum flexography oil patterned electrodes; (ii) an enabling Electron beam cleansing step for removal of oil remnants; and (iii) that careful selection of masking oils is needed for the materials used when flexographic patterning during R2R.
Investigation of Properties of the Zr,Hf-(Zr,Hf)N-(Zr,Hf,Me,Al)N Coatings, Where Me Means Cr, Ti, or Mo
Authors: Vereschaka Alexey , Sitnikov Nikolay , Volosova Marina , Seleznev Anton , Sotova Catherine , Bublikov Jury
Published: November 2021

The article describes the results of the investigation focused on the properties of the Zr,Hf-(Zr,Hf)N-(Zr,Hf,Me,Al)N coatings, where Me means chromium (Cr), titanium (Ti), or molybdenum (Mo). These coatings have three-layer architecture, including adhesion, transition, and wear-resistant layers, while the latter, in turn, has a nanolayer structure. Despite the fact that the coatings under study have close values of hardness and critical fracture load LC2, there are noticeable differences in wear resistance during the turning of steel. The tools with the coatings under study demonstrated better wear resistance compared to an uncoated tool and the tool with the commercial ZrN coating. The best wear resistance was detected for a tool with the Zr,Hf-(Zr,Hf)N-(Zr,Hf,Ti,Al)N coating. The study of the pattern of cracking in the structure of the coatings has found that, during the cutting process, active cracking occurs in the coating with Cr, which leads to the fracture of the coating, while the process of cracking is noticeably less active in the coatings with Ti or Mo.
Implementation of Augmented Reality in a Mechanical Engineering Training Context
Authors: Scaravetti Dominique , François Rémy
Published: November 2021

Global industry is at the heart of its fourth industrial revolution, being driven by the emergence of new digital solutions: Augmented reality allows us to consider the evolution towards the “the augmented operator”. This technology is currently little used in higher education, especially for mechanical engineers. We believe that it can facilitate learning and develop autonomy. The objective of this work is to assess the relevance of augmented reality in this context, as well as its impact on learning. The difficulties for a student approaching a technical system are related to reading and understanding 2D and even 3D representations, lack of knowledge on components functions, and the analysis of the chain of power transmission and transformation of movement. The research is intended to see if AR technologies are relevant to answer these issues and help beginners get started. To that end, several AR scenarios have been developed on different mechanical systems, using the relevant features of the AR interfaces that we have identified. Otherwise, these experiences have enabled us to identify specific issues linked to the implementation of AR. Our choice of AR devices and software allows us to have an integrated digital chain with digital tools and files used by mechanical engineers. Finally, we sought to assess how this technology made it possible to overcome the difficulties of learners, in different learning situations.
Recent Progress in Flexible Graphene-Based Composite Fiber Electrodes for Supercapacitors
Authors: Wu Songmei
Published: November 2021

Graphene has shown the world its fascinating properties, including high specific surface area, high conductivity, and extraordinary mechanical properties, which enable graphene to be a competent candidate for electrode materials. However, some challenges remain in the real applications of graphene-based electrodes, such as continuous preparation of graphene fibers with highly ordered graphene sheets as well as strong interlayer interactions. The combination of graphene with other materials or functional guests hence appears as a more promising pathway via post-treatment and in situ hybridism to produce composite fibers. This article firstly provides a full account of the classification of graphene-based composite fiber electrodes, including carbon allotropy, conductive polymer, metal oxide and other two-dimensional (2D) materials. The preparation methods of graphene-based composite fibers are then discussed in detail. The context further demonstrates the performance optimization of graphene-based composite fiber electrodes, involving microstructure design and surface modification, followed by the elaboration of the application of graphene-based composite fiber electrodes in supercapacitors. Finally, we present the remaining challenges that exist to date in order to provide meaningful guidelines in the development process and prospects of graphene-based composite fiber electrodes.
Addition of Salvage Immunotherapy to Targeted Therapy in Patients with Metastatic Renal Cell Carcinoma
Authors: Dawsey Scott J. , Ornstein Moshe C.
Published: November 2021

There have been significant advances in the treatment of metastatic renal cell carcinoma (mRCC), with immunotherapy (IO)-based combinations as the standard-of-care treatment in the front-line setting. IO in this setting is paired with another IO agent or with a vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitor (TKI). One IO/IO combination and four IO/TKI combinations are currently approved. However, the role of the salvage IO in patients with disease progression on TKI monotherapy is uncertain. Here, we present a case series of five patients who were on single-agent TKI therapy for treatment-refractory mRCC and upon disease progression had an IO agent added to their TKI. The median duration of TKI monotherapy was 11.2 months (range, 1.7–31.1 months), and the median duration of response after the addition of IO was 4 months (range, 2.8–10.5 months). Although IO salvage therapy has a plausible rationale, this case series did not show a clear benefit to this approach. Further clinical trials are needed to determine the clinical utility of IO salvage therapy in mRCC.
Subtle East–West Phylogeographic Break of Asteropyrum (Ranunculaceae) in Subtropical China and Adjacent Areas
Authors: Cheng Shanmei , Zeng Weidong , Fan Dengmei , Liang Hua , Yang Yi , Kou Yixuan , Zhang Zhiyong
Published: November 2021

East–west phylogeographic break is common among plant species in subtropical China. However, the estimation time of east–west phylogeographic break has always relied on inferences of calibrated phylogenies, and the contribution of environmental heterogeneity to population differentiation has largely been ignored. In this study, we estimated the divergence time of Asteropyrum populations through coalescent-based approaches based on DNA sequences of ten nuclear loci and evaluated the contribution of environmental heterogeneity to population differentiation. The results showed that there were two chloroplast clades and nuclear groups within Asteropyrum, displaying a subtle pattern of east–west differentiation. The divergence time of the two nuclear groups was dated to ~1.2 Ma, which is associated with climate changes during the Mid-Pleistocene transition. A genetic admixture event between the two genetic groups happened at ~0.46 Ma, resulting in several admixed populations. Isolation by environmental distance (IBE) explained the majority (46.32%) of population differentiation, but that isolation by geographic distance (IBD) only contributed 4.66%. The results of this study suggest that climate changes during the Pleistocene may be a major cause for the east–west phylogeographic break in subtropical China. However, the complex terrain and high environmental heterogeneity in the west of subtropical China (and adjacent regions such as the Hengduan Mountains and the Himalayan Moutains) caused by strong geological uplift may have profoundly shaped the population structure of plant species in subtropical China.
White Blood Cell Scintigraphy for Fracture-Related Infection: Is Semiquantitative Analysis of Equivocal Scans Accurate?
Authors: Bosch Paul , IJpma Frank F.A. , Govaert Geertje A.M. , Reininga Inge H.F. , de Vries Jean-Paul P.M. , Glaudemans Andor W. J. M.
Published: November 2021

Purpose: White blood cell (WBC) scintigraphy is considered the gold-standard nuclear imaging technique for diagnosing fracture-related infection (FRI). Correct interpretation of WBC scans in FRI is important since a false positive or false negative diagnosis has major consequences for the patient in terms of clinical decision-making. The European Association of Nuclear Medicine (EANM) guideline for correct analysis and interpretation of WBC scans recommends semiquantitative analysis of visually equivocal scans. Therefore, this study aims to assess the diagnostic accuracy of semiquantitative analysis of visually equivocal WBC scans for diagnosing FRI. Methods: A retrospective single-center study was performed in consecutive patients who received WBC scintigraphy in the diagnostic work-up for FRI between February 2012 and January 2017. All the visually equivocal scans were analysed using semiquantitative analysis by comparing leukocyte uptake in the manually selected suspected infection focus with the contralateral bone marrow (L/R ratio). Cut-off points for a ‘positive’ scan result of >0%, >10% and >20% leukocyte increase between the early and late scans were used in separate analyses. The discriminative ability was quantified by calculating the sensitivity, specificity and diagnostic accuracy. Results: In total, 153 WBC scans were eligible for inclusion. After visual assessment of all the scans, 28 visually equivocal scans were included. Dichotomization of the ratios using the cut-off of >0% resulted in a sensitivity of 30%, a specificity of 45% and a diagnostic accuracy of 40%. The >10% cut-off point resulted in a sensitivity of 18%, a specificity of 82% and a diagnostic accuracy of 66%. The >20% cut-off point resulted in a sensitivity of 0%, a specificity of 89% and a diagnostic accuracy of 67%. Conclusion: Semiquantitative analysis of visually equivocal WBC scans is insufficient for correctly diagnosing FRI.
Natalizumab Induces Changes of Cerebrospinal Fluid Measures in Multiple Sclerosis
Authors: Ganapathy Subramanian Ranjani , Horakova Dana , Vaneckova Manuela , Lorincz Balazs , Krasensky Jan , Kubala Havrdova Eva , Uher Tomas
Published: November 2021

Background: There is a lack of knowledge about the evolution of cerebrospinal fluid (CSF) markers in multiple sclerosis (MS) patients undergoing natalizumab treatment. Aim: We aimed to evaluate the effect of natalizumab on basic inflammatory CSF and MRI measures. Methods: Together, 411 patients were screened for eligibility and 93 subjects with ≥2 CSF examinations ≤6 months before and ≥12 months after natalizumab initiation were recruited. The effect of natalizumab on CSF as well as clinical and paraclinical measures was analyzed using adjusted mixed models. Results: Natalizumab induced a decrease in CSF leukocytes (p < 1 × 10−15), CSF protein (p = 0.00007), the albumin quotient (p = 0.007), the IgG quotient (p = 6 × 10−15), the IgM quotient (p = 0.0002), the IgG index (p = 0.0004), the IgM index (p = 0.003) and the number of CSF-restricted oligoclonal bands (OCBs) (p = 0.0005). CSF-restricted OCBs positivity dropped from 94.6% to 86% but 26 patients (28%) had an increased number of OCBs at the follow-up. The baseline to follow-up EDSS and T2-LV were stable; a decrease in the relapse rate was consistent with a decrease in the CSF inflammatory markers and previous knowledge about the effectiveness of natalizumab. The average annualized brain volume loss during the follow-up was −0.50% (IQR = −0.96, −0.16) and was predicted by the baseline IgM index (B = −0.37; p = 0.003). Conclusions: Natalizumab is associated with a reduction of basic CSF inflammatory measures supporting its strong anti-inflammatory properties. The IgM index at the baseline predicted future brain volume loss during the course of natalizumab treatment.
Depressive and Anxious Symptoms in Hepatitis C Virus Infected Patients Receiving DAA-Based Therapy
Authors: Danilescu Claudia Monica , Sandulescu Daniela Larisa , Pirlog Mihail Cristian , Streba Costin Teodor , Rogoveanu Ion
Published: November 2021

Hepatitis C virus (HCV) represents the most important etiologic factor for advanced fibrosis/cirrhosis and hepatocellular carcinoma associated with a psychological dimension. Our study aims to assess, on a sample comprising of 90 HCV-infected subjects (96.67% F3–F4 METAVIR), the relationship between Direct-Acting Antiviral (DAA) therapies and the psychological effects of the liver disease, focused on the anxious and depressive symptoms. The comprehensive evaluation was done before starting the DAA treatment (BSL), after 12 weeks (End of Treatment—EOT), respectively after another 12 weeks (Sustained Viral Response—SVR). Presumable depressive and/or anxious symptoms were evaluated by Hospital Anxiety and Depression Scale (HADS). The reported depressive symptoms decreased from 21.11% (BSL) to 1.11% (SVR) (p < 0.00001), while the anxious ones dropped from 43.34% (BSL) to 4.44% (SVR) (p < 0.00001), without a clear evolutionary pattern. We identified no statistically significant interaction between comorbidities (anemia, CKD, obesity) over HADS scores evolution (p > 0.05), while the DAAs side-effects (fatigue, headache, pruritus) significantly influenced the anxious and depressive symptoms (p < 0.05). During and after the DAA-based therapy, patients with HCV infection presented a significantly reduced rate of the associated depressive and anxious relevant symptoms.
A Multi-Method Survey on the Use of Sentiment Analysis in Multivariate Financial Time Series Forecasting
Authors: Liapis Charalampos M. , Karanikola Aikaterini , Kotsiantis Sotiris
Published: November 2021

In practice, time series forecasting involves the creation of models that generalize data from past values and produce future predictions. Moreover, regarding financial time series forecasting, it can be assumed that the procedure involves phenomena partly shaped by the social environment. Thus, the present work is concerned with the study of the use of sentiment analysis methods in data extracted from social networks and their utilization in multivariate prediction architectures that involve financial data. Through an extensive experimental process, 22 different input setups using such extracted information were tested, over a total of 16 different datasets, under the schemes of 27 different algorithms. The comparisons were structured under two case studies. The first concerns possible improvements in the performance of the forecasts in light of the use of sentiment analysis systems in time series forecasting. The second, having as a framework all the possible versions of the above configuration, concerns the selection of the methods that perform best. The results, as presented by various illustrations, indicate, on the one hand, the conditional improvement of predictability after the use of specific sentiment setups in long-term forecasts and, on the other, a universal predominance of long short-term memory architectures.
The “Hockey” Assist Makes the Difference—Validation of a Defensive Disruptiveness Model to Evaluate Passing Sequences in Elite Soccer
Authors: Forcher Leander , Kempe Matthias , Altmann Stefan , Forcher Leon , Woll Alexander
Published: November 2021

With the growing availability of position data in sports, spatiotemporal analysis in soccer is a topic of rising interest. The aim of this study is to validate a performance indicator, namely D-Def, measuring passing effectiveness. D-Def calculates the change of the teams’ centroid, centroids of formation lines (e.g., defensive line), teams’ surface area, and teams’ spread in the following three seconds after a pass and therefore results in a measure of disruption of the opponents’ defense following a pass. While this measure was introduced earlier, in this study we aim to prove the usefulness to evaluate attacking sequences. In this study, 258 games of Dutch Eredivisie season 2018/19 were included, resulting in 13,094 attacks. D-Def, pass length, pass velocity, and pass angle of the last four passes of each attack were calculated and compared between successful and unsuccessful attacks. D-Def showed higher values for passes of successful compared to unsuccessful attacks (0.001 < p ≤ 0.029, 0.06 ≤ d ≤ 0.23). This difference showed the highest effects sizes in the penultimate pass (d = 0.23) and the maximal D-Def value of an attack (d = 0.23). Passing length (0.001 < p ≤ 0.236, 0.08 ≤ d ≤ 0.17) and passing velocity (0.001 < p ≤ 0.690, −0.09 ≤ d ≤ 0.12) showed inconsistent results in discriminating between successful and unsuccessful attacks. The results indicate that D-Def is a useful indicator for the measurement of pass effectiveness in attacking sequences, highlighting that successful attacks are connected to disruptive passing. Within successful attacks, at least one high disruptive action (pass with D-Def > 28) needs to be present. In addition, the penultimate pass (“hockey assist”) of an attack seems crucial in characterizing successful attacks.
Deep Dive into Digital Transformation in Higher Education Institutions
Authors: Alenezi Mamdouh
Published: November 2021

In the present times, digital transformation has gained momentum. Contemporary higher education institutions have been embracing new technologies and transforming their practices, business models and process. Digital transformation in the higher education institutions is about the development of new more advanced and effective methods and practices in pursuit of the higher education’s mission. The present paper links digital transformation and higher education institutions. The paper discusses existing models for the incorporation of digital transformation in higher education institutions. The paper also delineates the challenges faced by higher education institutions in pursuit of digital transformation.
Determinants of the Entrepreneurial Influence on Academic Entrepreneurship—Lessons Learned from Higher Education Students in Portugal
Authors: Lopes João M. , Oliveira Márcio , Oliveira José , Sousa Marlene , Santos Tânia , Gomes Sofia
Published: November 2021

Academic entrepreneurship is becoming increasingly important to the field of research as well as to policy makers due to its ability to contribute to the economic, technological, and social development of regions and countries. This research aims to evaluate the determinants that influence the interest of Portuguese higher education students (HEI’s) to become entrepreneurs. The methodology used is quantitative and uses structural model equations. The results obtained demonstrate that the student’s perception of business skills, business growth skills, strategy, and successful business are key factors that students take into account in their entrepreneurial orientation. The research contributes to this theory by adding new knowledge to the literature on the perception of the HEI’s students to become entrepreneurs, specifically the students of Portuguese universities. In practical terms, the contributions offered within this research are based on suggestions for the third mission of universities, explicitly knowledge transfer to the community, business groups, and policy makers, as well as the creation of the essentials within university boundaries to promote entrepreneurship amongst its students. The research is original and innovative, as no research on this field with all the aggregated elements under study has been previously performed in Portugal. Furthermore, the obtained results can translate into ideas that potentially create jobs.
Study and Research Paths to Improve Web-Based Inquiry Learning: Study Case of an ICT Course in Engineering
Authors: Moreno Andreu , Bartolomé Elena
Published: November 2021

Many active, inquiry-based learning activities nowadays rely upon the students’ capacity to perform efficient information research on the Internet. Study and Research Paths (SRPs) have been proposed to model inquiry learning, and successfully used as teaching formats in different areas. In an SRP the search for an answer to a generating question (Q0) leads to a sequence of derived questions and answers, which are modeled using a Q–A map. We have investigated the benefits of using SRPs and Q–A maps to improve Web-based inquiry learning. We designed an SRP for a course on Information and Communication Technologies (ICT), belonging to an Engineering degree. The class-session SRPs revolved around Q0 questions such as ‘What is a «firewall»?’, ‘What are the main features of 5G?’ etc. Our results, based on the analysis of six courses conducted between 2015/16–2020/21, show that the SRP is an enriching tool for learning ICT: content expands beyond that of the traditional course and is maintained up-to-date. Students are engaged and motivated by the active-search activity. In addition, the SRP helps in improving the students’ skills in searching and selecting information on the Internet. The Q–A maps served both the students, to structure their Web inquiry, and the teacher, to monitor the learning study process.