bluuebunny/crossref_metadata_2025 huggingface dataset:
Versatile Silver Nanoparticles-Based SERS Substrate with High Sensitivity and Stability
Authors: Liu Mimi , Bhandari Anjuli , Haqqani Mohammed Mujtaba Ali , Radu Daniela R. , Lai Cheng-Yu
Published: August 2021

Surface-enhanced Raman scattering has developed into a mature analytical technique useful in various applications; however, the reproducible fabrication of a portable SERS substrate with high sensitivity and good uniformity is still an ongoing pursuit. Reported herein is a rapid fabrication method of an inexpensive SERS substrate that enables sub-nanomolar detection of molecular analytes. The SERS substrate is obtained by application of silver nanoparticles (Ag NPs)-based ink in precisely design patterns with the aid of an in-house assembled printer equipped with a user-fillable pen. Finite-difference time-domain (FDTD) simulations show a 155-times Ag NP electric field enhancement for Ag nanoparticle pairs with particle spacing of 2 nm. By comparing the SERS performance of SERS substrate made with different support matrices and fabrication methods, the PET-printed substrate shows optimal performance, with an estimated sensitivity enhancement factor of 107. The quantitative analysis of rhodamine 6G absorbed on optimized SERS substrate exhibits a good linear relationship, with a correlation coefficient (R2) of 0.9998, between the SERS intensity at 610 cm−1 and the concentration in the range of 0.1 nM—1μM. The practical low limit detection of R6G is 10 pM. The optimized SERS substrates show good stability (at least one month) and have been effectively tested in the detection of cancer drugs, including doxorubicin and metvan.
Piezoelectric and Electromechanical Characteristics of Porous Poly(Ethylene-co-Vinyl Acetate) Copolymer Films for Smart Sensors and Mechanical Energy Harvesting Applications
Authors: Ennawaoui Chouaib , Hajjaji Abdelowahed , Samuel Cédric , Sabani Erroumayssae , Rjafallah Abdelkader , Najihi Ikrame , Laadissi El Mehdi , Loualid El Mehdi , Rguiti Mohamed , Ballouti Abdessamad El , Azim Azeddine
Published: August 2021

This paper investigates energy harvesting performances of porous piezoelectric polymer films to collect electrical energy from vibrations and power various sensors. The influence of void content on the elastic matrix, dielectric, electrical, and mechanical properties of porous piezoelectric polymer films produced from available commercial poly(ethylene-co-vinyl acetate) using an industrially applicable melt-state extrusion method (EVA) were examined and discussed. Electrical and mechanical characterization showed an increase in the harvested current and a decrease in Young’s modulus with the increasing ratio of voids. Thermal analysis revealed a decrease in piezoelectric constant of the porous materials. The authors present a mathematical model that is able to predict harvested current as a function of matrix characteristics, mechanical excitation and porosity percentage. The output current is directly proportional to the porosity percentage. The harvested power significantly increases with increasing strain or porosity, achieving a power value up to 0.23, 1.55, and 3.87 mW/m3 for three EVA compositions: EVA 0%, EVA 37% and EVA 65%, respectively. In conclusion, porous piezoelectric EVA films has great potential from an energy density viewpoint and could represent interesting candidates for energy harvesting applications. Our work contributes to the development of smart materials, with potential uses as innovative harvester systems of energy generated by different vibration sources such as roads, machines and oceans.
Sporadic E Layer with a Structure of Double Cusp in the Vertical Sounding Ionogram
Authors: Yusupov Kamil M. , Bakhmetieva Nataliya V.
Published: August 2021

In this study, we analyzed a large number of vertical sounding ionograms, obtained by the mid-latitude Cyclone ionosonde (55.85° N; 48.8° E) of Kazan (Volga Region) Federal University, which operates in a rapid-run mode of ionograms (1 ionogram per minute). Ionograms with a sporadic E layer type c, which have an unusual double cusp on the trace from the sporadic layer, were found among them. We attempted to simulate this unusual double cusp trace shape. Model calculations were performed to clarify the reasons for the appearance of the double cusp and to determine the shape of the lower part of the E and Es layers. The simulation was performed by fitting the profile of the electron densities of the E and Es layers, calculating the virtual reflection heights based on the refractive index using the Appleton-Hartree formula, and comparing them with the virtual heights of the layers on the ionogram. An estimate of the half-thickness of the lower part of the Es-layer was obtained. The possible reasons for the appearance of a trace with a double cusp of the Es layer are discussed. We assumed that the possible reasons for this phenomenon were the stratification of the E layer, and the interaction between the E and F layers in the form of descending or intermediate layers and atmospheric wave propagation. As an illustration of these phenomena, examples of an intermediate (descending) sporadic E layer and stratification of the E region and the Es layer are given according to observations of the lower ionosphere. These examples were obtained through the resonant scattering of probe radio waves by artificial periodic irregularities (API technique) of the ionospheric plasma, performed on the SURA mid-latitude heating facility (56.1° N; 46.1° E). The scattering of probe radio waves on the APIs generated by the heating facility made it possible to study various phenomena in the Earth’s ionosphere.
The Role of the Indian Ocean Basin-Wide and El Niño–Southern Oscillation Modes in Interannual Rainfall Variability over South America during Austral Summer
Authors: Kayano Mary T. , Andreoli Rita V. , Cerón Wilmar L. , Souza Rodrigo A. F.
Published: August 2021

This paper examines the relative role of the Indian Ocean basin-wide (IOBW) mode and El Niño–Southern Oscillation (ENSO) in the atmospheric circulation and rainfall interannual variations over South America (SA) during southern summer of the 1951‒2016 period. The effects of the warm IOBW and El Niño (EN) events, and of the cold IOBW and La Niña (LN) events are examined using partial correlations. The ENSO and IOBW modes, through the associated large-scale and regional anomalous circulation patterns, induce contrasting effects on the rainfall in northeastern SA. The EN without the warm IOBW effect induces anomalously dry conditions over eastern Amazon and part of northeastern Brazil (NEB) through anomalous sinking motions of the EN-related anomalous Walker and Hadley cells and strong moisture divergence associated with a vigorous anticyclone over tropical South Atlantic (TSA) and SA. The warm IOBW without the EN effect induces anomalously wet conditions in NEB, which is marginally related to the anomalous Walker and Hadley cells but is modulated by an anticyclone over SA between the equator and 20° S, and a cyclone in the southwestern Atlantic between 20° S and 40° S. The results here might be relevant for climate monitoring and modeling studies.
A Comparative Analysis of Emissions from a Compression–Ignition Engine Powered by Diesel, Rapeseed Biodiesel, and Biodiesel from Chlorella protothecoides Biomass Cultured under Different Conditions
Authors: Dębowski Marcin , Michalski Ryszard , Zieliński Marcin , Kazimierowicz Joanna
Published: August 2021

The priority faced by energy systems in road transport is to develop and implement clean technologies. These actions are expected to reduce emissions and slow down climate changes. An alternative in this case may be the use of biodiesel produced from microalgae. However, its production and use need to be justified economically and technologically. The main objective of this study was to determine the emissions from an engine powered by biodiesel produced from the bio-oil of Chlorella protothecoides cultured with different methods, i.e., using a pure chemical medium (BD-ABM) and a medium based on the effluents from an anaerobic reactor (BD-AAR). The results obtained were compared to the emissions from engines powered by conventional biodiesel from rapeseed oil (BD-R) and diesel from crude oil (D-CO). The use of effluents as a medium in Chlorella protothecoides culture had no significant effect on the properties of bio-oil nor the composition of FAME. In both cases, octadecatrienoic acid proved to be the major FAME (50% wt/wt), followed by oleic acid (ca. 22%) and octadecadienoic acid (over 15%). The effluents from UASB were found to significantly reduce the biomass growth rate and lipid content of the biomass. The CO2 emissions were comparable for all fuels tested and increased linearly along with an increasing engine load. The use of microalgae biodiesel resulted in a significantly lower CO emission compared to the rapeseed biofuel and contributed to lower NOx emission. Regardless of engine load tested, the HC emission was the highest in the engine powered by diesel. At low engine loads, it was significantly lower when the engine was powered by microalgae biodiesel than by rapeseed biodiesel.
Ionization Waves Enhance the Production of X-rays during Streamer Collisions
Authors: Cooray Vernon , Cooray Gerald , Rubinstein Marcos , Rachidi Farhad
Published: August 2021

Experimental data show that in laboratory sparks, X-rays are produced in time synchronization with the meeting of streamers of opposite polarity just before the final breakdown of the discharge gap. It has been suggested that the electric field enhancement created during the collision of streamers could provide the necessary conditions for electron acceleration, even though some of the theoretical studies show that the duration of the electric field is not long enough to do so. The experimental data on laboratory discharges show that. when streamers of opposite polarity meet each other, a potential or ionization wave that renders the streamer channels conducting is initiated. This paper shows that these ionization waves that convert the discharge channels from weakly conducting to highly conducting are associated with electric fields large enough to accelerate electrons to relativistic energies.
Type I Interferons in COVID-19 Pathogenesis
Authors: Palermo Enrico , Di Carlo Daniele , Sgarbanti Marco , Hiscott John
Published: August 2021

Among the many activities attributed to the type I interferon (IFN) multigene family, their roles as mediators of the antiviral immune response have emerged as important components of the host response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Viruses likewise have evolved multiple immune evasion strategies to circumvent the host immune response and promote virus propagation and dissemination. Therefore, a thorough characterization of host–virus interactions is essential to understand SARS-CoV-2 pathogenesis. Here, we summarize the virus-mediated evasion of the IFN responses and the viral functions involved, the genetic basis of IFN production in SARS-CoV-2 infection and the progress of clinical trials designed to utilize type I IFN as a potential therapeutic tool.
Comprehensive CircRNA Profiling and Selection of Key CircRNAs Reveal the Potential Regulatory Roles of CircRNAs throughout Ovarian Development and Maturation in Cynoglossus semilaevis
Authors: Li Jing , Shi Bao , Wang Chongnv , Shao Changwei , Liu Xuezhou , Zhang Daiqiang
Published: August 2021

CircRNAs are novel endogenous non-coding small RNAs involved in the regulation of multiple biological processes. However, little is known regarding circRNAs in ovarian development and maturation of fish. Our study, for the first time, provides the genome-wide overview of the types and relative abundances of circRNAs in tongue sole tissues during three ovarian developmental stages. We detected 6790 circRNAs in the brain, 5712 in the pituitary gland, 4937 in the ovary and 4160 in the liver. Some circRNAs exhibit tissue-specific expression, and qRT-PCR largely confirmed 6 differentially expressed (DE) circRNAs. Gene Ontology and KEGG pathway analyses of DE mRNAs were performed. Some DE circRNA parental genes were closely associated with biological processes in key signalling pathways and may play essential roles in ovarian development and maturation. We found that the selected circRNAs were involved in 10 pathways. RNase R digestion experiment and Sanger sequencing verified that the circRNA had a ring structure and was RNase R resistant. qRT-PCR results largely confirmed differential circRNA expression patterns from the RNA-seq data. These findings indicate that circRNAs are widespread in terms of present in production-related tissues of tongue sole with potentially important regulatory roles in ovarian development and maturation.
Mechanical Behavior of Blood Vessels: Elastic and Viscoelastic Contributions
Authors: Sánchez-Molina David , García-Vilana Silvia , Llumà Jordi , Galtés Ignasi , Velázquez-Ameijide Juan , Rebollo-Soria Mari Carmen , Arregui-Dalmases Carlos
Published: August 2021

The mechanical properties of the cerebral bridging veins (CBVs) were studied using advanced microtensile equipment. Detailed high-quality curves were obtained at different strain rates, showing a clearly nonlinear stress–strain response. In addition, the tissue of the CBVs exhibits stress relaxation and a preconditioning effect under cyclic loading, unequivocal indications of viscoelastic behavior. Interestingly, most previous literature that conducts uniaxial tensile tests had not found significant viscoelastic effects in CBVs, but the use of more sensitive tests allowed to observe the viscoelastic effects. For that reason, a careful mathematical analysis is presented, clarifying why in uniaxial tests with moderate strain rates, it is difficult to observe any viscoelastic effect. The analysis provides a theoretical explanation as to why many recent studies that investigated mechanical properties did not find a significant viscoelastic effect, even though in other circumstances, the CBV tissue would clearly exhibit viscoelastic behavior. Finally, this study provides reference values for the usual mechanical properties, as well as calculations of constitutive parameters for nonlinear elastic and viscoelastic models that would allow more accurate numerical simulation of CBVs in Finite Element-based computational models in future works.
The Regulatory Mechanism of Feeding a Diet High in Rice Grain on the Growth and microRNA Expression Profiles of the Spleen, Taking Goats as an Artiodactyl Model
Authors: Yan Qiongxian , Wang Kaijun , Han Xuefeng , Tan Zhiliang
Published: August 2021

Several researchers have testified that feeding with diets high in rice grain induces subacute ruminal acidosis and increases the risk of gastrointestinal inflammation. However, whether diets high in rice grain affect spleen growth and related molecular events remains unknown. Therefore, the present study was conducted to investigate the effects of feeding a high-concentrate (HC) diet based on rice on the growth and microRNA expression profiles in goat spleen. Sixteen Liuyang black goats were used as an artiodactyl model and fed an HC diet for five weeks. Visceral organ weight, LPS (lipopolysaccharide) concentration in the liver and spleen, and microRNA expression were analyzed. The results showed that feeding an HC diet increased the heart and spleen indexes and decreased the liver LPS concentration (p < 0.05). In total, 596 microRNAs were identified, and twenty-one of them were differentially expressed in the spleens of goats fed with the HC diet. Specifically, several microRNAs (miR-107, miR-512, miR-51b, miR-191, miR-296, miR-326, miR-6123 and miR-433) were upregulated. Meanwhile, miR-30b, miR-30d, miR-1468, miR-502a, miR-145, miR-139, miR-2284f, miR-101 and miR-92a were downregulated. Additionally, their target gene CPPED1, CDK6, CCNT1 and CASP7 expressions were inhibited (p < 0.05). These results indicated that the HC diet promoted the growth of the heart and spleen. The HC diet also regulated the expression of miR-326, miR-512-3p, miR-30b, miR-30d, miR-502a and their target genes (CPPED1, CDK6 and CCNT1) related to the enhancement of splenocyte proliferation. The HC diet also modulated the expression of miR-15b-5p, miR-1468 and miR-92a, related to the suppression of splenocyte apoptosis.
The Prognostic Value of Locoregional Interventions for BRAF V600E Metastatic Colorectal Cancer: A Retrospective Cohort Analysis
Authors: Ye Liu-Fang , Ji Xiao-Meng , Ren Chao , Wang Zhi-Qiang , Lin Chun-Ping , Chen Dong-Liang , Cai Yan-Qing , Jin Ying , Qiu Miao-Zhen , Du Zi-Ming , Xi Shao-Yan , Zhang Dong-Sheng , Wang Feng , Wang Feng-Hua , Xu Rui-Hua , Li Yu-Hong , Wang De-Shen
Published: August 2021

The prognostic heterogeneity in patients with BRAF V600E metastatic colorectal cancer (mCRC) remains poorly defined. Real-world data of 93 BRAF V600E mCRC patients from Sun Yat-sen University Cancer Center were evaluated using the prognostic factors affecting overall survival (OS). Treatment of metastases served as an independent prognosticator, where curative locoregional interventions (LRIs) were associated with superior clinical outcomes (adjusted hazard ratio (HR): 0.46, 95% confidence interval (CI): 0.22–0.98; p = 0.044). The LRIs group showed an improved median OS of 49.4 months versus 18.3 months for the palliative treatments (PTs) group. The median OS of patients with colorectal liver metastasis (CRLM) was significantly prolonged after undergoing LRIs (42.4 vs. 23.7 months; HR: 0.11, 95% CI: 0.01–1.22; p = 0.030), and patients in the LRIs plus liver-limited or lung-limited metastasis (LLM) group benefited more than those in the LRIs plus non-LLM group when compared to the PTs group (LLM from LRIs vs. PTs, HR: 0.16, 95% CI: 0.04–0.68; p = 0.006. Non-LLM from LRIs vs. PTs, HR: 0.47, 95% CI: 0.21–1.05; p = 0.074). In conclusion, we confirmed the positive prognostic value of LRIs in BRAF V600E mCRC, particularly in patients with CRLM or LLM.
Growth Suppression in Lung Cancer Cells Harboring EGFR-C797S Mutation by Quercetin
Authors: Huang Kuo-Yen , Wang Tong-Hong , Chen Chin-Chuan , Leu Yann-Lii , Li Hsin-Jung , Jhong Cai-Ling , Chen Chi-Yuan
Published: August 2021

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are approved treatments for non-small-cell lung cancer (NSCLC) patients harboring activating EGFR mutations. The EGFR C797S mutation is one of the known acquired-resistance mutations to the latest third-generation TKIs. At present, there are no clear options for treating patients who acquire resistance to third-generation TKIs. The acquisition of the EGFR C797S mutation was shown to upregulate the expression of AXL, a receptor tyrosine kinase of the TAM (TYRO3-AXL-MER) family, and the suppression of AXL is effective in reducing the growth of NSCLC cells harboring EGFR C797S. As quercetin was recently shown to inhibit AXL, quercetin may be effective in treating NSCLC cells harboring the EGFR C797S mutation. In this work, the cytotoxic effects of quercetin and its ability to inhibit tumor growth were examined in TKI-resistant NSCLC cells harboring the EGFR C797S mutation. We demonstrated that quercetin exhibited potent cytotoxic effects on NSCLC cells harboring the EGFR C797S mutation by inhibiting AXL and inducing apoptosis. Quercetin inhibited the tumor growth of xenografted NSCLC cells harboring the EGFR C797S mutation and appeared to act synergistically with brigatinib to inhibit of tumor growth in vivo. In summary, herein, we revealed that quercetin is an effective inhibitor for the treatment of non-small-cell lung cancer harboring the EGFR C797S mutation.
Matrix Metalloproteinases as Biomarkers and Treatment Targets in Mesothelioma: A Systematic Review
Authors: Štrbac Danijela , Dolžan Vita
Published: August 2021

Metalloproteinases (MMPs) have an important role in tissue remodeling and have been shown to have an effect on tumor progression, invasion, metastasis formation, and apoptosis in several tumors, including mesothelioma. Mesothelioma is a rare tumor arising from pleura and peritoneum and is frequently associated with asbestos exposure. We have performed a systematic search of PubMed.gov and ClinicalTrials.gov databases to retrieve and review three groups of studies: studies of MMPs expression in tumor tissue or body fluids in patients with mesothelioma, studies of MMPs genetic variability, and studies of MMPs as potential novel drug targets in mesothelioma. Several studies of MMPs in mesothelioma tissues reported a link between higher expression levels of commonly studied MMPs and clinical parameters, such as overall survival. Fewer studies have investigated genetic variability of MMP genes. Nevertheless, these studies suggested that certain genetic variants in MMP genes can have either protective or tumor-promoting effects on mesothelioma patients. MMPs have been also reported as novel drug targets, but so far no clinical trials of MMP inhibitors are registered in mesothelioma. In conclusion, MMPs play an important role in mesothelioma, but further studies are needed to elucidate the potentials of MMPs as biomarkers and drug targets in mesothelioma.
Design and Prototyping of Genetically Encoded Arsenic Biosensors Based on Transcriptional Regulator AfArsR
Authors: Khan Salma Saeed , Shen Yi , Fatmi Muhammad Qaiser , Campbell Robert E. , Bokhari Habib
Published: August 2021

Genetically encoded biosensors based on engineered fluorescent proteins (FPs) are essential tools for monitoring the dynamics of specific ions and molecules in biological systems. Arsenic ion in the +3 oxidation state (As3+) is highly toxic to cells due to its ability to bind to protein thiol groups, leading to inhibition of protein function, disruption of protein–protein interactions, and eventually to cell death. A genetically encoded biosensor for the detection of As3+ could potentially facilitate the investigation of such toxicity both in vitro and in vivo. Here, we designed and developed two prototype genetically encoded arsenic biosensors (GEARs), based on a bacterial As3+ responsive transcriptional factor AfArsR from Acidithiobacillus ferrooxidans. We constructed FRET-based GEAR biosensors by insertion of AfArsR between FP acceptor/donor FRET pairs. We further designed and engineered single FP-based GEAR biosensors by insertion of AfArsR into GFP. These constructs represent prototypes for a new family of biosensors based on the ArsR transcriptional factor scaffold. Further improvements of the GEAR biosensor family could lead to variants with suitable performance for detection of As3+ in various biological and environmental systems.
Publisher’s Note: Biomass—A New Open Access Journal
Authors: Stefenelli Giulia
Published: August 2021

A decisive challenge facing our generation is the continuing development of climate change conditions in a context of the ongoing expansion of the world population and energy demand [...]
Bio-Inspired Electricity Storage Alternatives to Support Massive Demand-Side Energy Generation: A Review of Applications at Building Scale
Authors: Dodón Alisson , Quintero Vanessa , Chen Austin Miguel , Mora Dafni
Published: August 2021

This work has its origin in the growing demands of energy regulations to meet future local targets and to propose a global implementation framework. A literature review related to conventional electrical energy storage systems has been carried out, presenting different cases analyzed at building scale to deepen in nature-inspired processes that propose reductions in environmental impact and present improvements in these storage devices. The use of batteries, especially lithium-ion batteries, is the most prominent among the electrical storage applications; however, improvements have been proposed through hydrogen batteries or the implementation of more environmentally friendly materials to manufacture the electrodes. In this sense, oriented to creating systems designed to protect the environment, important advances have been made in the development of storage systems based on biomimetic strategies. The latter range from the generation of energy through the respiratory processes of microorganisms to the recreation of the generation, storage, and release of energy using the thermoelectric and thermoregulatory characteristics of some insects. These facts show that the trend in research towards improving existing systems continues but reinforces the idea that new solutions must be environmentally friendly, so there is still a long way to improving the processes established thus far.
Psychological and Emotional Effects of Digital Technology on Children in COVID-19 Pandemic
Authors: Limone Pierpaolo , Toto Giusi Antonia
Published: August 2021

COVID-19 has caused obstacles in continuing normal life almost everywhere in the world by causing the implementation of social distancing and eventually imposing the lockdown. This has become the reason for the increase in technology usage in daily life for professional work as well as for entertainment purposes. There has been an increased prevalence of technology usage in adolescents and children during lockdown leaving its impact on their lives either in a positive or negative aspect. The overall documented percentage increase of technology usage in children was about 15%, of which smartphone usage has 61.7% of prevalence. Disturbance in brain functioning is suggested to be originated by compromise of neuroplasticity of the nerves. The radiofrequency (RF) radiations emitting from the smartphone are of doubtful concern as a brain tumor risk factor in children. The increased usage can have effects on brain functioning that will compromise sleep and cognitive abilities and develop risk for certain mental illnesses including, but not limited to, depression, anxiety, Alzheimer’s disease, and attention-deficit/hyperactive disorder (ADHD). Despite being a threat for developing mental illness, video games are proven to reduce depression and anxiety, and increase creativity, skills, and cognition in children. The increased usage of technology can have a positive and negative impact on the mental development of adolescents and children depending on the trends in the usage. However, parents should be monitoring their children’s mental health and behavior in these difficult times of pandemic.
Extra Virgin Oil Polyphenols Improve the Protective Effects of Hydroxytyrosol in an In Vitro Model of Hypoxia-Reoxygenation of Rat Brain
Authors: De La Cruz Cortés José Pedro , Pérez de Algaba Inmaculada , Martín-Aurioles Esther , Arrebola María Monsalud , Ortega-Hombrados Laura , Rodríguez-Pérez María Dolores , Fernández-Prior María África , Bermúdez-Oria Alejandra , Verdugo Cristina , González-Correa José Antonio
Published: August 2021

Hydroxytyrosol (HT) is the component primarily responsible for the neuroprotective effect of extra virgin olive oil (EVOO). However, it is less effective on its own than the demonstrated neuroprotective effect of EVOO, and for this reason, it can be postulated that there is an interaction between several of the polyphenols of EVOO. The objective of the study was to assess the possible interaction of four EVOO polyphenols (HT, tyrosol, dihydroxyphenylglycol, and oleocanthal) in an experimental model of hypoxia-reoxygenation in rat brain slices. The lactate dehydrogenase (LDH) efflux, lipid peroxidation, and peroxynitrite production were determined as measures of cell death, oxidative stress, and nitrosative stress, respectively. First, the polyphenols were incubated with the brain slices in the same proportions that exist in EVOO, comparing their effects with those of HT. In all cases, the cytoprotective and antioxidant effects of the combination were greater than those of HT alone. Second, we calculated the concentration–effect curves for HT in the absence or presence of each polyphenol. Tyrosol did not significantly modify any of the variables inhibited by HT. Dihydroxyphenylglycol only increased the cytoprotective effect of HT at 10 µM, while it increased its antioxidant effect at 50 and 100 µM and its inhibitory effect on peroxynitrite formation at all the concentrations tested. Oleocanthal increased the cytoprotective and antioxidant effects of HT but did not modify its inhibitory effect on nitrosative stress. The results of this study show that the EVOO polyphenols DHPG and OLC increase the cytoprotective effect of HT in an experimental model of hypoxia-reoxygenation in rat brain slices, mainly due to a possibly synergistic effect on HT’s antioxidant action. These results could explain the greater neuroprotective effect of EVOO than of the polyphenols alone.
Perspective: The Mechanobiology of Hepatocellular Carcinoma
Authors: Loneker Abigail E. , Wells Rebecca G.
Published: August 2021

Hepatocellular carcinoma (HCC) is the second most deadly primary cancer in the world and is thus a major global health challenge. HCC primarily develops in patients with an underlying chronic liver disease, the vast majority with advanced cirrhosis, characterized by increased matrix deposition and liver stiffness. Liver stiffness is highly associated with cancer development and poor patient outcome and is measured clinically to assess cancer risk; cirrhotic livers greatly exceed the threshold stiffness shown to alter hepatocyte cell behavior and to increase the malignancy of cancer cells. Recent studies have shown that cirrhotic liver cells have highly irregular nuclear morphologies and that nuclear deformation mediates mechanosensitive signaling. Separate research has shown that nuclear deformation can increase genetic instability and the accumulation of DNA damage in migrating cancer cells. We hypothesize that the mechanical changes associated with chronic liver disease are drivers of oncogenesis, activating mechanosensitive signaling pathways, increasing rates of DNA damage, and ultimately inducing malignant transformation.
Usp22 Overexpression Leads to Aberrant Signal Transduction of Cancer-Related Pathways but Is Not Sufficient to Drive Tumor Formation in Mice
Authors: Kuang Xianghong , McAndrew Michael J. , Mustachio Lisa Maria , Chen Ying-Jiun C. , Atanassov Boyko S. , Lin Kevin , Lu Yue , Shen Jianjun , Salinger Andrew , Macatee Timothy , Dent Sharon Y. R. , Koutelou Evangelia
Published: August 2021

Usp22 overexpression is observed in several human cancers and is correlated with poor patient outcomes. The molecular basis underlying this correlation is not clear. Usp22 is the catalytic subunit of the deubiquitylation module in the SAGA histone-modifying complex, which regulates gene transcription. Our previous work demonstrated that the loss of Usp22 in mice leads to decreased expression of several components of receptor tyrosine kinase and TGFβ signaling pathways. To determine whether these pathways are upregulated when Usp22 is overexpressed, we created a mouse model that expresses high levels of Usp22 in all tissues. Phenotypic characterization of these mice revealed over-branching of the mammary glands in females. Transcriptomic analyses indicate the upregulation of key pathways involved in mammary gland branching in mammary epithelial cells derived from the Usp22-overexpressing mice, including estrogen receptor, ERK/MAPK, and TGFβ signaling. However, Usp22 overexpression did not lead to increased tumorigenesis in any tissue. Our findings indicate that elevated levels of Usp22 are not sufficient to induce tumors, but it may enhance signaling abnormalities associated with oncogenesis.
Clinical and Product Features Associated with Outcome of DLBCL Patients to CD19-Targeted CAR T-Cell Therapy
Authors: Lamure Sylvain , Van Laethem François , De Verbizier Delphine , Lozano Claire , Gehlkopf Eve , Tudesq Jean-Jacques , Serrand Chris , Benzaoui Mehdi , Kanouni Tarik , Quintard Adeline , De Vos John , Tchernonog Emmanuelle , Platon Laura , Ayrignac Xavier , Ceballos Patrice , Sirvent Anne , François Mickael , Guedon Hanane , Quittet Philippe , Mongellaz Cedric , Conte Aurélie , Herbaux Charles , Bret Caroline , Taylor Naomi , Dardalhon Valérie , Cartron Guillaume
Published: August 2021

CD19-directed CAR T-cells have been remarkably successful in treating patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and transformed follicular lymphoma (t-FL). In this cohort study, we treated 60 patients with axicabtagene ciloleucel or tisagenlecleucel. Complete and partial metabolic responses (CMR/PMR) were obtained in 40% and 23% of patients, respectively. After 6.9 months of median follow-up, median progression-free survival (mPFS) and overall survival (mOS) were estimated at 3.1 and 12.3 months, respectively. Statistical analyses revealed that CMR, PFS, and OS were all significantly associated with age-adjusted international prognostic index (aaIPI, p < 0.05). T-cell subset phenotypes in the apheresis product tended to correlate with PFS. Within the final product, increased percentages of both CD4 and CD8 CAR+ effector memory cells (p = 0.02 and 0.01) were significantly associated with CMR. Furthermore, higher CMR/PMR rates were observed in patients with a higher maximal in vivo expansion of CAR T-cells (p = 0.05) and lower expression of the LAG3 and Tim3 markers of exhaustion phenotype (p = 0.01 and p = 0.04). Thus, we find that aaIPI at the time of infusion, phenotype of the CAR T product, in vivo CAR T-cell expansion, and low levels of LAG3/Tim3 are associated with the efficacy of CAR T-cell therapy in DLBCL patients.
Soluble Biomarkers with Prognostic and Predictive Value in Advanced Non-Small Cell Lung Cancer Treated with Immunotherapy
Authors: Honrubia-Peris Beatriz , Garde-Noguera Javier , García-Sánchez Jose , Piera-Molons Nuria , Llombart-Cussac Antonio , Fernández-Murga María Leonor
Published: August 2021

Numerous targeted therapies have been evaluated for the treatment of non-small cell lung cancer (NSCLC). To date, however, only a few agents have shown promising results. Recent advances in cancer immunotherapy, most notably immune checkpoint inhibitors (ICI), have transformed the treatment scenario for these patients. Although some patients respond well to ICIs, many patients do not benefit from ICIs, leading to disease progression and/or immune-related adverse events. New biomarkers capable of reliably predicting response to ICIs are urgently needed to improve patient selection. Currently available biomarkers—including programmed death protein 1 (PD-1) and its ligand (PD-L1), and tumor mutational burden (TMB)—have major limitations. At present, no well-validated, reliable biomarkers are available. Ideally, these biomarkers would be obtained through less invasive methods such as plasma determination or liquid biopsy. In the present review, we describe recent advances in the development of novel soluble biomarkers (e.g., circulating immune cells, TMB, circulating tumor cells, circulating tumor DNA, soluble factor PD-L1, tumor necrosis factor, etc.) for patients with NSCLC treated with ICIs. We also describe the potential use of these biomarkers as prognostic indicators of treatment response and toxicity.
Altered Serum Metabolic Profile Assessed by Advanced 1H-NMR in Breast Cancer Patients
Authors: Gumà Josep , Adriá-Cebrián Jose , Ruiz-Aguado Belen , Albacar Cinta , Girona Josefa , Rodríguez-Calvo Ricardo , Martínez-Micaelo Neus , Lam Eric W. F. , Masana Luis , Guaita-Esteruelas Sandra
Published: August 2021

Background: Altered lipid metabolism has been described in some types of cancer. To analyse in depth the metabolic modifications in breast cancer patients, advanced 1H-nuclear magnetic resonance was performed in these patients. The main objective of this paper was to define a specific lipidomic signature for these cancer patients. Materials and methods: Serum from 240 women (171 breast cancer patients and 69 control women) were studied and analysed by nuclear magnetic resonance. Results: Triglyceride-enriched particles, specifically very low-density lipoprotein triglycerides, intermediate-density lipoprotein triglycerides, low-density lipoprotein triglycerides, and high-density lipoprotein triglycerides, were positively associated with breast cancer. Moreover, alanine, tyrosine, and branched amino acids were also associated with increased risk of breast cancer. Conclusions: Breast cancer patients showed a modified metabolome, giving a very interesting tool to draw different radar charts between control women and breast cancer patients. To our knowledge, this is the first time that advanced nuclear magnetic resonance profiling has been used to identify relevant and specifically altered lipid or amino acid metabolites in BC serum samples. The altered metabolic signature could be analysed for early and reliable BC patient diagnosis and prognosis.
TP53 in Biology and Treatment of Osteosarcoma
Authors: Synoradzki Kamil Jozef , Bartnik Ewa , Czarnecka Anna M. , Fiedorowicz Michał , Firlej Wiktoria , Brodziak Anna , Stasinska Agnieszka , Rutkowski Piotr , Grieb Paweł
Published: August 2021

The TP53 gene is mutated in 50% of human tumors. Oncogenic functions of mutant TP53 maintain tumor cell proliferation and tumor growth also in osteosarcomas. We collected data on TP53 mutations in patients to indicate which are more common and describe their role in in vitro and animal models. We also describe animal models with TP53 dysfunction, which provide a good platform for testing the potential therapeutic approaches. Finally, we have indicated a whole range of pharmacological compounds that modulate the action of p53, stabilize its mutated versions or lead to its degradation, cause silencing or, on the contrary, induce the expression of its functional version in genetic therapy. Although many of the described therapies are at the preclinical testing stage, they offer hope for a change in the approach to osteosarcoma treatment based on TP53 targeting in the future.
Magnetic-Guided Axillary UltraSound (MagUS) Sentinel Lymph Node Biopsy and Mapping in Patients with Early Breast Cancer. A Phase 2, Single-Arm Prospective Clinical Trial
Authors: Jazrawi Allan , Pantiora Eirini , Abdsaleh Shahin , Bacovia Daniel Vasiliu , Eriksson Staffan , Leonhardt Henrik , Wärnberg Fredrik , Karakatsanis Andreas
Published: August 2021

Lymph Node Dissection (SLND) is standard of care for diagnosing sentinel lymph node (SLN) status in patients with early breast cancer. Study aim was to determine whether the combination of Superparamagnetic iron oxide nanoparticles (SPIO) MRI-lymphography (MRI-LG) and a Magnetic-guided Axillary UltraSound (MagUS) with biopsy can allow for minimally invasive, axillary evaluation to de-escalate surgery. Patients were injected with 2 mL of SPIO and underwent MRI-LG for SN mapping. Thereafter MagUS and core needle biopsy (CNB) were performed. Patients planned for neoadjuvant treatment, the SLN was clipped and SLND was performed after neoadjuvant with the addition of isotope. During surgery, SLNs were controlled for signs of previous biopsy or clip. The primary endpoint was MagUS SLN detection rate, defined as successful SLN detection of at least one SLN of those retrieved in SLND. In 79 patients, 48 underwent upfront surgery, 12 received neoadjuvant and 19 had recurrent cancer. MagUS traced the SLN in all upfront and neoadjuvant cases, detecting all patients with macrometastases (n = 10). MagUS missed only one micrometastasis, outperforming baseline axillary ultrasound AUS (AUC: 0.950 vs. 0.508, p < 0.001) and showing no discordance to SLND (p = 1.000). MagUS provides the niche for minimally invasive axillary mapping that can reduce diagnostic surgery.
External Validation of a Nomogram to Predict Survival and Benefit of Concurrent Chemoradiation for Stage II Nasopharyngeal Carcinoma
Authors: Yip Pui-Lam , Lee Shing-Fung , Choi Cheuk-Wai Horace , Chan Po-Chung Sunny , Cheung Ka-Wai Alice , Chow Chung-Hang James , Cheung Ka-Man , Lai Wing-Yu Jessica , Lee Ho-Fun Victor , Lam Ka-On , Chiang Chi-Leung , Wong Chun-Yin Edwin , Poon Ming-Chun Darren , Tong Macy , Au Kwok-Hung , Ng Wai-Tong , Ngan Kai-Cheong Roger , Lee Wing-Mui Anne , Tung Yuk Stewart
Published: August 2021

A nomogram was recently published by Sun et al. to predict overall survival (OS) and the additional benefit of concurrent chemoradiation (CCRT) vs. radiotherapy (RT) alone, in stage II NPC treated with conventional RT. We aimed to assess the predictors of OS and to externally validate the nomogram in the IMRT era. We analyzed stage II NPC patients treated with definitive RT alone or CCRT between 2001 and 2011 under the territory-wide Hong Kong NPC Study Group 1301 study. Clinical parameters were studied using the Cox proportional hazards model to estimate OS. The nomogram by Sun et al. was applied with 1000 times bootstrap resampling to calculate the concordance index, and we compared the nomogram predicted and observed 5-year OS. There were 482 patients included. The 5-year OS was 89.0%. In the multivariable analysis, an age > 45 years was the only significant predictor of OS (HR, 1.98; 95%CI, 1.15–3.44). Other clinical parameters were insignificant, including the use of CCRT (HR, 0.99; 95%CI, 0.62–1.58). The nomogram yielded a concordance index of 0.55 (95% CI, 0.49–0.62) which lacked clinically meaningful discriminative power. The nomogram proposed by Sun et al. should be interpreted with caution when applied to stage II NPC patients in the IMRT era. The benefit of CCRT remained controversial.
Breast Cancer—Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies—An Updated Review
Authors: Łukasiewicz Sergiusz , Czeczelewski Marcin , Forma Alicja , Baj Jacek , Sitarz Robert , Stanisławek Andrzej
Published: August 2021

Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide with more than 2 million new cases in 2020. Its incidence and death rates have increased over the last three decades due to the change in risk factor profiles, better cancer registration, and cancer detection. The number of risk factors of BC is significant and includes both the modifiable factors and non-modifiable factors. Currently, about 80% of patients with BC are individuals aged >50. Survival depends on both stage and molecular subtype. Invasive BCs comprise wide spectrum tumors that show a variation concerning their clinical presentation, behavior, and morphology. Based on mRNA gene expression levels, BC can be divided into molecular subtypes (Luminal A, Luminal B, HER2-enriched, and basal-like). The molecular subtypes provide insights into new treatment strategies and patient stratifications that impact the management of BC patients. The eighth edition of TNM classification outlines a new staging system for BC that, in addition to anatomical features, acknowledges biological factors. Treatment of breast cancer is complex and involves a combination of different modalities including surgery, radiotherapy, chemotherapy, hormonal therapy, or biological therapies delivered in diverse sequences.
Statin Use and Long-Term Mortality after Rectal Cancer Surgery
Authors: Pourlotfi Arvid , Bass Gary Alan , Ahl Hulme Rebecka , Forssten Maximilian Peter , Sjolin Gabriel , Cao Yang , Matthiessen Peter , Mohseni Shahin
Published: August 2021

Background: The current study aimed to assess the association between regular statin therapy and postoperative long-term all-cause and cancer-specific mortality following curative surgery for rectal cancer. The hypothesis was that statin exposure would be associated with better survival. Methods: Patients with stage I–III rectal cancer undergoing surgical resection with curative intent were extracted from the nationwide, prospectively collected, Swedish Colorectal Cancer Register (SCRCR) for the period from January 2007 and October 2016. Patients were defined as having ongoing statin therapy if they had filled a statin prescription within 12 months before and after surgery. Cox proportional hazards models were employed to investigate the association between statin use and postoperative five-year all-cause and cancer-specific mortality. Results: The cohort consisted of 10,743 patients who underwent a surgical resection with curative intent for rectal cancer. Twenty-six percent (n = 2797) were classified as having ongoing statin therapy. Statin users had a considerably decreased risk of all-cause (adjusted hazard ratio (HR) 0.66, 95% confidence interval (CI): 0.60–0.73, p < 0.001) and cancer-specific (adjusted HR 0.60, 95% CI: 0.47–0.75, p < 0.001) mortality up to five years following surgery. Conclusions: Statin use was associated with a lower risk of both all-cause and rectal cancer-specific mortality following curative surgical resections for rectal cancer. The findings should be confirmed in future prospective clinical trials.
Combination of Pembrolizumab with Electrochemotherapy in Cutaneous Metastases from Melanoma: A Comparative Retrospective Study from the InspECT and Slovenian Cancer Registry
Authors: Campana Luca G. , Peric Barbara , Mascherini Matteo , Spina Romina , Kunte Christian , Kis Erika , Rozsa Petra , Quaglino Pietro , Jones Rowan Pritchard , Clover A. James P. , Curatolo Pietro , Giorgione Roberto , Cemazar Maja , Terlizzi Francesca de , Bosnjak Masa , Sersa Gregor
Published: August 2021

Electrochemotherapy (ECT) is an effective locoregional therapy for cutaneous melanoma metastases and has been safely combined with immune checkpoint inhibitors in preliminary experiences. Since ECT is known to induce immunogenic cell death, its combination with immune checkpoint inhibitors might be beneficial. In this study, we aimed to investigate the effectiveness of ECT on cutaneous melanoma metastases in combination with pembrolizumab. We undertook a retrospective matched cohort analysis of stage IIIC–IV melanoma patients, included in the International Network for sharing practices of ECT (InspECT) and the Slovenian Cancer Registry. We compared the outcome of patients who received the following treatments: (a) pembrolizumab alone, (b) pembrolizumab plus ECT, and (c) ECT. The groups were matched for age, sex, performance status, and size of skin metastases. The local objective response rate (ORR) was higher in the pembrolizumab-ECT group than in the pembrolizumab group (78% and 39%, p < 0.001). The 1 year local progression-free survival (LPFS) rates were 86% and 51% (p < 0.001), and the 1 year systemic PFS rates were 64% and 39%, respectively (p = 0.034). The 1 year overall survival (OS) rates were 88% and 64%, respectively (p = 0.006). Our results suggest that skin-directed therapy with ECT improves superficial tumor control in melanoma patients treated with pembrolizumab. Interestingly, we observed longer PFS and OS in the pembrolizumab-ECT group than in the pembrolizumab group. These findings warrant prospective confirmation.
The Novel Antitumor Compound HCA Promotes Glioma Cell Death by Inducing Endoplasmic Reticulum Stress and Autophagy
Authors: Beteta-Göbel Roberto , Fernández-Díaz Javier , Arbona-González Laura , Rodríguez-Lorca Raquel , Torres Manuel , Busquets Xavier , Fernández-García Paula , Escribá Pablo V. , Lladó Victoria
Published: August 2021

Glioblastoma (GBM) is the most common and aggressive type of primary brain tumor in adults, and the median survival of patients with GBM is 14.5 months. Melitherapy is an innovative therapeutic approach to treat different diseases, including cancer, and it is based on the regulation of cell membrane composition and structure, which modulates relevant signal pathways. Here, we have tested the effects of 2-hydroxycervonic acid (HCA) on GBM cells and xenograft tumors. HCA was taken up by cells and it compromised the survival of several human GBM cell lines in vitro, as well as the in vivo growth of xenograft tumors (mice) derived from these cells. HCA appeared to enhance ER stress/UPR signaling, which consequently induced autophagic cell death of the GBM tumor cells. This negative effect of HCA on GBM cells may be mediated by the JNK/c-Jun/CHOP/BiP axis, and it also seems to be provoked by the cellular metabolite of HCA, C21:5n-3 (heneicosapentaenoic acid). These results demonstrate the efficacy of the melitherapeutic treatment used and the potential of using C21:5n-3 as an efficacy biomarker for this treatment. Given the safety profile in animal models, the data presented here provide evidence that HCA warrants further clinical study as a potential therapy for GBM, currently an important unmet medical need.