bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship of postsaccadic oscillation with the state of the pupil inside the iris and with cognitive processing
Authors: Yamagishi Shimpei , Yoneya Makoto , Furukawa Shigeto
Published: December 2019

Recent studies using video-based eye tracking have presented accumulating evidence that postsaccadic oscillation defined in reference to the pupil center (PSOp) is larger than that to the iris center (PSOi). This indicates that the relative motion of the pupil reflects the viscoelasticity of the tissue of the iris. It is known that the pupil size controlled by the sphincter/dilator pupillae muscles reflects many aspects of cognition. A hypothesis derived from this fact is that cognitive tasks affect the properties of PSOp due to the change in the state of these muscles. To test this hypothesis, we conducted pro- and antisaccade tasks for human participants and adopted the recent physical model of PSO to evaluate the dynamic properties of PSOp/PSOi. The results showed the dependence of the elasticity coefficient of the PSOp on the antisaccade task, but this effect was not significant for the PSOi. This suggests that cognitive tasks such as antisaccade tasks affect elasticity of the muscle of the iris. We found that the trial-by-trial fluctuation in the presaccade absolute pupil size correlated with the elasticity coefficient of PSOp. We also found the task dependence of the viscosity coefficient and overshoot amount of PSOi, which probably reflects the dynamics of the entire eyeball movement. The difference in task dependence between PSOp and PSOi indicates that the separate measures of these two can be means to distinguish factors related to the oculomotor neural system from those related to the physiological states of the iris tissue.

NEW & NOTEWORTHY The state of the eyeball varies dynamically moment by moment depending on underlying neural/cognitive processing. Combining simultaneous measurements of pupil-centric and iris-centric movements and a recent physical model of postsaccadic oscillation (PSO), we show that the pupil-centric PSO is sensitive to the type of saccade task, suggesting that the physical state of the iris muscles reflects the underlying cognitive processes.
Gaze direction as equilibrium: more evidence from spatial and temporal aspects of small-saccade triggering in the rhesus macaque monkey
Authors: Hafed Ziad M. , Goffart Laurent
Published: December 2019

Rigorous behavioral studies made in human subjects have shown that small-eccentricity target displacements are associated with increased saccadic reaction times, but the reasons for this remain unclear. Before characterizing the neurophysiological foundations underlying this relationship between the spatial and temporal aspects of saccades, we tested the triggering of small saccades in the male rhesus macaque monkey. We also compared our results to those obtained in human subjects, both from the existing literature and through our own additional measurements. Using a variety of behavioral tasks exercising visual and nonvisual guidance of small saccades, we found that small saccades consistently require more time than larger saccades to be triggered in the nonhuman primate, even in the absence of any visual guidance and when valid advance information about the saccade landing position is available. We also found a strong asymmetry in the reaction times of small upper versus lower visual field visually guided saccades, a phenomenon that has not been described before for small saccades, even in humans. Following the suggestion that an eye movement is not initiated as long as the visuo-oculomotor system is within a state of balance, in which opposing commands counterbalance each other, we propose that the longer reaction times are a signature of enhanced times needed to create the symmetry-breaking condition that puts downstream premotor neurons into a push-pull regime necessary for rotating the eyeballs. Our results provide an important catalog of nonhuman primate oculomotor capabilities on the miniature scale, allowing concrete predictions on underlying neurophysiological mechanisms.

NEW & NOTEWORTHY Leveraging a multitude of neurophysiological investigations in the rhesus macaque monkey, we generated and tested hypotheses about small-saccade latencies in this animal model. We found that small saccades always take longer, on average, than larger saccades to trigger, regardless of visual and cognitive context. Moreover, small downward saccades have the longest latencies overall. Our results provide an important documentation of oculomotor capabilities of an indispensable animal model for neuroscientific research in vision, cognition, and action.
Modularity underlying the performance of unusual locomotor tasks inspired by developmental milestones
Authors: Hinnekens Elodie , Berret Bastien , Do Manh-Cuong , Teulier Caroline
Published: December 2019

Motor behaviors are often hypothesized to be set up from the combination of a small number of modules encoded in the central nervous system. These modules are thought to combine such that a variety of motor tasks can be realized, from reproducible tasks such as walking to more unusual locomotor tasks that typically exhibit more step-by-step variability. We investigated the impact of step-by-step variability on the modular architecture of unusual tasks compared with walking. To this aim, 20 adults had to perform walking and two unusual modes of locomotion inspired by developmental milestones (cruising and crawling). Sixteen surface electromyography (EMG) signals were recorded to extract both spatial and temporal modules. Modules were extracted from both averaged and nonaveraged (i.e., single step) EMG signals to assess the significance of step-to-step variability when participants practiced such unusual locomotor tasks. The number of modules extracted from averaged data was similar across tasks, but a higher number of modules was required to reconstruct nonaveraged EMG data of the unusual tasks. Although certain walking modules were shared with cruising and crawling, task-specific modules were necessary to account for the muscle patterns underlying these unusual locomotion modes. These results highlight a more complex modularity (e.g., more modules) for cruising and crawling compared with walking, which was only apparent when the step-to-step variability of EMG patterns was considered. This suggests that considering nonaveraged data is relevant when muscle modularity is studied, especially in motor tasks with high variability as in motor development.

NEW & NOTEWORTHY This study addresses the general question of modularity in locomotor control. We demonstrate for the first time the importance of intraindividual variability in the muscle modularity of unusual locomotor behaviors that exhibit greater step-by-step variability than standard walking. Crawling and cruising, the unusual locomotor modes considered, are based on a more complex modular organization than walking. More spatial and temporal modules, task specific or shared with walking modules, are needed to reconstruct muscle patterns.
Burst-like conditioning electrical stimulation is more efficacious than continuous stimulation for inducing secondary hyperalgesia in humans
Authors: Gousset S. , Mouraux A. , van den Broeke E. N.
Published: December 2019

The aim of the present study was to compare the efficacy of burst-like conditioning electrical stimulation vs. continuous stimulation of cutaneous nociceptors for inducing increased pinprick sensitivity in the surrounding unstimulated skin (a phenomenon referred to as secondary hyperalgesia). In a first experiment ( n = 30), we compared the increase in mechanical pinprick sensitivity induced by 50-Hz burst-like stimulation ( n = 15) vs. 5-Hz continuous stimulation ( n = 15) while maintaining constant the total number of stimuli and the total duration of stimulation. We found a significantly greater increase in mechanical pinprick sensitivity in the surrounding unstimulated skin after 50-Hz burst-like stimulation compared with 5-Hz continuous stimulation ( P = 0.013, Cohen’s d = 0.970). Importantly, to control for the different frequency of stimulation, we compared in a second experiment ( n = 40) 5-Hz continuous stimulation ( n = 20) vs. 5-Hz burst-like stimulation ( n = 20), this time while keeping the total number of stimuli as well as the frequency of stimulation identical. Again, we found a significantly greater increase in pinprick sensitivity after 5-Hz burst-like stimulation compared with 5-Hz continuous stimulation ( P = 0.009, Cohen’s d = 0.868). To conclude, our data indicate that burst-like conditioning electrical stimulation is more efficacious than continuous stimulation for inducing secondary hyperalgesia.

NEW & NOTEWORTHY Burst-like electrical conditioning stimulation of cutaneous nociceptors is more efficacious than continuous stimulation for inducing heterosynaptic facilitation of mechanical nociceptive input in humans.
Intratumoral Heterogeneity Determines the Expression of mTOR-pathway Proteins in Prostate Cancer
Authors: Russo Giorgio Ivan , Hennenlotter Jörg , Vogel Ulrich , Kühs Ursula , Wurm Thomas Manfred , Gerber Valentina , Neumann Tim , Cimino Sebastiano , Stenzl Arnulf , Todenhöfer Tilman
Published: December 2019

The aim of this study was to evaluate the expression of mammalian target of rapamycin (mTOR), phosphorylated-mTOR (p-mTOR), and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) in prostate cancer (PCa) in order to assess intratumoral heterogeneity and correlation with clinicopathological parameters. Tissue samples from 115 patients undergoing radical prostatectomy were included in a tissue microarray comprising (A) tissue from the tumor center, (B) malignant border of the tumor, (C) tumor-adjacent benign tissue, and (D) tumor-distant benign prostatic tissue. Immune reactive scores 0-12 were correlated with clinical data in reference to localization. A meta-analysis of studies investigating the association between biochemical recurrence (BCR) and parameters of the mTOR pathway was conducted. Regardless of the location within the tumor, cancer tissue showed higher expression of mTOR, p-mTOR, and 4EB-P1 compared to benign tissue (p<0.01). Significant differences in expression between tissue samples from groups C and D were observed for mTOR and p-mTOR. When considering expression according to the pathological stage, we observed lower p-mTOR expression in pT3 vs. pT2 (7.9 and 6.3; p=0.01). After a median follow-up of 74.5 months (IQR 65.0-84.0), 27 patients (23.47%) developed BCR. Weak staining of mTOR was associated with shorter time to BCR (HR: 2.0; p=0.049) after correcting for PSA and T stage. However, a significant association of mTOR expression with BCR was found for specimens from the malignant border of the tumor (B) but not the tumor center (A) (p=0.0034 log rank). In a meta-analysis, we found that the expressions of mTOR (RR=0.70; 95% CI 0.43-1.12; p=0.13) and 4E-BP1 (RR=0.86; p=0.53) were not statistically associated with BCR, while strong staining of p-mTOR was associated with a lower risk of BCR (RR=0.57; p=0.002). All 3 markers showed stronger expression in PCa and exhibited local gradients in relation to the border of tumor and healthy tissue. Our results suggest an important role of intratumor heterogeneity for the use of mTOR parameters as biomarkers in PCa.
A Combination of an Antimitotic and a Bromodomain 4 Inhibitor Synergistically Inhibits the Metastatic MDA-MB-231 Breast Cancer Cell Line
Authors: Mqoco Thandi , Stander André , Engelbrecht Anna-Mart , Joubert Anna M
Published: December 2019

Current chemotherapeutic agents have many side effects and are toxic to normal cells, providing impetus to identify agents that can effectively eliminate tumorigenic cells without damaging healthy cells. The aim of this study was to examine whether combining a novel BRD4 inhibitor, ITH-47, with the antimitotic estradiol analogue, ESE-15-ol, would have a synergistic effect on inhibiting the growth of two different breast cancer cell lines in vitro. Our docking and molecular dynamics studies showed that compared to JQ1, ITH-47 showed a similar binding mode with hydrogen bonds forming between the ligand nitrogens of the pyrazole, ASN99, and water of the BRD4 protein. Data from cell growth studies revealed that the GI50 of ITH-47 and ESE-15-ol after 48 hours of exposure was determined to be 15 μM and 70 nM, respectively, in metastatic MDA-MB-231 breast cancer cells. In tumorigenic MCF-7 breast cancer cells, the GI50 of ITH-47 and ESE-15-ol was 75 μM and 60 nM, respectively, after 48 hours of exposure. Furthermore, the combination of 7.5 μM and 14 nM of ITH-47 and ESE-15-ol, respectively, resulted in 50% growth inhibition of MDA-MB-231 cells resulting in a synergistic combination index (CI) of 0.7. Flow cytometry studies revealed that, compared to the control, combination-treated MDA-MB-231 cells had significantly more cells present in the sub-G1 phase and the combination treatment induced apoptosis in the MDA-MB-231 cells. Compared to vehicle-treated cells, the combination-treated cells showed decreased levels of the BRD4, as well as c-Myc protein after 48 hours of exposure. In combination, the selective BRD4 inhibitor, ITH-47, and ESE-15-ol synergistically inhibited the growth of MDA-MB-231 breast cancer cells, but not of the MCF-7 cell line. This study provides evidence that resistance to BRD4 inhibitors may be overcome by combining inhibitors with other compounds, which may have treatment potential for hormone-independent breast cancers.
Influence of Resveratrol on Oxidation Processes and Lipid Phase Characteristics in Damaged Somatic Nerves
Authors: Pinyaev S. I. , Kuzmenko T. P. , Revina N. V. , Parchaykina M. V. , Pronin A. S. , Syusin I. V. , Novozhilova O. S. , Revin V. V. , Chudaikina E. V. , Revina E. S.
Published: December 2019

It has been shown that the intensification of oxidative processes is observed when somatic nerves of rats are damaged. Accumulation of malondialdehyde occurs, and the phase properties of the lipid bilayer change, especially in the distal part of the nerve. Under the same conditions, there are multidirectional changes in the activity of antioxidant enzymes, superoxide dismutase (SOD) activity decreases, and catalase (CAT) activity increases. Under the action of resveratrol, there is a decrease in the number of TBA-active products in both areas of the damaged nerve. Alongside resveratrol action, SOD and CAT activity tends to return towards the control values. Similar patterns are observed in the action of resveratrol on the phase states of lipids with the damage to somatic nerves. By summarizing the data obtained, it can be claimed that when the nerve is damaged, profound changes occur both in the lipid component and in the antioxidant system. Resveratrol has a stabilizing effect on the studied parameters, and a longer period of time is required for their complete recovery.
Auricular Electrical Stimulation Alleviates Headache through CGRP/COX-2/TRPV1/TRPA1 Signaling Pathways in a Nitroglycerin-Induced Migraine Rat Model
Authors: Liao Chung-Chih , Li Jung-Miao , Hsieh Ching-Liang
Published: December 2019

The study aimed to investigate effect of auricular electrical stimulation (ES) on migraine. Migraine was induced in rats by intraperitoneal administration of nitroglycerin (NTG, 10 mg/kg) three times. Auricular ES pretreatment was performed for five consecutive days. Migraine behaviors were observed by a video recording. Auricular ES pretreatment could reverse the decrease of the total time spent on exploratory (2619.0 ± 113.0 s vs 1581.7 ± 217.6 s, p=0.0029) and locomotor behaviors (271.3 ± 21.4 s vs 114.3 ± 19.7 s, p=0.0135) and also could reverse the increase of the total time spent on resting (19.0 ± 10.6 s vs 154.3 ± 46.5 s, p=0.0398) and grooming (369.9 ± 66.8 s vs 1302.0 ± 244.5 s, p=0.0324) behaviors. Auricular ES pretreatment could increase the frequency of rearing behaviors (38.0 ± 1.8 vs 7.7 ± 3.5, p<0.0001) and total distance traveled (1372.0 ± 157.9 cm vs 285.3 ± 85.6 cm, p<0.0001) and also could increase the percentage of inner zone time (6.0 ± 1.6% vs 0.4 ± 0.2%, p=0.0472). The CGRP, COX-2, TRPV1, and TRPA1 immunoreactive cells in the trigeminal ganglion increased in the NTG group compared with the control group (all p<0.0001); this increase could, however, be reduced by auricular ES pretreatment (27.8 ± 2.6 vs 63.0 ± 4.2, p<0.0001; 21.7 ± 1.2 vs 61.8 ± 4.0, p<0.0001; 24.3 ± 1.0 vs 36.5 ± 1.7, p=0.0003; and 20.7 ± 1.9 vs 90.8 ± 6.5, p<0.0001, respectively). Therefore, we suggest that auricular ES pretreatment is beneficial for the treatment of migraine and this effect is partly related to CGRP/COX-2/TRPV1/TRPA1 signaling pathways.
Melatonin Attenuates β-Glycerophosphate-Induced Calcification of Vascular Smooth Muscle Cells via a Wnt1/β-Catenin Signaling Pathway
Authors: Chen Wei Ren , Zhou Yu Jie , Yang Jia Qi , Liu Fang , Zhao Ying Xin , Sha Yuan
Published: December 2019

Background. Melatonin has been demonstrated to protect against calcification in cyclosporine nephrotoxicity. The wingless-type MMTV integration site family member 1 (Wnt1)/β-catenin pathway is associated with cardiovascular calcification. This study aimed to explore whether melatonin could attenuate VSMC calcification through regulating the Wnt1/β-catenin signaling pathway. Methods. The effects of melatonin on vascular calcification were investigated in vascular smooth muscle cells (VSMCs). Calcium deposits were visualized by Alizarin Red Staining. Calcium content and alkaline phosphatase (ALP) activity were used to evaluate osteogenic differentiation. Western blots were used to measure the expression of runt-related transcription factor 2 (Runx2), α-smooth muscle actin (α-SMA), and cleaved caspase-3. Results. Melatonin markedly ameliorated calcium deposition and ALP activity. Runx2 and cleaved caspase-3 were found to be reduced and α-SMA was found to be increased by melatonin, together with a decrease in apoptosis. Immunofluorescence assay revealed a lower Runx2 protein level in the melatonin group. Melatonin treatment significantly decreased the expression of Wnt1 and β-catenin. Treatment with lithium chloride or transglutaminase 2 abrogated the protective effects of melatonin. Conclusion. Melatonin can attenuate β-GP-induced VSMC calcification through the suppression of Wnt1/β-catenin system.
A Novel Technique for Resolver-to-Digital Conversion Using Principal Frequency Component S-Transform
Authors: He Like , Yi Jiliang
Published: December 2019

A novel technique for resolver-to-digital conversion (RDC) using principal frequency component S-transform (PFCST) is proposed in this paper. First, the mode envelope of two output signals of the resolver is extracted by PFCST. The envelope extracted by PFCST maintains the same time resolution as the original signal because it performs time-frequency conversion for each sampling point. Then, the quadrant of the resolver is determined by the judgment rule formed by the polarity of the optimum nonzero region of the signals, and the quadrant information is used to correct the arctangent to obtain the accurate rotor position. Finally, the simulations prove that the maximum angle error of the resolver estimated by this method occurs at the quadrant junction but does not exceed one deg., and the experiments are used to verify the effectiveness of the proposed method.
Carbon Dots: A Mystic Star in the World of Nanoscience
Authors: Gayen Biswajit , Palchoudhury Soubantika , Chowdhury Joydeep
Published: December 2019

Carbon dots (CDs) have received significant attention worldwide from the beginning of this century, and recently, it has bloomed in every branch of applied sciences. Because of their outstanding physical and chemical properties together with biocompatibilities, CDs find a wide spectrum of applications in drug delivery, explosive detection, chemical sensing, food safety, bioimaging, energy conversion, photocatalysis, etc. This brief review is focused on the synthesis of CDs and their applications. The photophysical properties of CDs are also discussed herewith.
Hypoxia-Induced ROS Contribute to Myoblast Pyroptosis during Obstructive Sleep Apnea via the NF-κB/HIF-1α Signaling Pathway
Authors: Yu Li-Ming , Zhang Wei-Hua , Han Xin-Xin , Li Yuan-Yuan , Lu Yun , Pan Jie , Mao Jia-Qi , Zhu Lu-Ying , Deng Jia-Jia , Huang Wei , Liu Yue-Hua
Published: December 2019

Tissue hypoxia caused by upper airway collapse is a main cause of excessive oxidative stress and systemic inflammation in obstructive sleep apnea (OSA) patients. Increased reactive oxygen species (ROS) and inflammatory responses affect cell survival and ultimately contribute to tissue injury. In the present study, we proposed that the induction of ROS by hypoxia, as an intrinsic stress, activates myoblast pyroptosis in OSA. We found increased cell death and abnormal expression of pyroptosis markers in the skeletal muscle of OSA mice. In vitro studies showed hypoxia-induced pyroptotic death of C2C12 myoblasts, as evidenced by the activation of caspase-1 and gasdermin D (GSDMD). Hypoxia induced ROS overproduction and accumulation in myoblasts. More importantly, applying N-acetylcysteine (NAC), an ROS scavenger, rescued cell swelling, downregulated the inflammatory response, and prevented pyroptotic death in hypoxia-cultured myoblasts. Hypoxia stimulation promoted NF-κB P65 phosphorylation and HIF-1α nuclear translocation. Moreover, hypoxia increased the nuclear level of cleaved caspase-1 and GSDMD. NAC inhibited hypoxia-induced variations in the HIF-1α and NF-κB signaling pathway. Taken together, our results determined that hypoxia-induced ROS contribute to myoblast pyroptosis. Therefore, our findings suggest that ROS may be a potential therapeutic target for ameliorating hypoxia-induced cell death and tissue injury, especially in OSA and hypoxia-related diseases.
Induction Motor Stator Interturn Short Circuit Fault Detection in Accordance with Line Current Sequence Components Using Artificial Neural Network
Authors: Rajamany Gayatridevi , Srinivasan Sekar , Rajamany Krishnan , Natarajan Ramesh K.
Published: December 2019

The intention of fault detection is to detect the fault at the beginning stage and shut off the machine immediately to avoid motor failure due to the large fault current. In this work, an online fault diagnosis of stator interturn fault of a three-phase induction motor based on the concept of symmetrical components is presented. A mathematical model of an induction motor with turn fault is developed to interpret machine performance under fault. A Simulink model of a three-phase induction motor with stator interturn fault is created for extraction of sequence components of current and voltage. The negative sequence current can provide a decisive and rapid monitoring technique to detect stator interturn short circuit fault of the induction motor. The per unit change in negative sequence current with positive sequence current is the main fault indicator which is imported to neural network architecture. The output of the feedforward backpropagation neural network classifies the short circuit fault level of stator winding.
Complex Resistivity Dispersion Characteristics of Water‐Bearing Coal Based on Double Cole‐Cole Model
Authors: Li Jian , Lei Dongji , Zhao Chenguang , Meng Hui
Published: December 2019

Reservoir fracture evaluation is an important research topic in the coalfield. In recent years, complex resistivity (CR) has been widely used in oil logging and achieved good results, such as permeability evaluation, water saturation (Sw) prediction, and aquifer identification. Therefore, the method has the potential to evaluate coal seam fracture. In the experiment, the real part R and imaginary part X of bituminous and anthracite coal with different Sw were measured by the impedance measuring instrument, then the Double Cole-Cole model was used to fit experimental data and analyze conductive mechanism. The main results are as follows: (1) the dispersion of CR parameters Reρ and Imρ is closely related to the metamorphism degree, frequency, and Sw; (2) induced polarization is the fundamental reason for the variation of coal samples’ complex resistivity parameters with frequency change; and (3) the Double Cole-Cole model agrees well with the experimental data, and the model parameters m1 and τ2 are strongly correlated with Sw. The parameters m1 and τ2 can be used to evaluate the Sw of fractures in coal seams and thus to evaluate the effect of hydraulic fracturing.
Computing the Mean‐Variance‐Sustainability Nondominated Surface by ev‐MOGA
Authors: Garcia-Bernabeu A. , Salcedo J. V. , Hilario A. , Pla-Santamaria D. , Herrero Juan M.
Published: December 2019

Despite the widespread use of the classical bicriteria Markowitz mean‐variance framework, a broad consensus is emerging on the need to include more criteria for complex portfolio selection problems. Sustainable investing, also called socially responsible investment, is becoming a mainstream investment practice. In recent years, some scholars have attempted to include sustainability as a third criterion to better reflect the individual preferences of those ethical or green investors who are willing to combine strong financial performance with social benefits. For this purpose, new computational methods for optimizing this complex multiobjective problem are needed. Multiobjective evolutionary algorithms (MOEAs) have been recently used for portfolio selection, thus extending the mean‐variance methodology to obtain a mean‐variance‐sustainability nondominated surface. In this paper, we apply a recent multiobjective genetic algorithm based on the concept of ε‐dominance called ev‐MOGA. This algorithm tries to ensure convergence towards the Pareto set in a smart distributed manner with limited memory resources. It also adjusts the limits of the Pareto front dynamically and prevents solutions belonging to the ends of the front from being lost. Moreover, the individual preferences of socially responsible investors could be visualised using a novel tool, known as level diagrams, which helps investors better understand the range of values attainable and the tradeoff between return, risk, and sustainability.
Global Solar Radiation Models in Minas Gerais, Southeastern Brazil
Authors: Martins Monteiro Ana Flávia , Martins Fabrina Bolzan
Published: December 2019

Accurate and complete global solar radiation (Hs) data at a specific region are crucial for regional climate assessment, crop growth modeling, and all operations that use solar energy. However, in the Minas Gerais state, Southeastern Brazil (SEB), the number of weather stations that measure global solar radiation is scarce, and when it is available, it presents gaps in the time series. An attractive alternative to solve the data gap problem is to estimate global solar radiation using empirical models. In this study, thirteen models based on maximum and minimum air temperatures, precipitation, sunshine duration, and extraterrestrial solar radiation were compared in the daily estimation ofHs.Data from 10 weather stations, from 1999 to 2017, located in Minas Gerais were used. Also, cluster analysis was used to group the localities (weather stations) with similar patterns of model performance, climatic classification (Köppen–Geiger and Thornthwaite), and seasonal data variability, considering minimum and maximum air temperatures, precipitation, sunshine duration, and global solar radiation. Although it is apparently simple, studies on this subject are scarce and the few existing ones in Minas Gerais have flaws, which justifies this study. The models were evaluated by root mean square error (RMSE), mean absolute percentage error (MAPE), mean bias error (BIAS), Willmott’s index of agreement (d), and performance index (c-index). Models based on sunshine duration, such as those proposed by Ertekin and Yaldiz and by Newland, showed the best performance (averagec-index = 0.71). Models based on temperature and precipitation showed the worst results (averagec-index = 0.41). Cluster analysis showed that there is a similar pattern between the performance of the models, climatic classification, and seasonal variability of data among the localities of Minas Gerais. In general, models that presented extremely poor performance were formed with weather stations located in the dry zone, but with different climate classification, and models that presented very good (and good) performance were composed by weather stations located in the humid zone (dry subhumid) with the same climate classification and similar seasonal variability. Furthermore, the models based on temperature have a tendency to overestimate radiation values below 10 MJ·m−2 day−1and to underestimate values higher than 25 MJ·m−2 day−1. This point is a limitation of the model for estimating global solar radiation below and above these levels, showing the influence of atmospheric systems and atmospheric attenuation mechanisms of global solar radiation.
Placental Delta-Like 1 Gene DNA Methylation Levels Are Related to Mothers’ Blood Glucose Concentration
Authors: Zhao Bai-Hui , Jiang Ying , Zhu Hong , Xi Fang-Fang , Chen Yuan , Xu Ye-Tao , Liu Fang , Wang Ya-Yun , Hu Wen-Sheng , Lv Wei-Guo , Luo Qiong
Published: December 2019

Purpose. We aim to identify the methylation status of delta-like 1 (DLK1) in the placenta and the correlation between DLK1 methylation and maternal serum glucose level and fetal birth weight. Methods. We analyzed the gene expression of DLK1 gene in both maternal and fetal sides of the placenta in a GDM group (n=15) and a control group (n=15) using real-time polymerase chain reaction. With MethylTargetTM technique, we detected the methylation status of DLK1 promotor in the placenta. Furthermore, Pearson’s correlation was used to confirm the association of methylation alteration of DLK1 promoter and maternal 2 h OGTT glucose level and fetal birth weight. Results. In our study, we found that DLK1 expression in both maternal and fetal sides of the placenta decreased significantly in GDM group compared with control group, and it was caused by hypermethylation of DLK1 promoter region. Additionally, the methylation status of DLK1 gene in the maternal side of the placenta highly correlated with maternal 2 h OGTT glucose level (coefficient=0.7968, P<0.0001), while the methylation status in the fetal side of the placenta was closely related to fetal birth weight (coefficient=0.6233, P<0.0001). Conclusions. Our results demonstrated that altered expression of DLK1 was caused by the hypermethylation of DLK1 promoter region in the placenta, and intrauterine exposure to GDM has long-lasting effects on the epigenome of the offspring.
Wide Excision of a Retroperitoneal Liposarcoma with En Bloc Ureterectomy and Renal Salvage by Autotransplantation
Authors: Paloyo Siegfredo R. , Ramirez Arjel D. , David-Paloyo Ferri P. , Dofitas Rodney B.
Published: December 2019

Liposarcoma is a malignant mesenchymal neoplasm composed of adipose tissue with varying degrees of atypia. These tumors grow slowly and may reach an enormous size particularly if located in the retroperitoneum. We report a 40-year-old male with a 6-month history of gradual abdominal enlargement. Computed tomography (CT) of the abdomen showed a huge retroperitoneal mass with characteristic features consistent with liposarcoma. On laparotomy, the mass was noted to be encasing the right ureter for which a wide excision with en bloc ureterectomy and subsequent renal autotransplantation for organ preservation was done. Post-operative course was uneventful with excellent outcome after 6 months of follow-up. Final histopathologic diagnosis was low-grade, well differentiated liposarcoma, which has favorable prognosis following radical surgery. This was the first report of such a case in the Philippines.
Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians
Authors: Lu Yingchang , Kweon Sun-Seog , Cai Qiuyin , Tanikawa Chizu , Shu Xiao-Ou , Jia Wei-Hua , Xiang Yong-Bing , Huyghe Jeroen R. , Harrison Tabitha A. , Kim Jeongseon , Shin Aesun , Kim Dong-Hyun , Matsuo Keitaro , Jee Sun Ha , Guo Xingyi , Wen Wanqing , Shi Jiajun , Li Bingshan , Wang Nan , Shin Min-Ho , Li Hong-Lan , Ren Zefang , Oh Jae Hwan , Oze Isao , Ahn Yoon-Ok , Jung Keum Ji , Gao Jing , Gao Yu-Tang , Pan Zhi-Zhong , Kamatani Yoichiro , Chan Andrew T. , Gsur Andrea , Hampe Jochen , Le Marchand Loic , Li Li , Lindblom Annika , Moreno Victor , Newcomb Polly A. , Offit Kenneth , Pharoah Paul D.P. , van Duijnhoven Franzel J.B. , Van Guelpen Bethany , Vodicka Pavel , Weinstein Stephanie J. , Wolk Alicja , Wu Anna H. , Hsu Li , Zeng Yi-Xin , Long Jirong , Peters Ulrike , Matsuda Koichi , Zheng Wei
Published: December 2019

Background:

Risk variants identified so far for colorectal cancer explain only a small proportion of familial risk of this cancer, particularly in Asians.

Methods:

We performed a genome-wide association study (GWAS) of colorectal cancer in East Asians, including 23,572 colorectal cancer cases and 48,700 controls. To identify novel risk loci, we selected 60 promising risk variants for replication using data from 58,131 colorectal cancer cases and 67,347 controls of European descent. To identify additional risk variants in known colorectal cancer loci, we performed conditional analyses in East Asians.

Results:

An indel variant, rs67052019 at 1p13.3, was found to be associated with colorectal cancer risk at P = 3.9 × 10–8 in Asians (OR per allele deletion = 1.13, 95% confidence interval = 1.08–1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 (P = 7.7 × 10–3). Of the remaining 59 variants, 12 showed an association at P < 0.05 in the European-ancestry study, including rs11108175 and rs9634162 at P < 5 × 10−8 and two variants with an association near the genome-wide significance level (rs60911071, P = 5.8 × 10−8; rs62558833, P = 7.5 × 10−8) in the combined analyses of Asian- and European-ancestry data. In addition, using data from East Asians, we identified 13 new risk variants at 11 loci reported from previous GWAS.

Conclusions:

In this large GWAS, we identified three novel risk loci and two highly suggestive loci for colorectal cancer risk and provided evidence for potential roles of multiple genes and pathways in the etiology of colorectal cancer. In addition, we showed that additional risk variants exist in many colorectal cancer risk loci identified previously.

Impact:

Our study provides novel data to improve the understanding of the genetic basis for colorectal cancer risk.
Whole Exome Sequencing of Highly Aggregated Lung Cancer Families Reveals Linked Loci for Increased Cancer Risk on Chromosomes 12q, 7p, and 4q
Authors: Musolf Anthony M. , Moiz Bilal A. , Sun Haiming , Pikielny Claudio W. , Bossé Yohan , Mandal Diptasri , de Andrade Mariza , Gaba Colette , Yang Ping , Li Yafang , You Ming , Govindan Ramaswamy , Wilson Richard K. , Kupert Elena Y. , Anderson Marshall W. , Schwartz Ann G. , Pinney Susan M. , Amos Christopher I. , Bailey-Wilson Joan E.
Published: December 2019

Background:

Lung cancer kills more people than any other cancer in the United States. In addition to environmental factors, lung cancer has genetic risk factors as well, though the genetic etiology is still not well understood. We have performed whole exome sequencing on 262 individuals from 28 extended families with a family history of lung cancer.

Methods:

Parametric genetic linkage analysis was performed on these samples using two distinct analyses—the lung cancer only (LCO) analysis, where only patients with lung cancer were coded as affected, and the all aggregated cancers (AAC) analysis, where other cancers seen in the pedigree were coded as affected.

Results:

The AAC analysis yielded a genome-wide significant result at rs61943670 in POLR3B at 12q23.3. POLR3B has been implicated somatically in lung cancer, but this germline finding is novel and is a significant expression quantitative trait locus in lung tissue. Interesting genome-wide suggestive haplotypes were also found within individual families, particularly near SSPO at 7p36.1 in one family and a large linked haplotype spanning 4q21.3-28.3 in a different family. The 4q haplotype contains potential causal rare variants in DSPP at 4q22.1 and PTPN13 at 4q21.3.

Conclusions:

Regions on 12q, 7p, and 4q are linked to increased cancer risk in highly aggregated lung cancer families, 12q across families and 7p and 4q within a single family. POLR3B, SSPO, DSPP, and PTPN13 are currently the best candidate genes.

Impact:

Functional work on these genes is planned for future studies and if confirmed would lead to potential biomarkers for risk in cancer.
High-Negative Anti–Helicobacter pylori IgG Antibody Titers and Long-Term Risk of Gastric Cancer: Results from a Large-Scale Population-Based Cohort Study in Japan
Authors: Inoue Manami , Sawada Norie , Goto Atsushi , Shimazu Taichi , Yamaji Taiki , Iwasaki Motoki , Tsugane Shoichiro
Published: December 2019

Background:

Serologic testing of anti–Helicobacter pylori antibody, together with testing of pepsinogen I and II, is now widely used to stratify groups at high risk of gastric cancer in Japan. Those with a negative anti–H. pylori IgG titer, especially “high-negative” (3–<10 U/mL), are speculated to have higher risk of gastric cancer. We aimed to evaluate the association between a high-negative anti–H. pylori IgG titer and the long-term risk of gastric cancer in the Japan Public Health Center-based Prospective Study (JPHC Study) Cohort II.

Methods:

The study population consisted of 19,106 Japanese men and women who were followed from 1993 to 2013. A Cox proportional hazards model was used to assess the risk of gastric cancer for plasma anti–H. pylori IgG titers, together with the severity of atrophic gastritis by pepsinogen I and II levels. A total of 595 cases of gastric cancer occurred during an average of 18 years of follow-up.

Results:

Compared with those with a low-negative anti–H. pylori IgG titer (≤3 U/mL), subjects with a high-negative titer (3–<10 U/mL) showed a significantly elevated risk of gastric cancer [HR = 2.81; 95% confidence interval (CI) = 1.62–4.89]. Among those with a high-negative titer, risk increase was observed under moderate or severe atrophic gastritis (HR = 18.73; 95% CI = 8.83–39.70).

Conclusions:

Our results suggest that those with a high-negative anti–H. pylori IgG titer and moderate and severe atrophic gastritis are at increased long-term risk of gastric cancer.

Impact:

Development of moderate or severe atrophic gastritis in subjects with high-negative anti–H. pylori IgG titer is suggested to increase risk of gastric cancer.
Clinical Application of Next-Generation Sequencing–Based Panel toBRAFWild-Type Advanced Melanoma Identifies Key Oncogenic Alterations and Therapeutic Strategies
Authors: Park Changhee , Kim Miso , Kim Min Jung , Kim Hyeongmin , Ock Chan-Young , Keam Bhumsuk , Kim Tae Min , Kim Dong-Wan , Kim Jong-Il , Heo Dae Seog
Published: December 2019

Molecular profiling with next-generation sequencing (NGS) has been applied in multiple solid cancers to discover potential therapeutic targets. Here, we describe the results of a clinical NGS panel in patients with advanced melanoma. Thirty-six tumor tissues from patients with BRAF wild-type melanoma at Seoul National University Hospital (SNUH; Seoul, Republic of Korea) were collected and deep-sequenced using the SNUH FIRST-Cancer NGS panel to assess single-nucleotide variants, small insertions/deletions, copy number variations, and structural variations to estimate tumor mutation burden (TMB). We discovered 106 oncogenic alterations and most of the patients (n = 33, 92%) harbored at least one oncogenic alteration, including 2 patients who were initially diagnosed as BRAF V600E–negative but were later confirmed to be positive. Altogether, 36 samples were classified into RAS/BRAF/NF1–mutant (n = 14, 39%) or triple wild-type (n = 22, 61%) melanoma subtypes. The estimated median TMB was 8.2 mutations per Mb, ranging from 0 to 146.67 mutations per Mb. Of the 36 patients, 25 (70%) had actionable alterations with currently developed drugs, and 7 (19.4%) were enrolled in clinical trials with an RAF inhibitor, multiple receptor tyrosine kinase inhibitor, and anti-programmed cell death-1 (PD-1) antibody. TMB tended to associate with progression-free survival (PFS) of treatment with anti-PD-1/PDL-1 antibody (HR, 0.96; 95% confidence interval, 0.92–1.00; P = 0.07). High-TMB (≥13) group was associated with longer PFS than the low-TMB group (median 34.0 vs. 11.0 weeks, P = 0.04). Overall, the clinical use of a NGS panel in patients with advanced melanoma shows association with clinical outcomes and several therapeutic strategies.
MAIT Cells Promote Tumor Initiation, Growth, and Metastases via Tumor MR1
Authors: Yan Juming , Allen Stacey , McDonald Elizabeth , Das Indrajit , Mak Jeffrey Y.W. , Liu Ligong , Fairlie David P. , Meehan Bronwyn S. , Chen Zhenjun , Corbett Alexandra J. , Varelias Antiopi , Smyth Mark J. , Teng Michele W.L.
Published: December 2019

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that require MHC class I–related protein 1 (MR1) for their development. The role of MAIT cells in cancer is unclear, and to date no study has evaluated these cells in vivo in this context. Here, we demonstrated that tumor initiation, growth, and experimental lung metastasis were significantly reduced in Mr1−/− mice, compared with wild-type mice. The antitumor activity observed in Mr1−/− mice required natural killer (NK) and/or CD8+ T cells and IFNγ. Adoptive transfer of MAIT cells into Mr1−/− mice reversed metastasis reduction. Similarly, MR1-blocking antibodies decreased lung metastases and suppressed tumor growth. Following MR1 ligand exposure, some, but not all, mouse and human tumor cell lines upregulated MR1. Pretreatment of tumor cells with the stimulatory ligand 5-OP-RU or inhibitory ligand Ac-6-FP increased or decreased lung metastases, respectively. MR1-deleted tumors resulted in fewer metastases compared with parental tumor cells. MAIT cell suppression of NK-cell effector function was tumor-MR1–dependent and partially required IL17A. Our studies indicate that MAIT cells display tumor-promoting function by suppressing T and/or NK cells and that blocking MR1 may represent a new therapeutic strategy for cancer immunotherapy.

Significance:

Contradicting the perception that MAIT cells kill tumor cells, here MAIT cells promoted tumor initiation, growth, and metastasis. MR1-expressing tumor cells activated MAIT cells to reduce NK-cell effector function, partly in a host IL17A–dependent manner. MR1-blocking antibodies reduced tumor metastases and growth, and may represent a new class of cancer therapeutics.

This article is highlighted in the In This Issue feature, p. 1
Expression of miR-133a-5p and ROCK2 in Heart in Methamphetamine-Induced Rats and Intervention of Rhynchophylline
Authors: Zhou Yuting , Lin Yingbo , Chen Zhijie , Zhu Chen , Li Chan , Li Hancheng , Huo Chuying , Ou Jinying , Li Jing , Luo Chaohua , Mo Zhixian
Published: December 2019

Introduction: Rhynchophylline, as a traditional Chinese medicine, was used for the treatment of drug addiction. Objective: To investigate miRNAs expression profile in the rat hearts of methamphetamine dependence and the intervention mechanisms of rhynchophylline. Materials and Methods: This study detected the expression profile of miRNAs in the methamphetamine-induced rat hearts by microarray and verified the expression of miR-133a-5P and Rho-associated, coiled-coil containing protein kinase 2 (ROCK2) protein. Results: After conditioned place preference training, methamphetamine significantly increased the time spent in the drug-paired compartment, while rhynchophylline and MK-801 could reduce the time. Cluster analysis results of miRNAs showed that compared with the control group, the expression of miR-133a-5p in methamphetamine-induced rat hearts was decreased significantly; rhynchophylline could significantly increase the expression of miR-133a-5p. The result was verified by real-time polymerase chain reaction. The results of target gene predictive software and related research showed that ROCK2 protein may be the target gene of miR-133a-5p. The immunohistochemistry results of heart tissues showed that the expression of ROCK2 protein was significantly upregulated in the methamphetamine group and downregulate in the rhynchophylline group; the difference between the MK-801 group and the methamphetamine group was not significant. The result of western blot was consistent with the immunohistochemistry. Conclusion: The active ingredient of Chinese herbal medicine rhynchophylline can effectively inhibit the formation of methamphetamine-dependent conditional place preference (CPP) effect in rats to some extent. MiR-133a-5p may participate in the cardioprotective effects of CPP rats by targeting ROCK2.
Microvascular Invasion and a Size Cutoff Value of 2 cm Predict Long-Term Oncological Outcome in Multiple Hepatocellular Carcinoma: Reappraisal of the American Joint Committee on Cancer Staging System and Validation Using the Surveillance, Epidemiology, and End-Results Database
Authors: Shindoh Junichi , Kobayashi Yuta , Kawamura Yusuke , Akuta Norio , Kobayashi Masahiro , Suzuki Yoshiyuki , Ikeda Kenji , Hashimoto Masaji
Published: December 2019

Introduction: For prognostication of hepatocellular carcinoma (HCC), the optimal size cutoff value and the significance of microvascular invasion (mvi) remain inconclusive. Objective: This study sought to revisit the inconclusive components of current American Joint Committee on Cancer (AJCC) staging system and to develop a new practical prognostication model for patients with HCC based on 2 large cohorts. Method: In 1,175 patients who underwent resection for HCC (training cohort), prognostic significance of mvi, and optimal size cutoff value were revisited and a new staging model was established. Then, its performance was validated using 5,249 patients derived from a population-based database (validation cohort). Results: The optimal size cutoff value was 2 cm in multiple HCC, similar to that for solitary HCC. Multivariate analyses confirmed that mvi, a size >2 cm, and multiple lesions were independent predictors with similar weights for disease-specific survival. Based on these results, earlier stages of HCC were reclassified according to the number of the following factors: multiple tumors, >2 cm in diameter, and presence of mvi. Also, given the similar prognosis of Stages IIIB and IVA according to the AJCC 8th edition, these groups were reclassified into the same stage. This new staging model had a better performance than the AJCC 8th edition in both training cohort (c-statistics, 0.648 vs. 0.629) and the validation cohort (c-statistics, 0.646 vs. 0.645) regardless of the presence of cirrhosis. Conclusions: Inclusion of a size cutoff value of 2 cm and mvi could reclassify the current version of the AJCC staging system and offer an alternative prognostication model using a single size-cutoff value of HCC.