bluuebunny/crossref_metadata_2025 huggingface dataset:
Soil Water and Nitrogen Fluxes in Response to Climate Change in a Wheat–Maize Double Cropping System
Authors: He Yong , Shi Yilin , Liang Hao , Hu Kelin , Hou Lingling
Published: June 2020

The impact of soil nutrient depletion on crop production is a thoroughly researched issue; however, robust assessments on the impact of climate change on water and N fluxes in agroecosystem are lacking. The complexity of soil water and N fluxes in response to climate change under agroecosystems makes simulation-based approaches to this issue appealing. This study evaluated the responses of crop yield, soil water, and N fluxes of a wheat–maize rotation to two Representative Concentration Pathways climate scenarios (RCP4.5 and RCP8.5) at Tai’an, a representative site on the North China Plain (NCP). Results showed that the mean air temperature and accumulated precipitation for both winter wheat (Triticum aestivum L.) and summer maize (Zea mays L.) growing seasons changed in both magnitude and pattern under various climate scenarios. The temperature increases shortened the growth periods of these two crops by more than 13 days and decrease summer maize yields (P < 0.05). These results are illustrated by lower yield results associated with RCP4.5 (20.5%) and RCP8.5 (19.3%) climate scenarios, respectively. During the winter wheat growing season, water drainage examined in the climate scenarios was significantly higher (more than double) than the baseline, and there was no significant change to nitrate leaching and denitrification. In the summer maize growing season, with continuously rising temperatures, the ranking for evaporation was in the order baseline < RCP4.5 < RCP8.5, however, the opposite ranking applied for transpiration and evapotranspiration. The increase in water drainage was 1.4 times higher than the baseline, whereas the nitrate leaching in soil significantly decreased. Our simulation results provide an opportunity to improve the understanding of soil water and N fluxes in agroecosystems, which can lead to deficient or excess N under future climate conditions.
Species-Specific, pH-Independent, Standard Redox Potential of Selenocysteine and Selenocysteamine
Authors: Pálla Tamás , Mirzahosseini Arash , Noszál Béla
Published: June 2020

Microscopic redox equilibrium constants and standard redox potential values were determined to quantify selenolate-diselenide equilibria of biological significance. The highly composite, codependent acid-base and redox equilibria of selenolates could so far be converted into pH-dependent, apparent parameters (equilibrium constants, redox potentials) only. In this work, the selenolate-diselenide redox equilibria of selenocysteamine and selenocysteine against dithiothreitol were analyzed by quantitative nuclear magnetic resonance (NMR) methods to characterize the interfering acid-base and redox equilibria. The directly obtained, pH-dependent, conditional redox equilibrium constants were then decomposed by our method into pH-independent, microscopic constants, which characterize the two-electron redox transitions of selenocysteamine and selenocysteine. The 12 different, species-specific parameter values show close correlation with the respective selenolate basicities, providing a tool to estimate otherwise inaccessible site-specific selenolate-diselenide redox potentials of related moieties in large peptides and proteins.
Fe Porphyrin-Based SOD Mimic and Redox-Active Compound, (OH)FeTnHex-2-PyP4+, in a Rodent Ischemic Stroke (MCAO) Model: Efficacy and Pharmacokinetics as Compared to Its Mn Analogue, (H2O)MnTnHex-2-PyP5+
Authors: Li Litao , Tovmasyan Artak , Sheng Huaxin , Xu Bin , Sampaio Romulo S. , Reboucas Julio S. , Warner David S. , Batinic-Haberle Ines , Spasojevic Ivan
Published: June 2020

Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, (H2O)MnTnHex-2-PyP5+ (MnHex) carrying long hexyl chains, is a lipophilic mimic of superoxide dismutase (SOD) and a redox-active drug candidate. MnHex crosses the blood–brain barrier, and improved neurologic outcome and decreased infarct size and inflammation in a rat middle cerebral artery occlusion (MCAO) ischemic stroke model. Yet, the dose and the therapeutic efficacy of Mn porphyrin were limited by an adverse effect of arterial hypotension. An equally lipophilic Fe analog, (OH)FeTnHex-2-PyP4+ (FeHex), is as redox-active and potent SOD mimic in vitro. With different coordination geometry of the metal site, FeHex has one hydroxo (OH) ligand (instead of water) bound to the Fe center in the axial position. It has ~2 orders of magnitude higher efficacy than MnHex in an SOD-deficient E. coli model of oxidative stress. In vivo, it does not cause arterial hypotension and is less toxic to mice. We thus evaluated FeHex versus MnHex in a rodent MCAO model. We first performed short- and long-term pharmacokinetics (PK) of both porphyrins in the plasma, brain, and liver of rats and mice. Given that damage to the brain during stroke occurs very rapidly, fast delivery of a sufficient dose of drug is important. Therefore, we aimed to demonstrate if, and how fast after reperfusion, Fe porphyrin reaches the brain relative to the Mn analog. A markedly different plasma half-life was found with FeHex (~23 h) than with MnHex (~1.4 h), which resulted in a more than 2-fold higher plasma exposure (AUC) in a 7-day twice-daily treatment of rats. The increased plasma half-life is explained by the much lower liver retention of FeHex than typically found in Mn analogs. In the brain, a 3-day mouse PK study showed similar levels of MnHex and FeHex. The same result was obtained in a 7-day rat PK study, despite the higher plasma exposure of FeHex. Importantly, in a short-term PK study with treatment starting 2 h post MCAO, both Fe- and Mn- analogs distributed at a higher level to the injured brain hemisphere, with a more pronounced effect observed with FeHex. While a 3-day mouse MCAO study suggested the efficacy of Fe porphyrin, in a 7-day rat MCAO study, Mn-, but not Fe porphyrin, was efficacious. The observed lack of FeHex efficacy was discussed in terms of significant differences in the chemistry of Fe vs. the Mn center of metalloporphyrin; relative to MnHex, FeHex has the propensity for axial coordination, which in vivo would preclude the reactivity of the Fe center towards small reactive species.
When Oxidative Stress Meets Epigenetics: Implications in Cancer Development
Authors: García-Guede Álvaro , Vera Olga , Ibáñez-de-Caceres Inmaculada
Published: June 2020

Cancer is one of the leading causes of death worldwide and it can affect any part of the organism. It arises as a consequence of the genetic and epigenetic changes that lead to the uncontrolled growth of the cells. The epigenetic machinery can regulate gene expression without altering the DNA sequence, and it comprises methylation of the DNA, histones modifications, and non-coding RNAs. Alterations of these gene-expression regulatory elements can be produced by an imbalance of the intracellular environment, such as the one derived by oxidative stress, to promote cancer development, progression, and resistance to chemotherapeutic treatments. Here we review the current literature on the effect of oxidative stress in the epigenetic machinery, especially over the largely unknown ncRNAs and its consequences toward cancer development and progression.
NRF2 and Primary Cilia: An Emerging Partnership
Authors: Martin-Hurtado Ana , Lastres-Becker Isabel , Cuadrado Antonio , Garcia-Gonzalo Francesc R.
Published: June 2020

When not dividing, many cell types target their centrosome to the plasma membrane, where it nucleates assembly of a primary cilium, an antenna-like signaling structure consisting of nine concentric microtubule pairs surrounded by membrane. Primary cilia play important pathophysiological roles in many tissues, their dysfunction being associated with cancer and ciliopathies, a diverse group of congenital human diseases. Several recent studies have unveiled functional connections between primary cilia and NRF2 (nuclear factor erythroid 2-related factor 2), the master transcription factor orchestrating cytoprotective responses to oxidative and other cellular stresses. These NRF2-cilia relationships are reciprocal: primary cilia, by promoting autophagy, downregulate NRF2 activity. In turn, NRF2 transcriptionally regulates genes involved in ciliogenesis and Hedgehog (Hh) signaling, a cilia-dependent pathway with major roles in embryogenesis, stem cell function and tumorigenesis. Nevertheless, while we found that NRF2 stimulates ciliogenesis and Hh signaling, a more recent study reported that NRF2 negatively affects these processes. Herein, we review the available evidence linking NRF2 to primary cilia, suggest possible explanations to reconcile seemingly contradictory data, and discuss what the emerging interplay between primary cilia and NRF2 may mean for human health and disease.
BNC Biosynthesis with Increased Productivity in a Newly Designed Surface Air-Flow Bioreactor
Authors: Cielecka Izabela , Ryngajłło Małgorzata , Bielecki Stanisław
Published: June 2020

The application of bacterial cellulose (BNC) could be widely expanded if the production costs were reduced. This study aims to determine factors simultaneously affecting the yield and tensile strength of BNC in a newly designed surface air-flow bioreactor (SAF). For this purpose, a two-stage study was done. Firstly, the most important factors for high yield were determined based on the Plackett–Burman Design. Secondly, impact of the chosen variables on both responses was assessed in a wide range of factor values. The greatest influence on the yield and mechanical strength was proved for such factors as air-flow ratio, glucose concentration, and culture time. The productivity in a SAF bioreactor with controlled air-flow ratio was enhanced by 65%. In terms of mechanical properties, the stress of BNC membranes varied from 0.8 to 6.39 MPa depending on the culture conditions. The results of the performed tests make a useful basis for future optimizations.
A Creep Model of Asphalt Mixture Based on Variable Order Fractional Derivative
Authors: Luo Wenbo , Li Bo , Zhang Yongjun , Yin Boyuan , Dai Jingling
Published: June 2020

In order to quantitatively describe the time-varying mechanical properties of asphalt mixture during creep process, a nonlinear viscoelastoplastic creep model was proposed, by using variable-order fractional calculus. The differential order of the variable-order fractional element of the model is no longer constant, but a variable that changes with time, which reflects the changes of the mechanical properties of the material during the creep process. Whereas the tertiary creep phase is modeled by the viscoplastic element with time-varying viscosity, which is attributed to damage evolution. The uniaxial creep compression tests of AC-13C asphalt mixture under different stress levels (0.7 MPa, 0.9 MPa, 1.1 MPa, 1.3 MPa, 1.5 MPa, 1.7 MPa) were carried out with MTS-809 testing machine at 25 °C, and the test results were analyzed by the model using Levenberg–Marquardt optimization algorithm. It is shown that creep damage occurs when the applied stress exceeds a certain critical value, and the damage incubation time depends on the applied stress level. The higher stress decreases the damage incubation time. The model is in good agreement with the experimental results, and is applicable to describe the entire creep process, which consists of primary, steady and tertiary stages. Moreover, the variation of the model parameter can describe the change of viscoelastic properties of the material during the creep process. The differential order of the variable-order fractional element is constant during the primary creep stage, indicating that the creep behavior of the asphalt mixture is linear viscoelastic in small strain range. For the same stress level, the fractional order of the steady creep stage is greater than that of the primary creep stage, and it increases with the increasing stress level, which shows that the viscous behavior in the steady creep is more remarkable than that in the primary creep, and the higher the stress level, the more prominent the viscous performance exhibits.
A Compact High-Efficient Equivalent Circuit Model of Multi-Quantum-Well Vertical-Cavity Surface-Emitting Lasers for High-Speed Interconnects
Authors: Li Shanglin , Nezami Mohammadreza Sanadgol , Rolston David , Liboiron-Ladouceur Odile
Published: June 2020

Due to their low power consumption, high modulation speed, and low cost, vertical-cavity surface-emitting lasers (VCSEL) dominate short-reach data communications as the light source. In this paper, we propose a compact equivalent circuit model with noise effects for high-speed multi-quantum-well (MQW) VCSELs. The model comprehensively accounts for the carrier and photons dynamisms of a MQW structure, which includes separate confinement heterostructure (SCH) layers, barrier (B) layers, and quantum well (QW) layers. The proposed model is generalized to various VCSEL designs and accommodates a flexible number of quantum wells. Experimental validation of the model is performed at 25 Gb/s with a self-wire-bonded 850 nm VCSEL.
Preliminary Tests on the Sensitivity of the FORAIR_IT Air Quality Forecasting System to Different Meteorological Drivers
Authors: Adani Mario , Piersanti Antonio , Ciancarella Luisella , D’Isidoro Massimo , Villani Maria Gabriella , Vitali Lina
Published: June 2020

Since 2017, the operational high-resolution air quality forecasting system FORAIR_IT, developed and maintained by the Italian National Agency for New Technologies, Energy and Sustainable Economic Development, has been providing three-day forecasts of concentrations of atmospheric pollutants over Europe and Italy, on a daily basis, with high spatial resolution (20 km on Europe, 4 km on Italy). The system is based on the Atmospheric Modelling System of the National Integrated Assessment Model for Italy (AMS-MINNI), which is a national modelling system evaluated in several studies across Italy and Europe. AMS-MINNI, in its forecasting setup, is presently a candidate model for the Copernicus Atmosphere Monitoring Service’s regional production, dedicated to European-scale ensemble model forecasts of air quality. In order to improve the quality of the meteorological input into the chemical transport model component of FORAIR_IT, several tests were carried out on daily forecasts of NO2 and O3 concentrations for January and August 2019 (representative of the meteorological seasons of winter and summer, respectively). The aim was to evaluate the sensitivity to the meteorological input in NO2 and O3 concentration forecasting. More specifically, the Weather Research and Forecasting model (WRF) was tested to potentially improve the meteorological driver with respect to the Regional Atmospheric Modelling System (RAMS), which is currently embedded in FORAIR_IT. In this work, the WRF chain is run in several setups, changing the parameterization of several micrometeorological variables (snow, mixing height, albedo, roughness length, soil heat flux + friction velocity, Monin–Obukhov length), with the main objective being to take advantage of WRF’s consistent physics in the calculation of both mesoscale variables and micrometeorological parameters for air quality simulations. Daily forecast concentrations produced by the different meteorological model configurations are compared to the available measured concentrations, showing the general good performance of WRF-driven results, even if performance skills are different according to the single meteorological configuration and to the pollutant type. WRF-driven forecasts clearly improve the model reproduction of the temporal variability of concentrations, while the bias of O3 is higher than in the RAMS-driven configuration. The results suggest that we should keep testing WRF configurations, with the objective of obtaining a robust improvement in forecast concentrations with respect to RAMS-driven forecasts.
Improved Simulation of the Antarctic Stratospheric Final Warming by Modifying the Orographic Gravity Wave Parameterization in the Beijing Climate Center Atmospheric General Circulation Model
Authors: Lu Yixiong , Wu Tongwen , Xu Xin , Zhang Li , Chu Min
Published: June 2020

The Antarctic stratospheric final warming (SFW) is usually simulated with a substantial delay in climate models, and the corresponding temperatures in austral spring are lower than observations, implying insufficient stratospheric wave drag. To investigate the role of orographic gravity wave drag (GWD) in modeling the Antarctic SFW, in this study the orographic GWD parameterization scheme is modified in the middle-atmosphere version of the Beijing Climate Center Atmospheric General Circulation Model. A pair of simulations are conducted to compare two orographic GWD schemes in simulating the breakdown of the stratospheric polar vortex over Antarctica. The control simulation with the default orographic GWD scheme exhibits delayed vortex breakdown and the cold-pole bias seen in most climate models. In the simulation with modified orographic GWD scheme, the simulated vortex breaks down earlier by 8 days, and the associated cold-pole bias is reduced by more than 2 K. The modified scheme provides stronger orographic GWD in the lower stratosphere, which drives an accelerated polar downwelling branch of the Brewer–Dobson circulation and, in turn, produces adiabatic warming. Our study suggests that modifying orographic GWD parameterizations in climate models would be a valid way of improving the SFW simulation over Antarctica.
Reconstructing Elemental Carbon Long-Term Trend in the Po Valley (Italy) from Fog Water Samples
Authors: Gilardoni Stefania , Tarozzi Leone , Sandrini Silvia , Ielpo Pierina , Contini Daniele , Putaud Jean-Philippe , Cavalli Fabrizia , Poluzzi Vanes , Bacco Dimitri , Leonardi Cristina , Genga Alessandra , Langone Leonardo , Fuzzi Sandro
Published: June 2020

Elemental carbon (EC), a ubiquitous component of fine atmospheric aerosol derived from incomplete combustion, is an important player for both climate change and air quality deterioration. Several policy measures have been implemented over the last decades to reduce EC emissions from anthropogenic sources, but still, long-term EC measurements to verify the efficacy of such measurements are limited. In this study, we analyze the concentration of EC suspended in fog water samples, collected over the period 1997–2016 in a rural background site of the southern Po Valley. The comparison between EC in fog water and EC atmospheric aerosol concentration measured since 2012 allowed us to reconstruct EC atmospheric concentration from fog water chemical composition dating back to 1997. The results agree with the EC atmospheric observations performed at the European Monitoring and Evaluation Program (EMEP) station of Ispra in the northern part of the Po Valley since 2002, and confirm that the Po Valley is a pollution hotspot, not only in urban areas, but also in rural locations. The reconstructed trend over the period 1997–2016 indicates that EC concentration during the winter season has decreased on average by 4% per year, in agreement with the emission reduction rate, confirming the effectiveness of air quality measures implemented during the past 20 years.
Significance of STAT3 in Immune Infiltration and Drug Response in Cancer
Authors: Chen Wei , Dai Xiaoshuo , Chen Yihuan , Tian Fang , Zhang Yanyan , Zhang Qiushuang , Lu Jing
Published: June 2020

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor and regulates tumorigenesis. However, the functions of STAT3 in immune and drug response in cancer remain elusive. Hence, we aim to reveal the impact of STAT3 in immune infiltration and drug response comprehensively by bioinformatics analysis. The expression of STAT3 and its relationship with tumor stage were explored by Tumor Immune Estimation Resource (TIMER), Human Protein Altas (HPA), and UALCAN databases. The correlations between STAT3 and immune infiltration, gene markers of immune cells were analyzed by TIMER. Moreover, the association between STAT3 and drug response was evaluated by the Cancer Cell Line Encyclopedia (CCLE) and Cancer Therapeutics Response Portal (CTRP). The results suggested that the mRNA transcriptional level of STAT3 was lower in tumors than normal tissues and mostly unrelated to tumor stage. Besides, the protein expression of STAT3 decreased in colorectal and renal cancer compared with normal tissues. Importantly, STAT3 was correlated with immune infiltration and particularly regulated tumor-associated macrophage (TAM), M2 macrophage, T-helper 1 (Th1), follicular helper T (Treg), and exhausted T-cells. Remarkably, STAT3 was closely correlated with the response to specified inhibitors and natural compounds in cancer. Furthermore, the association between STAT3 and drug response was highly cell line type dependent. Significantly, the study provides thorough insight that STAT3 is associated with immunosuppression, as well as drug response in clinical treatment.
Effects of Flavanols on Enteroendocrine Secretion
Authors: Grau-Bové Carme , González-Quilen Carlos , Terra Ximena , Blay M. Teresa , Beltrán-Debón Raul , Jorba-Martín Rosa , Espina Beatriz , Pinent Montserrat , Ardévol Anna
Published: June 2020

Some beneficial effects of grape seed proanthocyanidin extract (GSPE) can be explained by the modulation of enterohormone secretion. As GSPE comprises a combination of different molecules, the pure compounds that cause these effects need to be elucidated. The enterohormones and chemoreceptors present in the gastrointestinal tract differ between species, so if humans are to gain beneficial effects, species closer to humans—and humans themselves—must be used. We demonstrate that 100 mg/L of GSPE stimulates peptide YY (PYY) release, but not glucagon-like peptide 1 (GLP-1) release in the human colon. We used a pig ex vivo system that differentiates between apical and basolateral intestinal sides to analyse how apical stimulation with GSPE and its pure compounds affects the gastrointestinal tract. In pigs, apical GSPE treatment stimulates the basolateral release of PYY in the duodenum and colon and that of GLP-1 in the ascending, but not the descending colon. In the duodenum, luminal stimulation with procyanidin dimer B2 increased PYY secretion, but not CCK secretion, while catechin monomers (catechin/epicatechin) significantly increased CCK release, but not PYY release. The differential effects of GSPE and its pure compounds on enterohormone release at the same intestinal segment suggest that they act through chemosensors located apically and unevenly distributed along the gastrointestinal tract.
Molecular Pathways and Targeted Therapies for Malignant Ovarian Germ Cell Tumors and Sex Cord–Stromal Tumors: A Contemporary Review
Authors: Maoz Asaf , Matsuo Koji , Ciccone Marcia A. , Matsuzaki Shinya , Klar Maximilian , Roman Lynda D. , Sood Anil K. , Gershenson David M.
Published: June 2020

Non-epithelial ovarian tumors are heterogeneous and account for approximately 10% of ovarian malignancies. The most common subtypes of non-epithelial ovarian tumors arise from germ cells or sex cord and stromal cells of the gonads. These tumors are usually detected at an early stage, and management includes surgical staging and debulking. When indicated for advanced disease, most respond to chemotherapy; however, options for patients with refractory disease are limited, and regimens can be associated with significant toxicities, including permanent organ dysfunction, secondary malignancies, and death. Targeted therapies that potentially decrease chemotherapy-related adverse effects and improve outcomes for patients with chemotherapy-refractory disease are needed. Here, we review the molecular landscape of non-epithelial ovarian tumors for the purpose of informing rational clinical trial design. Recent genomic discoveries have uncovered recurring somatic alterations and germline mutations in subtypes of non-epithelial ovarian tumors. Though there is a paucity of efficacy data on targeted therapies, such as kinase inhibitors, antibody–drug conjugates, immunotherapy, and hormonal therapy, exceptional responses to some compounds have been reported. The rarity and complexity of non-epithelial ovarian tumors warrant collaboration and efficient clinical trial design, including high-quality molecular characterization, to guide future efforts.
Cabozantinib Inhibits Photodynamic Therapy-Induced Auto- and Paracrine MET Signaling in Heterotypic Pancreatic Microtumors
Authors: Broekgaarden Mans , Alkhateeb Ahmed , Bano Shazia , Bulin Anne-Laure , Obaid Girgis , Rizvi Imran , Hasan Tayyaba
Published: June 2020

Extensive desmoplasia is a hallmark of pancreatic ductal adenocarcinoma (PDAC), which frequently associates with treatment resistance. Recent findings indicate that a combination of photodynamic therapy and the multi-kinase inhibitor cabozantinib achieved local tumor control and a significant decrease in tumor metastases in preclinical PDAC models, but the underlying therapeutic mechanisms remain unclear. This study elucidates the molecular basis of this multi-agent regimen, focusing on the role of MET signaling. Since MET activation stems from its interaction with hepatocyte growth factor (HGF), which is typically secreted by fibroblasts, we developed heterotypic PDAC microtumor models that recapitulate these interactions. In these models, MET signaling can be constitutively activated through paracrine and autocrine mechanisms. Photodynamic therapy caused significant elevations in HGF secretion by fibroblasts, suggesting it plays a complex role in the modulation of the paracrine HGF–MET signaling cascade in desmoplastic tumors. Blocking MET phosphorylation with adjuvant cabozantinib caused a significant improvement in photodynamic therapy efficacy, most notably by elevating spheroid necrosis at low radiant exposures. These findings highlight that adjuvant photodynamic therapy can augment chemotherapy efficacies, and potentially achieve improved management of desmoplastic PDAC in a more tolerable manner.
Gastric Cancer Staging: Is It Time for Magnetic Resonance Imaging?
Authors: Renzulli Matteo , Clemente Alfredo , Spinelli Daniele , Ierardi Anna Maria , Marasco Giovanni , Farina Davide , Brocchi Stefano , Ravaioli Matteo , Pettinari Irene , Cescon Matteo , Reginelli Alfonso , Cappabianca Salvatore , Carrafiello Gianpaolo , Golfieri Rita
Published: June 2020

Gastric cancer (GC) is a common cancer worldwide. Its incidence and mortality vary depending on geographic area, with the highest rates in Asian countries, particularly in China, Japan, and South Korea. Accurate imaging staging has become crucial for the application of various treatment strategies, especially for curative treatments in early stages. Unfortunately, most GCs are still diagnosed at an advanced stage, with the peritoneum (61–80%), distant lymph nodes (44–50%), and liver (26–38%) as the most common metastatic locations. Metastatic disease is limited to the peritoneum in 58% of cases; in nonperitoneal distant metastases, the most involved GC metastasization site is the liver (82%). The eighth edition of the tumor-node-metastasis staging system is the most commonly used system for determining GC prognosis. Endoscopic ultrasonography, computed tomography, and 18-fluorideoxyglucose positron emission tomography are historically the most accurate imaging techniques for GC staging. However, studies have recently shown renewed interest in magnetic resonance imaging (MRI) as a useful tool in GC staging, especially for distant metastasis assessment. The technical improvement of diffusion-weighted imaging and the increasing use of hepatobiliary contrast agents have been shown to increase the diagnostic performance of MRI, particularly for detecting peritoneal and liver metastasis. However, no principal oncological guidelines have included the use of MRI as a first-line technique for distant metastasis evaluation during the GC staging process, such as the National Comprehensive Cancer Network Guidelines. This review analyzed the role of the principal imaging techniques in GC diagnosis and staging, focusing on the potential role of MRI, especially for assessing peritoneal and liver metastases.
A H-REV107 Peptide Inhibits Tumor Growth and Interacts Directly with Oncogenic KRAS Mutants
Authors: Han Chang Woo , Jeong Mi Suk , Ha Sung Chul , Jang Se Bok
Published: June 2020

Kirsten-RAS (KRAS) has been the target of drugs because it is the most mutated gene in human cancers. Because of the low affinity of drugs for KRAS mutations, it was difficult to target these tumor genes directly. We found a direct interaction between KRAS G12V and tumor suppressor novel H-REV107 peptide with high binding affinity. We report the first crystal structure of an oncogenic mutant, KRAS G12V-H-REV107. This peptide was shown to interact with KRAS G12V in the guanosine diphosphate (GDP)-bound inactive state and to form a stable complex, blocking the activation function of KRAS. We showed that the peptide acted as an inhibitor of mutant KRAS targets by [α-32P] guanosine triphosphate (GTP) binding assay. The H-REV107 peptide inhibited pancreatic cancer and colon cancer cell lines in cell proliferation assay. Specially, the H-REV107 peptide can suppress pancreatic tumor growth by reduction of tumor volume and weight in xenotransplantation mouse models. Overall, the results presented herein will facilitate development of novel drugs for inhibition of KRAS mutations in cancer patients.
Pharmacogenomic Analysis Reveals CCNA2 as a Predictive Biomarker of Sensitivity to Polo-Like Kinase I Inhibitor in Gastric Cancer
Authors: Lee Yunji , Lee Chae Eun , Oh Sejin , Kim Hakhyun , Lee Jooyoung , Kim Sang Bum , Kim Hyun Seok
Published: June 2020

Despite recent innovations and advances in early diagnosis, the prognosis of advanced gastric cancer remains poor due to a limited number of available therapeutics. Here, we employed pharmacogenomic analysis of 37 gastric cancer cell lines and 1345 small-molecule pharmacological compounds to investigate biomarkers predictive of cytotoxicity among gastric cancer cells to the tested drugs. We discovered that expression of CCNA2, encoding cyclin A2, was commonly associated with responses to polo-like kinase 1 (PLK1) inhibitors (BI-2536 and volasertib). We also found that elevated CCNA2 expression is required to confer sensitivity to PLK1 inhibitors through increased mitotic catastrophe and apoptosis. Further, we demonstrated that CCNA2 expression is elevated in KRAS mutant gastric cancer cell lines and primary tumors, resulting in an increased sensitivity to PLK1 inhibitors. Our study suggests that CCNA2 is a novel biomarker predictive of sensitivity to PLK1 inhibitors for the treatment of advanced gastric cancer, particularly cases carrying KRAS mutation.
Retrospective Multicentric Study on Non-Optic CNS Tumors in Children and Adolescents with Neurofibromatosis Type 1
Authors: Santoro Claudia , Picariello Stefania , Palladino Federica , Spennato Pietro , Melis Daniela , Roth Jonathan , Cirillo Mario , Quaglietta Lucia , D’Amico Alessandra , Gaudino Giuseppina , Meucci Maria Chiara , Ferrara Ursula , Constantini Shlomi , Perrotta Silverio , Cinalli Giuseppe
Published: June 2020

The natural history of non-optic central nervous system (CNS) tumors in neurofibromatosis type 1 (NF1) is largely unknown. Here, we describe prevalence, clinical presentation, treatment, and outcome of 49 non-optic CNS tumors observed in 35 pediatric patients (0–18 years). Patient- and tumor-related data were recorded. Overall survival (OS) and progression-free survival (PFS) were evaluated. Eighteen patients (51%) harbored an optic pathway glioma (OPG) and eight (23%) had multiple non-optic CNS lesions. The majority of lesions (37/49) were managed with a wait-and-see strategy, with one regression and five reductions observed. Twenty-one lesions (42.9%) required surgical treatment. Five-year OS was 85.3%. Twenty-four patients progressed with a 5-year PFS of 41.4%. Patients with multiple low-grade gliomas progressed earlier and had a lower 5-year PFS than those with one lesion only (14.3% vs. 57.9%), irrespective of OPG co-presence. Non-optic CNS tumors are common in young patients with NF1. Neither age and symptoms at diagnosis nor tumor location influenced time to progression in our series. Patients with multiple lesions tended to have a lower age at onset and to progress earlier, but with a good OS.
Functional Characterization of POFUT1 Variants Associated with Colorectal Cancer
Authors: Deschuyter Marlène , Pennarubia Florian , Pinault Emilie , Legardinier Sébastien , Maftah Abderrahman
Published: June 2020

Background: Protein O-fucosyltransferase 1 (POFUT1) overexpression, which is observed in many cancers such as colorectal cancer (CRC), leads to a NOTCH signaling dysregulation associated with the tumoral process. In rare CRC cases, with no POFUT1 overexpression, seven missense mutations were found in human POFUT1. Methods: Recombinant secreted forms of human WT POFUT1 and its seven mutated counterparts were produced and purified. Their O-fucosyltransferase activities were assayed in vitro using a chemo-enzymatic approach with azido-labeled GDP-fucose as a donor substrate and NOTCH1 EGF-LD26, produced in E. coli periplasm, as a relevant acceptor substrate. Targeted mass spectrometry (MS) was carried out to quantify the O-fucosyltransferase ability of all POFUT1 proteins. Findings: MS analyses showed a significantly higher O-fucosyltransferase activity of six POFUT1 variants (R43H, Y73C, T115A, I343V, D348N, and R364W) compared to WT POFUT1. Interpretation: This study provides insights on the possible involvement of these seven missense mutations in colorectal tumors. The hyperactive forms could lead to an increased O-fucosylation of POFUT1 protein targets such as NOTCH receptors in CRC patients, thereby leading to a NOTCH signaling dysregulation. It is the first demonstration of gain-of-function mutations for this crucial glycosyltransferase, modulating NOTCH activity, as well as that of other potential glycoproteins.
Association of a CT-Based Clinical and Radiomics Score of Non-Small Cell Lung Cancer (NSCLC) with Lymph Node Status and Overall Survival
Authors: Botta Francesca , Raimondi Sara , Rinaldi Lisa , Bellerba Federica , Corso Federica , Bagnardi Vincenzo , Origgi Daniela , Minelli Rocco , Pitoni Giovanna , Petrella Francesco , Spaggiari Lorenzo , Morganti Alessio G. , Del Grande Filippo , Bellomi Massimo , Rizzo Stefania
Published: June 2020

Background: To evaluate whether a model based on radiomic and clinical features may be associated with lymph node (LN) status and overall survival (OS) in lung cancer (LC) patients; to evaluate whether CT reconstruction algorithms may influence the model performance. Methods: patients operated on for LC with a pathological stage up to T3N1 were retrospectively selected and divided into training and validation sets. For the prediction of positive LNs and OS, the Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression model was used; univariable and multivariable logistic regression analysis assessed the association of clinical-radiomic variables and endpoints. All tests were repeated after dividing the groups according to the CT reconstruction algorithm. p-values < 0.05 were considered significant. Results: 270 patients were included and divided into training (n = 180) and validation sets (n = 90). Transfissural extension was significantly associated with positive LNs. For OS prediction, high- and low-risk groups were different according to the radiomics score, also after dividing the two groups according to reconstruction algorithms. Conclusions: a combined clinical–radiomics model was not superior to a single clinical or single radiomics model to predict positive LNs. A radiomics model was able to separate high-risk and low-risk patients for OS; CTs reconstructed with Iterative Reconstructions (IR) algorithm showed the best model performance.
Combined Targeting of Glioblastoma Stem-Like Cells by Neutralizing RNA-Bio-Drugs for STAT3
Authors: Esposito Carla Lucia , Nuzzo Silvia , Ibba Maria Luigia , Ricci-Vitiani Lucia , Pallini Roberto , Condorelli Gerolama , Catuogno Silvia , de Franciscis Vittorio
Published: June 2020

An important drawback in the management of glioblastoma (GBM) patients is the frequent relapse upon surgery and therapy. A likely explanation is that conventional therapies poorly affect a small population of stem-like cancer cells (glioblastoma stem cells, GSCs) that remain capable of repopulating the tumour mass. Indeed, the development of therapeutic strategies able to hit GSCs while reducing the tumour burden has become an important challenge to increase a patient’s survival. The signal transducer and activator of transcription-3 (STAT3) has been reported to play a pivotal role in maintaining the tumour initiating capacity of the GSC population. Therefore, in order to impair the renewal and propagation of the PDGFRβ-expressing GSC population, here we took advantage of the aptamer–siRNA chimera (AsiC), named Gint4.T-STAT3, that we previously have shown to efficiently antagonize STAT3 in subcutaneous PDGFRβ-positive GBM xenografts. We demonstrate that the aptamer conjugate is able to effectively and specifically prevent patient-derived GSC function and expansion. Moreover, because of the therapeutic potential of using miR-10b inhibitors and of the broad expression of the Axl receptor in GBM, we used the GL21.T anti-Axl aptamer as the targeting moiety for anti-miR-10b, showing that, in combination with the STAT3 AsiC, the aptamer–miR-10b antagonist treatment further enhances the inhibition of GSC sphere formation. Our results highlight the potential to use a combined approach with targeted RNA therapeutics to inhibit GBM tumour dissemination and relapse.
Micrometastases in Sentinel Lymph Nodes Represent a Significant Negative Prognostic Factor in Early-Stage Cervical Cancer: A Single-Institutional Retrospective Cohort Study
Authors: Kocian Roman , Slama Jiri , Fischerova Daniela , Germanova Anna , Burgetova Andrea , Dusek Ladislav , Dundr Pavel , Nemejcova Kristyna , Jarkovsky Jiri , Sebestova Silvie , Fruhauf Filip , Dostalek Lukas , Ballaschova Tereza , Cibula David
Published: June 2020

The data on the prognostic significance of low volume metastases in lymph nodes (LN) are inconsistent. The aim of this study was to retrospectively analyze the outcome of a large group of patients treated with sentinel lymph node (SLN) biopsy at a single referral center. Patients with cervical cancer, stage T1a-T2b, common tumor types, negative LN on preoperative staging, treated by primary surgery between 01/2007 and 12/2016, with at least unilateral SLN detection were included. Patients with abandoned radical surgery due to intraoperative SLN positivity detected by frozen section were excluded. All SLNs were postoperatively processed by an intensive protocol for pathological ultrastaging. Altogether, 226 patients were analyzed. Positive LN were detected in 38 (17%) cases; macrometastases (MAC), micrometastases (MIC), isolated tumor cells (ITC) in 14, 16, and 8 patients. With the median follow-up of 65 months, 22 recurrences occurred. Disease-free survival (DFS) reached 90% in the whole group, 93% in LN-negative cases, 89% in cases with MAC, 69% with MIC, and 87% with ITC. The presence of MIC in SLN was associated with significantly decreased DFS and OS. Patients with MIC and MAC should be managed similarly, and SLN ultrastaging should become an integral part of the management of patients with early-stage cervical cancer.
SPON2 Is Upregulated through Notch Signaling Pathway and Promotes Tumor Progression in Gastric Cancer
Authors: Kang Hyeon-Gu , Kim Won-Jin , Noh Myung-Giun , Chun Kyung-Hee , Kim Seok-Jun
Published: June 2020

Spondin-2 (SPON2) is involved in cancer progression and metastasis of many tumors; however, its role and underlying mechanism in gastric cancer are still obscure. In this study, we investigated the role of SPON2 and related signaling pathway in gastric cancer progression and metastasis. SPON2 expression levels were found to be upregulated in gastric cancer cell lines and patient tissues compared to normal gastric epithelial cells and normal controls. Furthermore, SPON2 silencing was observed to decrease cell proliferation and motility and reduce tumor growth in xenograft mice. Conversely, SPON2 overexpression was found to increase cell proliferation and motility. Subsequently, we focused on regulatory mechanism of SPON2 in gastric cancer. cDNA microarray and in vitro study showed that Notch signaling is significantly correlated to SPON2 expression. Therefore, we confirmed how Notch signaling pathway regulate SPON2 expression using Notch signaling-related transcription factor interaction and reporter gene assay. Additionally, activation of Notch signaling was observed to increase cell proliferation, migration, and invasion through SPON2 expression. Our study demonstrated that Notch signaling-mediated SPON2 upregulation is associated with aggressive progression of gastric cancer. In conclusion, we suggest upregulated SPON2 via Notch signaling as a potential target gene to inhibit gastric cancer progression.
Metabolic Profiling of Early and Late Recurrent Pancreatic Ductal Adenocarcinoma Using Patient-Derived Organoid Cultures
Authors: Braun Lukas M. , Lagies Simon , Klar Rhena F. U. , Hussung Saskia , Fritsch Ralph M. , Kammerer Bernd , Wittel Uwe A.
Published: June 2020

Pancreatic ductal adenocarcinoma (PDAC) is associated with high mortality and will become the second most common cause of cancer-associated mortality by 2030. The poor prognosis arises from a lack of sensitive biomarkers, limited therapeutic options, and the astonishingly high recurrence rate after surgery of 60–80%. The factors driving this recurrence, however, remain enigmatic. Therefore, we generated patient-derived organoids (PDOs) from early- and late-recurrent PDAC patients. Cellular identity of PDOs was confirmed by qPCR, ddPCR, and IHC analyses. This is the first study investigating the metabolism in PDOs of different, clinically significant PDAC entities by untargeted GC/MS profiling. Partial least square discriminant analysis unveiled global alterations between the two sample groups. We identified nine metabolites to be increased in early recurrent PDOs in comparison to late recurrent PDOs. More than four-times increased were fumarate, malate, glutamate, aspartate, and glutamine. Hence, α-keto acids were elevated in PDO-conditioned medium derived from early recurrent patients. We therefore speculate that an increased anaplerotic metabolism fuels the Krebs-cycle and a corresponding higher accessibility to energy fastens the recurrence in PDAC patients. Therein, a therapeutic intervention could delay PDAC recurrence and prolong survival of affected patients or could serve as biomarker to predict recurrence in the future.
A Germline Mutation in the POT1 Gene Is a Candidate for Familial Non-Medullary Thyroid Cancer
Authors: Srivastava Aayushi , Miao Beiping , Skopelitou Diamanto , Kumar Varun , Kumar Abhishek , Paramasivam Nagarajan , Bonora Elena , Hemminki Kari , Försti Asta , Bandapalli Obul Reddy
Published: June 2020

Non-medullary thyroid cancer (NMTC) is a common endocrine malignancy with a genetic basis that has yet to be unequivocally established. In a recent whole-genome sequencing study of five families with occurrence of NMTCs, we shortlisted promising variants with the help of bioinformatics tools. Here, we report in silico analyses and in vitro experiments on a novel germline variant (p.V29L) in the highly conserved oligonucleotide/oligosaccharide binding domain of the Protection of Telomeres 1 (POT1) gene in one of the families. The results showed a reduction in telomere-bound POT1 levels in the mutant protein as compared to its wild-type counterpart. HEK293T cells carrying POT1 p.V29L showed increased telomere length in comparison to wild-type cells, suggesting that the mutation causes telomere dysfunction and may play a role in predisposition to NMTC in this family. While one germline mutation in POT1 has already been reported in a melanoma-prone family with prevalence of thyroid cancers, we report the first of such mutations in a family affected solely by NMTCs, thus expanding current knowledge on shelterin complex-associated cancers.
Adenosine A2AReceptors in Substance Use Disorders: A Focus on Cocaine
Authors: Wydra Karolina , Gawliński Dawid , Gawlińska Kinga , Frankowska Małgorzata , Borroto-Escuela Dasiel O. , Fuxe Kjell , Filip Małgorzata
Published: June 2020

Several psychoactive drugs can evoke substance use disorders (SUD) in humans and animals, and these include psychostimulants, opioids, cannabinoids (CB), nicotine, and alcohol. The etiology, mechanistic processes, and the therapeutic options to deal with SUD are not well understood. The common feature of all abused drugs is that they increase dopamine (DA) neurotransmission within the mesocorticolimbic circuitry of the brain followed by the activation of DA receptors. D2 receptors were proposed as important molecular targets for SUD. The findings showed that D2 receptors formed heteromeric complexes with other GPCRs, which forced the addiction research area in new directions. In this review, we updated the view on the brain D2 receptor complexes with adenosine (A)2A receptors (A2AR) and discussed the role of A2AR in different aspects of addiction phenotypes in laboratory animal procedures that permit the highly complex syndrome of human drug addiction. We presented the current knowledge on the neurochemical in vivo and ex vivo mechanisms related to cocaine use disorder (CUD) and discussed future research directions for A2AR heteromeric complexes in SUD.
Early Reperfusion Following Ischemic Stroke Provides Beneficial Effects, Even After Lethal Ischemia with Mature Neural Cell Death
Authors: Tanaka Yasue , Nakagomi Nami , Doe Nobutaka , Nakano-Doi Akiko , Sawano Toshinori , Takagi Toshinori , Matsuyama Tomohiro , Yoshimura Shinichi , Nakagomi Takayuki
Published: June 2020

Ischemic stroke is a critical disease caused by cerebral artery occlusion in the central nervous system (CNS). Recent therapeutic advances, such as neuroendovascular intervention and thrombolytic therapy, have allowed recanalization of occluded brain arteries in an increasing number of stroke patients. Although previous studies have focused on rescuing neural cells that still survive despite decreased blood flow, expanding the therapeutic time window may allow more patients to undergo reperfusion in the near future, even after lethal ischemia, which is characterized by death of mature neural cells, such as neurons and glia. However, it remains unclear whether early reperfusion following lethal ischemia results in positive outcomes. The present study used two ischemic mouse models—90-min transient middle cerebral artery occlusion (t-MCAO) paired with reperfusion to induce lethal ischemia and permanent middle cerebral artery occlusion (p-MCAO)—to investigate the effect of early reperfusion up to 8 w following MCAO. Although early reperfusion following 90-min t-MCAO did not rescue mature neural cells, it preserved the vascular cells within the ischemic areas at 1 d following 90-min t-MCAO compared to that following p-MCAO. In addition, early reperfusion facilitated the healing processes, including not only vascular but also neural repair, during acute and chronic periods and improved recovery. Furthermore, compared with p-MCAO, early reperfusion after t-MCAO prevented behavioral symptoms of neurological deficits without increasing negative complications, including hemorrhagic transformation and mortality. These results indicate that early reperfusion provides beneficial effects presumably via cytoprotective and regenerative mechanisms in the CNS, suggesting that it may be useful for stroke patients that experienced lethal ischemia.