bluuebunny/crossref_metadata_2025 huggingface dataset:
Fuzzy Based Collaborative Task Offloading Scheme in the Densely Deployed Small-Cell Networks with Multi-Access Edge Computing
Authors: Hossain Md Delowar , Sultana Tangina , Nguyen VanDung , Rahman Waqas ur , Nguyen Tri D. T. , Huynh Luan N. T. , Huh Eui-Nam
Published: April 2020

Accelerating the development of the 5G network and Internet of Things (IoT) application, multi-access edge computing (MEC) in a small-cell network (SCN) is designed to provide computation-intensive and latency-sensitive applications through task offloading. However, without collaboration, the resources of a single MEC server are wasted or sometimes overloaded for different service requests and applications; therefore, it increases the user’s task failure rate and task duration. Meanwhile, the distinct MEC server has faced some challenges to determine where the offloaded task will be processed because the system can hardly predict the demand of end-users in advance. As a result, the quality-of-service (QoS) will be deteriorated because of service interruptions, long execution, and waiting time. To improve the QoS, we propose a novel Fuzzy logic-based collaborative task offloading (FCTO) scheme in MEC-enabled densely deployed small-cell networks. In FCTO, the delay sensitivity of the QoS is considered as the Fuzzy input parameter to make a decision where to offload the task is beneficial. The key is to share computation resources with each other and among MEC servers by using fuzzy-logic approach to select a target MEC server for task offloading. As a result, it can accommodate more computation workload in the MEC system and reduce reliance on the remote cloud. The simulation result of the proposed scheme show that our proposed system provides the best performances in all scenarios with different criteria compared with other baseline algorithms in terms of the average task failure rate, task completion time, and server utilization.
Using Data Mining in Educational Administration: A Case Study on Improving School Attendance
Authors: Moodley Raymond , Chiclana Francisco , Carter Jenny , Caraffini Fabio
Published: April 2020

Pupil absenteeism remains a significant problem for schools across the globe with negative impacts on overall pupil performance being well-documented. Whilst all schools continue to emphasize good attendance, some schools still find it difficult to reach the required average attendance, which in the UK is 96%. A novel approach is proposed to help schools improve attendance that leverages the market target model, which is built on association rule mining and probability theory, to target sessions that are most impactful to overall poor attendance. Tests conducted at Willen Primary School, in Milton Keynes, UK, showed that significant improvements can be made to overall attendance, attendance in the target session, and persistent (chronic) absenteeism, through the use of this approach. The paper concludes by discussing school leadership, research implications, and highlights future work which includes the development of a software program that can be rolled-out to other schools.
Optimization of a T-Shaped MIMO Antenna for Reduction of EMI
Authors: Kapoor Dipesh , Sangwan Vivek , Tan Cher Ming , Paliwal Vani , Tanwar Nirdosh
Published: April 2020

In this paper, optimization of a miniaturized multiple-inputs multiple-outputs (MIMO) antenna was performed. This antenna was composed of a T-shape radiating element with stub and reduced ground plane and a compact size of 25 mm × 25 mm × 1.6 mm. The behavior of antenna was evaluated in terms of return loss (S-parameter < −10 dB), electromagnetic interference (EMI), and operation frequency. The antenna design is applicable to many applications. A 2K factorial design combined with a genetic algorithm (GA) optimization technique were used to identify the key design parameters responsible for affecting the performance quality of the antenna. Optimization of the antenna design for EMI reduction was utilized, and the optimal design showed enhanced bandwidth of the antenna and reduced power consumption.
The Use of Neural Networks in Combination with Evolutionary Algorithms to Optimise the Copper Flotation Enrichment Process
Authors: Jamróz Dariusz , Niedoba Tomasz , Pięta Paulina , Surowiak Agnieszka
Published: April 2020

The paper presents a way of combining neural networks with evolutionary algorithms in order to find optimal parameters of the copper flotation enrichment process. The neural network was used in order to build a model describing the flotation process. The network learning was carried out with the use of samples from previous empirical measurements of the actual process. The model created in this way made it possible to find optimal parameters not only from among the measurement spaces, but also those that go beyond the measurements. Then, evolutionary algorithms were used in order to find optimal flotation parameters. The learned neural network previously described was used to calculate the criterion in the evolutionary algorithm.
Railway Lines across the Alps: Analysis of Their Usage through a New Railway Link Cost Function
Authors: Lupi Marino , Pratelli Antonio , Conte Daniele , Farina Alessandro
Published: April 2020

In this paper, the usage of railway lines across the Alps is evaluated, both at present and after the new lines and base tunnels will be in operation. The railway network of a large part of Europe has been modelled through a graph, and the best routes between some of the most important origin/destination pairs in Italy and Europe have been determined. A new cost function has been developed for the links of the network. The proposed cost function is an improvement of those existing in the literature, because all cost components are taken into account in detail, while the traction cost and the number of locomotives utilized explicitly depend on the geometrical characteristics of rail lines. This last aspect is crucial in analyzing the rail lines across the Alps, as they are often operated in double or triple traction. The results of the study show the importance of new Alpine rail lines and base tunnels: the Ceneri base tunnel will remove a bottleneck on the Gotthard line, while the Brenner and Frejus base tunnels will take up a quota of demand currently served by other lines. Moreover, the new Alpine lines will create an east–west rail connection, through the Italian Padan Plain, alternative to the rail route which currently bypasses the Alps to the north.
Impact of Fake Below-Ground Meridional Wind on Hadley Circulation: Climatology, Interannual Variability, and Long-Term Trends
Authors: Cheng Jianbo , Xu Zhihang , Hou Xiaoya
Published: April 2020

The fake below-ground meridional wind (FBGMW) exists in reanalysis products which is not present in the real atmosphere and should be removed before calculating the mass stream function (MSF). In this study, the impacts of FBGMW on Hadley circulation (HC) in terms of climatology, interannual variability, and long-term trends were investigated using five reanalysis data sets based on three different computing methods. Generally, the impacts of FBGMW on the HC are most notable, although the absolute magnitude of the FBGMW is rather small. The key finding of this study is that the FBGMW has vital influences on the Northern Hemisphere (NH) HC during boreal summer. This is because the NH HC during boreal summer is very weak; the errors of the MSF caused by not considering FBGMW have more obvious influences on the NH HC during boreal summer than that in other months. The previous analysis without considering FBGMW led to overestimation of the poleward expansion of the NH HC during boreal summer, and the long-term trends of the HC should be more accurately estimated after considering the FBGMW. This finding suggests that the previous studies related to the NH HC during boreal summer without considering FBGMW should be reconsidered.
Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18
Authors: Neumann Alexander , Engel Viktor , Mahardhika Andhika B. , Schoeder Clara T. , Namasivayam Vigneshwaran , Kieć-Kononowicz Katarzyna , Müller Christa E.
Published: April 2020

GPR18 is an orphan G protein-coupled receptor (GPCR) expressed in cells of the immune system. It is activated by the cannabinoid receptor (CB) agonist ∆9-tetrahydrocannabinol (THC). Several further lipids have been proposed to act as GPR18 agonists, but these results still require unambiguous confirmation. In the present study, we constructed a homology model of the human GPR18 based on an ensemble of three GPCR crystal structures to investigate the binding modes of the agonist THC and the recently reported antagonists which feature an imidazothiazinone core to which a (substituted) phenyl ring is connected via a lipophilic linker. Docking and molecular dynamics simulation studies were performed. As a result, a hydrophobic binding pocket is predicted to accommodate the imidazothiazinone core, while the terminal phenyl ring projects towards an aromatic pocket. Hydrophobic interaction of Cys251 with substituents on the phenyl ring could explain the high potency of the most potent derivatives. Molecular dynamics simulation studies suggest that the binding of imidazothiazinone antagonists stabilizes transmembrane regions TM1, TM6 and TM7 of the receptor through a salt bridge between Asp118 and Lys133. The agonist THC is presumed to bind differently to GPR18 than to the distantly related CB receptors. This study provides insights into the binding mode of GPR18 agonists and antagonists which will facilitate future drug design for this promising potential drug target.
Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment
Authors: Hwang Eun , Song Seon
Published: April 2020

Nicotinamide (NAM) at doses far above those recommended for vitamins is suggested to be effective against a wide spectrum of diseases and conditions, including neurological dysfunctions, depression and other psychological disorders, and inflammatory diseases. Recent increases in public awareness on possible pro-longevity effects of nicotinamide adenine dinucleotide (NAD+) precursors have caused further growth of NAM consumption not only for clinical treatments, but also as a dietary supplement, raising concerns on the safety of its long-term use. However, possible adverse effects and their mechanisms are poorly understood. High-level NAM administration can exert negative effects through multiple routes. For example, NAM by itself inhibits poly(ADP-ribose) polymerases (PARPs), which protect genome integrity. Elevation of the NAD+ pool alters cellular energy metabolism. Meanwhile, high-level NAM alters cellular methyl metabolism and affects methylation of DNA and proteins, leading to changes in cellular transcriptome and proteome. Also, methyl metabolites of NAM, namely methylnicotinamide, are predicted to play roles in certain diseases and conditions. In this review, a collective literature search was performed to provide a comprehensive list of possible adverse effects of NAM and to provide understanding of their underlying mechanisms and assessment of the raised safety concerns. Our review assures safety in current usage level of NAM, but also finds potential risks for epigenetic alterations associated with chronic use of NAM at high doses. It also suggests directions of the future studies to ensure safer application of NAM.
Lignin and Quercetin Synthesis Underlies Berry Russeting in ‘Sunshine Muscat’ Grape
Authors: Huang Yan , Liang Dong , Xia Hui , Lin Li-Jin , Wang Jin , Lv Xiu-Lan
Published: April 2020

In order to further explore the mechanism of ‘sunshine muscat’ grape russet formation, transcriptomic and metabolomic analyses were performed on ‘sunshine muscat’ grape peels with and without russet. A total of 1491 differentially expressed genes (DEGs) were discovered based on these analyses. The phenylpropane synthesis pathway was the key metabolic pathway identified, and 28 DEGs related to phenylpropane synthesis pathway were screened, of which 16 were related to lignin synthesis. In addition, 60 differential metabolites were screened. There were 29 phenolic substances among the differential metabolites, which were all up-regulated and 10 were quercetin-related glycosides. Our results indicate that phenols likely play a dominant role in the formation of ‘sunshine muscat’ grape russet, and the synthesis of lignin and quercetin may be the key factors underlying russet formation.
MotP Subunit is Critical for Ion Selectivity and Evolution of a K+-Coupled Flagellar Motor
Authors: Naganawa Shun , Ito Masahiro
Published: April 2020

The bacterial flagellar motor is a sophisticated nanomachine embedded in the cell envelope. The flagellar motor is driven by an electrochemical gradient of cations such as H+, Na+, and K+ through ion channels in stator complexes embedded in the cell membrane. The flagellum is believed to rotate as a result of electrostatic interaction forces between the stator and the rotor. In bacteria of the genus Bacillus and related species, the single transmembrane segment of MotB-type subunit protein (MotB and MotS) is critical for the selection of the H+ and Na+ coupling ions. Here, we constructed and characterized several hybrid stators combined with single Na+-coupled and dual Na+- and K+-coupled stator subunits, and we report that the MotP subunit is critical for the selection of K+. This result suggested that the K+ selectivity of the MotP/MotS complexes evolved from the single Na+-coupled stator MotP/MotS complexes. This finding will promote the understanding of the evolution of flagellar motors and the molecular mechanisms of coupling ion selectivity.
Factors Affecting the Retention Efficiency and Physicochemical Properties of Spray Dried Lipid Nanoparticles Loaded with Lippia sidoides Essential Oil
Authors: Baldim Iara , Rosa Débora M. , Souza Claudia R. F. , Da Ana Raquel , Durazzo Alessandra , Lucarini Massimo , Santini Antonello , Souto Eliana B. , Oliveira Wanderley P.
Published: April 2020

Essential oils (EOs) are widely used in various industrial sectors but can present several instability problems when exposed to environmental factors. Encapsulation technologies are effective solutions to improve EOs properties and stability. Currently, the encapsulation in lipid nanoparticles has received significant attention, due to the several recognized advantages over conventional systems. The study aimed to investigate the influence of the lipid matrix composition and spray-drying process on the physicochemical properties of the lipid-based nanoparticles loaded with Lippia sidoides EO and their retention efficiency for the oil. The obtained spray-dried products were characterized by determination of flow properties (Carr Index: from 25.0% to 47.93%, and Hausner ratio: from 1.25 to 1.38), moisture (from 3.78% to 5.20%), water activity (<0.5), and powder morphology. Zeta potential, mean particle size and polydispersity index, of the redispersed dried product, fell between −25.9 mV and −30.9 mV, 525.3 nm and 1143 nm, and 0.425 and 0.652, respectively; showing slight differences with the results obtained prior to spray-drying (from −16.4 mV to −31.6 mV; 147 nm to 1531 nm; and 0.459 to 0.729). Thymol retention in the dried products was significantly lower than the values determined for the liquid formulations and was affected by the drying of nanoparticles.
HPV Involvement in the Tumor Microenvironment and Immune Treatment in Head and Neck Squamous Cell Carcinomas
Authors: Lechien Jérôme R. , Descamps Géraldine , Seminerio Imelda , Furgiuele Sonia , Dequanter Didier , Mouawad Francois , Badoual Cécile , Journe Fabrice , Saussez Sven
Published: April 2020

Head and neck squamous cell carcinomas (HNSCC) are one of the most prevalent cancers worldwide. Active human papillomavirus (HPV) infection has been identified as an important additional risk factor and seems to be associated with a better prognosis in non-drinker and non-smoker young patients with oropharyngeal SCC. The better response of the immune system against the HPV-induced HNSCC is suspected as a potential explanation for the better prognosis of young patients. To further assess this hypothesis, our review aims to shed light the current knowledge about the impact of HPV infection on the immune response in the context of HNSCC, focusing on the innate immune system, particularly highlighting the role of macrophages, Langerhans and myeloid cells, and on the adaptative immune system, pointing out the involvement of T regulatory, T CD8 and T CD4 lymphocytes. In addition, we also review the preventive (HPV vaccines) and therapeutic (checkpoint inhibitors) strategies against HPV-related HNSCC, stressing the use of anti-CTLA4, PD-L1, PD-L2 antibodies alone and in combination with other agents able to modulate immune responses.
The Clinical Impact of Low-Volume Lymph Nodal Metastases in Early-Stage Cervical Cancer: The Senticol 1 and Senticol 2 Trials
Authors: Guani Benedetta , Balaya Vincent , Magaud Laurent , Lecuru Fabrice , Mathevet Patrice
Published: April 2020

Background: With the development of the sentinel node technique in early-stage cervical cancer, it is imperative to define the clinical significance of micrometastases (MICs) and isolated tumor cells (ITCs). Methods: We included all patients who participated in the Senticol 1 and Senticol 2 studies. We analyzed the factors associated with the presence of low-volume metastasis, the oncological outcomes of patients with MIC and ITC and the correlation of recurrences and risk factors. Results: Twenty-four patients (7.5%) had low-volume metastasis. The risk factors associated with the presence of low-volume metastasis were a higher stage (p = 0.02) and major stromal invasion (p = 0.01) in the univariate analysis. The maximum specificity and sensitivity were found at a cutoff of 8 mm of stromal invasion. In multivariate analysis, the higher stage (p = 0.02) and the positive lymphovascular space invasion (p = 0.02) were significantly associated with the MIC and ITC. Patients with low-volume metastasis had similar disease-free survival (DFS) (92.7%) to node-negative patients (93.6%). The addition of adjuvant treatment in presence of low-volume metastasis did not modify the DFS. Conclusions: These results confirm our previous analysis of Senticol 1: the presence of low-volume metastasis did not decrease the DFS in early-stage cervical cancer patients.
FGF2 Induces Resistance to Nilotinib through MAPK Pathway Activation in KIT Mutated Melanoma
Authors: Tétu Pauline , Delyon Julie , André Jocelyne , Reger de Moura Coralie , Sabbah Malak , Ghanem Ghanem E , Battistella Maxime , Mourah Samia , Lebbé Céleste , Dumaz Nicolas
Published: April 2020

KIT is a bona fide oncogene in a subset of melanoma and, ex vivo, KIT inhibitors are very efficient at killing KIT-mutant melanoma cell lines. However, KIT-mutant melanoma tumors tend to show a de novo resistance in most cases and a limited duration of response when response is achieved. We performed pharmacodynamic studies on patients with KIT-mutated melanoma treated with nilotinib, which suggested that the FGF2 axis may be a mechanism of resistance in this subset of melanoma. Using several melanoma cell lines, which are dependent on oncogenic KIT, we showed that although KIT inhibition markedly decreased cell viability in melanoma cell lines with distinct KIT mutations, this effect was lessened in the presence of FGF2 due to inhibition of BIM expression by MAPK pathway activation. Addition of a MEK inhibitor reversed the FGF2-driven resistance for all KIT mutants. We confirmed the expression of FGF2 and activation of MEK-ERK in melanoma patients using in situ data from a clinical trial. Therefore, the combined inhibition of KIT with FGFR or MEK may be a next-step effective clinical strategy in KIT-mutant melanoma.
Endogenously-Activated Ultrasmall-in-Nano Therapeutics: Assessment on 3D Head and Neck Squamous Cell Carcinomas
Authors: Santi Melissa , Mapanao Ana Katrina , Cassano Domenico , Vlamidis Ylea , Cappello Valentina , Voliani Valerio
Published: April 2020

Negative or positive HPV-associated Head and Neck Squamous Cell Carcinomas (HNSCCs) are high recurrence neoplasms usually resulting in a poor prognosis, mainly due to metastasis formation. Despite the low overall patient survival rate and the severe side effects, the treatment of choice is still cisplatin-based chemotherapy. Here, we report a straightforward protocol for the production of high throughput 3D models of negative or positive HPV-associated HNSCCs, together with their employment in the therapeutic evaluation of gold ultrasmall-in-nano architectures comprising an endogenously-activatable cisplatin prodrug. Beyond enhancing the biosafety of cisplatin, our approach paves the way for the establishment of synergistic co-therapies for HNSCCs based on excretable noble metals.
Prognostic Value of SDF-1α Expression in Patients with Esophageal Squamous Cell Carcinoma Receiving Esophagectomy
Authors: Chen Yen-Hao , Li Shau-Hsuan , Lu Hung-I , Lo Chien-Ming
Published: April 2020

Stromal cell-derived factor-1α (SDF-1α) is a chemokine that has been reported to be involved in tumor progression in several malignancies. This study aimed to evaluate the crucial role of SDF-1α in patients with esophageal squamous cell carcinoma (ESCC) who underwent esophagectomy. A total of 169 patients with ESCC were identified, including overexpression of SDF-1α in 60 patients and low expression of SDF-1α in 109 patients by immunohistochemical analysis. Two ESCC cell lines, TE1 and KYSE30, were selected to evaluate the tumor cell proliferative effect of SDF-1α. Univariate and multivariate analyses showed that high tumor (T) status, positive lymph node metastasis, tumors located in the upper esophagus, and SDF-1α overexpression were significantly related to worse disease-free survival and overall survival. In addition, the two cell lines were treated with SDF-1α, AMD3100 (an SDF-1α-ligand receptor antagonist), and chemotherapeutic agents (cisplatin). Our in vitro study results showed that SDF-1α promoted the proliferation of tumor cells, and blocking the SDF-1α pathway displayed a growth inhibition effect in a dose-dependent manner. SDF-1α plays an important role in the progression of ESCC and is an independent prognostic factor for ESCC patients who underwent esophagectomy.
Oncobiosis and Microbial Metabolite Signaling in Pancreatic Adenocarcinoma
Authors: Kiss Borbála , Mikó Edit , Sebő Éva , Toth Judit , Ujlaki Gyula , Szabó Judit , Uray Karen , Bai Péter , Árkosy Péter
Published: April 2020

Pancreatic adenocarcinoma is one of the most lethal cancers in both men and women, with a median five-year survival of around 5%. Therefore, pancreatic adenocarcinoma represents an unmet medical need. Neoplastic diseases, such as pancreatic adenocarcinoma, often are associated with microbiome dysbiosis, termed oncobiosis. In pancreatic adenocarcinoma, the oral, duodenal, ductal, and fecal microbiome become dysbiotic. Furthermore, the pancreas frequently becomes colonized (by Helicobacter pylori and Malassezia, among others). The oncobiomes from long- and short-term survivors of pancreatic adenocarcinoma are different and transplantation of the microbiome from long-term survivors into animal models of pancreatic adenocarcinoma prolongs survival. The oncobiome in pancreatic adenocarcinoma modulates the inflammatory processes that drive carcinogenesis. In this review, we point out that bacterial metabolites (short chain fatty acids, secondary bile acids, polyamines, indole-derivatives, etc.) also have a role in the microbiome-driven pathogenesis of pancreatic adenocarcinoma. Finally, we show that bacterial metabolism and the bacterial metabolome is largely dysregulated in pancreatic adenocarcinoma. The pathogenic role of additional metabolites and metabolic pathways will be identified in the near future, widening the scope of this therapeutically and diagnostically exploitable pathogenic pathway in pancreatic adenocarcinoma.
Novel Oncolytic Virus Armed with Cancer Suicide Gene and Normal Vasculogenic Gene for Improved Anti-Tumor Activity
Authors: Jeong Su-Nam , Yoo So Young
Published: April 2020

Here, we developed a novel oncolytic vaccinia virus (NOV) with the dual advantages of cancer selectivity and normal vessel reconstructive activity by replacing the viral thymidine kinase (vTk) and vaccinia growth factor (VGF) genes with genes encoding TNF-related apoptosis-inducing ligand (TRAIL) and angiopoietin 1 (Ang1), respectively. The pan-cancer-specific oncolytic potency of NOV was confirmed in various human and mouse cancer cell lines (colon, liver, pancreas, cholangiocarcinoma, cervical cancer, osteosarcoma, and melanoma). Vaccinia virus (VV) treatment directly induced early apoptosis in tumors within 24 h, and this effect was enhanced with further engineering; VGF and Tk deletion with Ang1 and TRAIL insertion. Meanwhile, treatment with the conventional anti-cancer drug cisplatin did not induce apoptosis. A virus-treated CT26 mouse colon cancer syngeneic model showed attenuated tumor growth, which was in accordance with the results of percent survival measurement, CD8 expression analysis, and TUNEL staining with advanced genetic engineering (vAng1 < vTRAIL < NOV). Taken together, our results indicate that NOV induces cancer tissue apoptosis and anti-tumor immunity and may constitute a highly advantageous therapeutic agent for next-generation solid tumor virotherapy with pan-cancer-specific oncolytic activity and high biosafety.
Role of Calcium Signaling in Prostate Cancer Progression: Effects on Cancer Hallmarks and Bone Metastatic Mechanisms
Authors: Ardura Juan A. , Álvarez-Carrión Luis , Gutiérrez-Rojas Irene , Alonso Verónica
Published: April 2020

Advanced prostate cancers that progress to tumor metastases are often considered incurable or difficult to treat. The etiology of prostate cancers is multi-factorial. Among other factors, de-regulation of calcium signals in prostate tumor cells mediates several pathological dysfunctions associated with tumor progression. Calcium plays a relevant role on tumor cell death, proliferation, motility-invasion and tumor metastasis. Calcium controls molecular factors and signaling pathways involved in the development of prostate cancer and its progression. Such factors and pathways include calcium channels and calcium-binding proteins. Nevertheless, the involvement of calcium signaling on prostate cancer predisposition for bone tropism has been relatively unexplored. In this regard, a diversity of mechanisms triggers transient accumulation of intracellular calcium in prostate cancer cells, potentially favoring bone metastases development. New therapies for the treatment of prostate cancer include compounds characterized by potent and specific actions that target calcium channels/transporters or pumps. These novel drugs for prostate cancer treatment encompass calcium-ATPase inhibitors, voltage-gated calcium channel inhibitors, transient receptor potential (TRP) channel regulators or Orai inhibitors. This review details the latest results that have evaluated the relationship between calcium signaling and progression of prostate cancer, as well as potential therapies aiming to modulate calcium signaling in prostate tumor progression.
Imaging Accuracy in Preoperative Staging of T3-T4 Laryngeal Cancers
Authors: Benazzo Marco , Sovardi Fabio , Preda Lorenzo , Mauramati Simone , Carnevale Sergio , Bertino Giulia , Berton Francesca , Meroni Matteo , Herman Irene , Trisolini Giuseppe , Morbini Patrizia
Published: April 2020

Background: Preoperative imaging impacts treatment planning and prognosis in laryngeal cancers. We investigated the accuracy of standard computed tomography (CT) in evaluating tumor invasions at critical glottic areas. Methods: CT scans of glottic cancers treated by partial or total laryngectomy between Jan 2015 and Aug 2019 were reviewed to assess levels of tumor invasion at critical glottic subsites. CT accuracy in the identification of tumor extensions was determined against the gold standard of histopathological analysis of surgical samples. Results: This study included 64 patients. In the anterior commissure, CT showed high rates of false positives at all levels (sensitivity 56.2–70%, specificity 87.8–92.3%); in the anterior vocal fold, it overestimated the deep invasion (19.5% specificity, 90.3% sensitivity), while it underestimated the extralaryngeal spread (63.6% sensitivity, 98.1% specificity). In the posterior paraglottic space (pPGS), false negative results were more frequent for superficial extensions (25% sensitivity, 95.8% specificity) and deep invasions (58.8% sensitivity, 82.3% specificity). Shorter disease-specific and disease-free survivals were associated with pStage IV (p: 0.045 and 0.008) and with the pathological involvement of pPGS (p: 0.045 and 0.015). Conclusions: Negative prognostic correlation of pPGS involvement was confirmed on histopathological data. CT staging did not provide a satisfactory prognostic stratification and should be complemented with magnetic resonance imaging.
Tumor-Infiltrating CD8 T Cells Predict Clinical Breast Cancer Outcomes in Young Women
Authors: Jin Yong Won , Hu Pingzhao
Published: April 2020

Young women with breast cancer have disproportionately poor clinical outcomes compared to their older counterparts. The underlying biological differences behind this age-dependent disparity are still unknown and warrant investigation. Recently, the tumor immune landscape has received much attention for its prognostic value and therapeutic targets. The differential tumor immune landscape between age groups in breast cancer has not yet been characterized, and may contribute to the age-related differences in clinical outcomes. Computational deconvolution was used to quantify abundance of immune cell types from bulk transcriptome profiles of breast cancer patients from two independent datasets. No significant differences in immune cell composition that were consistent in the two cohorts were found between the young and old age groups. Regardless of absence of significant differences, the higher tumor infiltration of several immune cell types, such as CD8+ T and CD4+ T cells, was associated with better clinical outcomes in the young but not in the old age group. Mutational signatures analysis showed signatures previously not found in breast cancer to be associated with tumor-infiltrating lymphocyte (TIL) levels in the young age group, whereas in the old group, all significant signatures were those previously found in breast cancer. Pathway analysis revealed different gene sets associated with TIL levels for each age group from the two cohorts. Overall, our results show trends towards better clinical outcomes for high TIL levels, especially CD8+ T cells, but only in the young age group. Furthermore, our work suggests that the underlying biological differences may involve multiple levels of tumor physiology.
Clinical Variables Associated with PSA Response to Lutetium-177-PSMA ([177Lu]-PSMA-617) Radionuclide Treatment in Men with Metastatic Castration-Resistant Prostate Cancer
Authors: Gadot Moran , Davidson Tima , Aharon Margalit , Atenafu Eshetu G. , Malki Avraham , Levartovsky Meital , Saad Akram , Domachevsky Liran , Berger Raanan , Leibowitz Raya
Published: April 2020

Lutetium-177-PSMA ([177Lu]-PSMA-617), a radiolabeled small molecule, binds with high affinity to prostate-specific membrane antigen (PSMA), enabling targeted radiation therapy to metastatic prostate lesions. Our objective was to retrospectively analyze the activity of [177Lu]-PSMA-617 given off-trial to men with metastatic castration resistant prostate cancer (mCRPC) and identify clinical factors associated with PSA response. Electronic medical records of all men treated with [177Lu]-PSMA-617 were reviewed and analyzed. Overall survival was calculated using the Kaplan–Meier method. The association between potential variables and PSA response was analyzed by univariate analysis, using either logistic regression or χ2/Fisher’s exact test. Multivariable analysis was carried out using logistic regression on all categorical variables with a P-value of <0.1 on univariate analysis. Variables found to be statistically significant were then used to define a categorical score. A total of 52 patients received at least one cycle of [177Lu]-PSMA-617. Clinical benefit was observed in 28 patients (52%). PSA decline ≥20% and ≥50% was observed in 26 (50%) and 18 patients (35%), respectively. Achievement of any PSA decline at first measurement was significantly associated with survival. There was a negative association between the number of previous chemotherapy lines and PSA decline above 20%. Univariate analysis followed by multivariable analysis showed that older age and higher hemoglobin were significantly associated with a PSA decline >20%. A score combining these two parameters was significantly associated with PSA response. In summary, [177Lu]-PSMA-617 is active in the ‘real-life’ setting of heavily pretreated men with mCRPC.
Erratum: Berndsen, R.H., et al. Colorectal Cancer Growth Retardation through Induction of Apoptosis, Using an Optimized Synergistic Cocktail of Axitinib, Erlotinib, and Dasatinib, Cancers 2019, 11, 1878
Authors: Berndsen Robert H. , Swier Nathalie , van Beijnum Judy R. , Nowak-Sliwinska Patrycja
Published: April 2020

The authors wish to make the following corrections to this paper [...]
Ribosomal Protein S27/Metallopanstimulin-1 (RPS27) in Glioma—A New Disease Biomarker?
Authors: Feldheim Jonas , Kessler Almuth F. , Schmitt Dominik , Salvador Ellaine , Monoranu Camelia M. , Feldheim Julia J. , Ernestus Ralf-Ingo , Löhr Mario , Hagemann Carsten
Published: April 2020

Despite its significant overexpression in several malignant neoplasms, the expression of RPS27 in the central nervous system (CNS) is widely unknown. We identified the cell types expressing RPS27 in the CNS under normal and disease conditions. We acquired specimens of healthy brain (NB), adult pilocytic astrocytoma (PA) World Health Organization (WHO) grade I, anaplastic PA WHO grade III, gliomas WHO grade II/III with or without isocitrate dehydrogenase (IDH) mutation, and glioblastoma multiforme (GBM). RPS27 protein expression was examined by immunohistochemistry and double-fluorescence staining and its mRNA expression quantified by RT-PCR. Patients’ clinical and tumor characteristics were collected retrospectively. RPS27 protein was specifically expressed in tumor cells and neurons, but not in healthy astrocytes. In tumor tissue, most macrophages were positive, while this was rarely the case in inflamed tissue. Compared to NB, RPS27 mRNA was in mean 6.2- and 8.8-fold enhanced in gliomas WHO grade II/III with (p < 0.01) and without IDH mutation (p = 0.01), respectively. GBM displayed a 4.6-fold increased mean expression (p = 0.02). Although RPS27 expression levels did not affect the patients’ survival, their association with tumor cells and tumor-associated macrophages provides a rationale for a future investigation of a potential function during gliomagenesis and tumor immune response.
Effects of Beta-Blockers on Melanoma Microenvironment and Disease Survival in Human
Authors: Wrobel Ludovic Jean , Gayet-Ageron Angèle , Le Gal Frédérique-Anne
Published: April 2020

Background: The regulation of melanoma by noradrenergic signaling has gain attention since pre-clinical and clinical studies suggested a benefit of using beta-blockers to control disease progression. We need to confirm that human melanoma recapitulates the mechanisms described from pre-clinical models. Methods: The sources and targets of norepinephrine in the microenvironment of 20 human melanoma samples was investigated using immunostaining. The effect of an exposure to beta-blockers on immune cell type distribution and expression of immune response markers was assessed with immunostaining on 212 human primary melanoma. A statistical analysis explored the effect of an exposure to beta-blockers on progression free survival, melanoma related survival, and overall survival on the 286 eligible patients. Results: Tumor cells and macrophages may be a source of norepinephrine in melanoma microenvironment. Tumors from patients exposed to wide spectrum beta-blockers recapitulate the increased infiltration of T-lymphocytes and the increased production of granzyme B observed in pre-clinical models. An exposure to beta-blockers is associated with a better outcome in our cohort of melanoma patients. Conclusion: This study shows the association between an exposure to wide spectrum beta-blockers and markers of an effective anti-tumor immune response as well as the protective effect of beta-blockers in human melanoma patients.
Suicide Gene Therapy Mediated with Exosomes Produced by Mesenchymal Stem/Stromal Cells Stably Transduced with HSV Thymidine Kinase
Authors: Pastorakova Andrea , Jakubechova Jana , Altanerova Ursula , Altaner Cestmir
Published: April 2020

Mesenchymal stem/stromal cells (MSCs) prepared from various human tissues were stably transduced with the suicide gene herpes simplex virus thymidine kinase (HSVTK) by means of retrovirus infection. HSVTK-transduced MSCs express the suicide gene and in prodrug ganciclovir (GCV) presence induced cell death by intracellular conversion of GCV to GCV-triphosphate. The homogenous population of HSVTK-MSCs were found to release exosomes having mRNA of the suicide gene in their cargo. The exosomes were easily internalized by the tumor cells and the presence of ganciclovir caused their death in a dose-dependent manner. Efficient tumor cell killing of glioma cell lines and primary human glioblastoma cells mediated by HSVTK-MSC exosomes is reported. Exosomes produced by suicide gene transduced MSCs represent a new class of highly selective tumor cell targeted drug acting intracellular with curative potential.
The Role of miRNA for the Treatment of MGMT Unmethylated Glioblastoma Multiforme
Authors: Kirstein Anna , Schmid Thomas E. , Combs Stephanie E.
Published: April 2020

Glioblastoma multiforme (GBM) is the most common high-grade intracranial tumor in adults. It is characterized by uncontrolled proliferation, diffuse infiltration due to high invasive and migratory capacities, as well as intense resistance to chemo- and radiotherapy. With a five-year survival of less than 3% and an average survival rate of 12 months after diagnosis, GBM has become a focus of current research to urgently develop new therapeutic approaches in order to prolong survival of GBM patients. The methylation status of the promoter region of the O6-methylguanine–DNA methyltransferase (MGMT) is nowadays routinely analyzed since a methylated promoter region is beneficial for an effective response to temozolomide-based chemotherapy. Furthermore, several miRNAs were identified regulating MGMT expression, apart from promoter methylation, by degrading MGMT mRNA before protein translation. These miRNAs could be a promising innovative treatment approach to enhance Temozolomide (TMZ) sensitivity in MGMT unmethylated patients and to increase progression-free survival as well as long-term survival. In this review, the relevant miRNAs are systematically reviewed.
Genetic and Immune Changes Associated with Disease Progression under the Pressure of Oncolytic Therapy in A Neuroblastoma Outlier Patient
Authors: Franco-Luzón Lidia , García-Mulero Sandra , Sanz-Pamplona Rebeca , Melen Gustavo , Ruano David , Lassaletta Álvaro , Madero Luís , González-Murillo África , Ramírez Manuel
Published: April 2020

Little is known about the effect of oncolytic adenovirotherapy on pediatric tumors. Here we present the clinical case of a refractory neuroblastoma that responded positively to Celyvir (ICOVIR-5 oncolytic adenovirus delivered by autologous mesenchymal stem cells) for several months. We analyzed samples during tumor evolution in order to identify molecular and mutational features that could explain the interactions between treatment and tumor and how the balance between both of them evolved. We identified a higher adaptive immune infiltration during stabilized disease compared to progression, and also a higher mutational rate and T-cell receptor (TCR) diversity during disease progression. Our results indicate an initial active role of the immune system controlling tumor growth during Celyvir therapy. The tumor eventually escaped from the control exerted by virotherapy through acquisition of resistance by the tumor microenvironment that exhausted the initial T cell response.
The Prognostic and Predictive Value of SOX2+ Cell Densities in Patients Treated for Colorectal Cancer
Authors: Miller Tim J. , McCoy Melanie J. , Lee-Pullen Tracey F. , Anyaegbu Chidozie C. , Hemmings Christine , Bulsara Max K. , Platell Cameron F.
Published: April 2020

SOX2 (sex-determining region-Y homeobox-2) is a transcription factor essential for the maintenance of pluripotency and is also associated with stem-cell-like properties in preclinical cancer models. Our previous study on a cohort of stage III colon cancer patients demonstrated high SOX2+ cell densities were associated with poor prognosis. However, most patients were treated with adjuvant chemotherapy so the prognostic value of SOX2 could not be assessed independently from its value as a predictive marker for non-response to chemotherapy. This study aimed to assess whether SOX2 was a true prognostic marker or a marker for chemotherapy response in a historical cohort of patients, a high proportion of whom were chemotherapy-naïve. SOX2 immunostaining was performed on tissue micro-arrays containing tumor cores from 797 patients with stage II and III colorectal cancer. SOX2+ cell densities were then quantified with StrataQuest digital image analysis software. Overall survival was assessed using Kaplan–Meier estimates and Cox regression. It was found that high SOX2+ cell densities were not associated with poor overall survival. Furthermore, all patients had a significant improvement in survival after 5-fluorouracil (5-FU) treatment, irrespective of their SOX2+ cell density. Therefore, SOX2+ cell densities were not associated with prognosis or chemotherapy benefit in this study. This is in contrast to our previous study, in which most patients received oxaliplatin as part of their treatment, in addition to 5-FU. This suggests SOX2 may predict response to oxaliplatin treatment, but not 5-FU.
Analysis of a Real-World Cohort of Metastatic Breast Cancer Patients Shows Circulating Tumor Cell Clusters (CTC-clusters) as Predictors of Patient Outcomes
Authors: Costa Clotilde , Muinelo-Romay Laura , Cebey-López Victor , Pereira-Veiga Thais , Martínez-Pena Inés , Abreu Manuel , Abalo Alicia , Lago-Lestón Ramón M. , Abuín Carmen , Palacios Patricia , Cueva Juan , Piñeiro Roberto , López-López Rafael
Published: April 2020

Circulating tumor cell (CTC) enumeration has emerged as a powerful biomarker for the assessment of prognosis and the response to treatment in metastatic breast cancer (MBC). Moreover, clinical evidences show that CTC-cluster counts add prognostic information to CTC enumeration, however, their significance is not well understood, and more clinical evidences are needed. We aim to evaluate the prognostic value of longitudinally collected single CTCs and CTC-clusters in a heterogeneous real-world cohort of 54 MBC patients. Blood samples were longitudinally collected at baseline and follow up. CTC and CTC-cluster enumeration was performed using the CellSearch® system. Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using Cox proportional hazards modelling. Elevated CTC counts and CTC-clusters at baseline were significantly associated with a shorter survival time. In joint analysis, patients with high CTC counts and CTC-cluster at baseline were at a higher risk of progression and death, and longitudinal analysis showed that patients with CTC-clusters had significantly shorter survival compared to patients without clusters. Moreover, patients with CTC-cluster of a larger size were at a higher risk of death. A longitudinal analysis of a real-world cohort of MBC patients indicates that CTC-clusters analysis provides additional prognostic value to single CTC enumeration, and that CTC-cluster size correlates with patient outcome.
Stress Management: Death Receptor Signalling and Cross-Talks with the Unfolded Protein Response in Cancer
Authors: Lafont Elodie
Published: April 2020

Throughout tumour progression, tumour cells are exposed to various intense cellular stress conditions owing to intrinsic and extrinsic cues, to which some cells are remarkably able to adapt. Death Receptor (DR) signalling and the Unfolded Protein Response (UPR) are two stress responses that both regulate a plethora of outcomes, ranging from proliferation, differentiation, migration, cytokine production to the induction of cell death. Both signallings are major modulators of physiological tissue homeostasis and their dysregulation is involved in tumorigenesis and the metastastic process. The molecular determinants of the control between the different cellular outcomes induced by DR signalling and the UPR in tumour cells and their stroma and their consequences on tumorigenesis are starting to be unravelled. Herein, I summarize the main steps of DR signalling in relation to its cellular and pathophysiological roles in cancer. I then highlight how the UPR and DR signalling control common cellular outcomes and also cross-talk, providing potential opportunities to further understand the development of malignancies.
Improving the Diagnostic Accuracy of the PD-L1 Test with Image Analysis and Multiplex Hybridization
Authors: Humphries Matthew P. , Bingham Victoria , Abdullahi Sidi Fatima , Craig Stephanie G. , McQuaid Stephen , James Jacqueline , Salto-Tellez Manuel
Published: April 2020

Targeting of the programmed cell death protein (PD-1)/programmed death-ligand 1 (PD-L1) axis with checkpoint inhibitors has changed clinical practice in non-small cell lung cancer (NSCLC). However, clinical assessment remains complex and ambiguous. We aim to assess whether digital image analysis (DIA) and multiplex immunofluorescence can improve the accuracy of PD-L1 diagnostic testing. A clinical cohort of routine NSCLC patients reflex tested for PD-L1 (SP263) immunohistochemistry (IHC), was assessed using DIA. Samples of varying assessment difficulty were assessed by multiplex immunofluorescence. Sensitivity, specificity, and concordance was evaluated between manual diagnostic evaluation and DIA for chromogenic and multiplex IHC. PD-L1 expression by DIA showed significant concordance (R² = 0.8248) to manual assessment. Sensitivity and specificity was 86.8% and 91.4%, respectively. Evaluation of DIA scores revealed 96.8% concordance to manual assessment. Multiplexing enabled PD-L1+/CD68+ macrophages to be readily identified within PD-L1+/cytokeratin+ or PD-L1-/cytokeratin+ tumor nests. Assessment of multiplex vs. chromogenic IHC had a sensitivity and specificity of 97.8% and 91.8%, respectively. Deployment of DIA for PD-L1 diagnostic assessment is an accurate process of case triage. Multiplex immunofluorescence provided higher confidence in PD-L1 assessment and could be offered for challenging cases by centers with appropriate expertise and specialist equipment.
Selective Formation of Para-Xylene by Methanol Aromatization over Phosphorous Modified ZSM-5 Zeolites
Authors: Niu Xianjun , Wang Kai , Bai Yang , Du Yi-en , Chen Yongqiang , Dong Mei , Fan Weibin
Published: April 2020

Phosphorous modified ZSM-5 zeolites were synthesized by incipient wetness impregnation. Their performances for the methanol to aromatics conversion (MTA) were subsequently evaluated and the relationship between the catalyst structure and performance was focused on. The obtained results indicated that the introduction of phosphorous resulted in the modification of the catalyst structure characteristics and acidic properties, i.e., the reduction in the external surface area and micropore volume, the narrowing of the pore size, and the decrease in the quantity and strength of acid sites. As a result, the P/HZSM-5 catalyst exhibited the enhanced selectivity for the para-xylene (PX) in xylene isomers and xylene in aromatics, and their increase degrees were intensified with the increasing P content. The selectivity of PX in X increased from 23.8% to nearly 90% when P content was 5 wt.%. Meanwhile, the selectivity of xylene in aromatics was enhanced from 41.3% to 60.2%.