bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancer Cell-Derived Exosomes Promote HCC Tumorigenesis Through Hedgehog Pathway
Authors: Li Li , Zhao Jing , Zhang Quanbao , Tao Yifeng , Shen Conghuan , Li Ruidong , Ma Zhengyu , Li Jianhua , Wang Zhengxin
Published: October 2021

Purpose

Hepatocellular carcinoma (HCC) accounts for more than 80% of primary liver cancers and is one of the leading causes of cancer-related death in many countries. Cancer cell-derived exosomes are shown to mediate communications between cancer cells and the microenvironment, promoting tumorigenesis. Hedgehog signaling pathway plays important roles in cancer development of HCC.

Methods

Exosomes were isolated from culture medium of HCC cell lines PLC/PRF/5 and MHCC-97H and were found to promote cancer cell growth measured with cell proliferation and colony formation assay. HCC cells cultured with cancer cell-derived exosome had increased cancer stem cell (CSC) population demonstrated by increased cell sphere formation CSC marker expressions. Hedgehog protein Shh was found to be highly expressed in these two HCC cell lines and preferably carried by exosomes. When Shh was knocked down with shRNA, the resulting exosomes had a reduced effect on promoting cancer cell growth or CSC population increase compared to normal cell-derived exosomes.

Results

The ability of PLC/PRF/5 cells to form tumor in a xenograft model was increased by the addition of the exosomes from control cancer cells but not the exosomes from Shh knocked down cancer cells. Finally, the higher plasma Exo-Shh levels were associated with later tumor stages, higher histological grades, multiple tumors, and higher recurrence rates.

Conclusion

This study demonstrated that HCC cells secreted Shh via exosome and promote tumorigenesis through the activated Hedgehog pathway.
Analysis of Global and Local DNA Methylation Patterns in Blood Samples of Patients With Autism Spectrum Disorder
Authors: García-Ortiz María Victoria , Torre-Aguilar María José de la , Morales-Ruiz Teresa , Gómez-Fernández Antonio , Flores-Rojas Katherine , Gil-Campos Mercedes , Martin-Borreguero Pilar , Ariza Rafael R. , Roldán-Arjona Teresa , Perez-Navero Juan Luis
Published: October 2021

The goal of this investigation was to determine whether there are alterations in DNA methylation patterns in children with autism spectrum disorder (ASD).

Material and Methods: Controlled prospective observational case-control study. Within the ASD group, children were sub-classified based on the presence (AMR subgroup) or absence (ANMR subgroup) of neurodevelopmental regression during the first 2 years of life. We analyzed the global levels of DNA methylation, reflected in LINE-1, and the local DNA methylation pattern in two candidate genes, Neural Cell Adhesion Molecule (NCAM1) and Nerve Growth Factor (NGF) that, according to our previous studies, might be associated to an increased risk for ASD. For this purpose, we utilized blood samples from pediatric patients with ASD (n = 53) and their corresponding controls (n = 45).

Results: We observed a slight decrease in methylation levels of LINE-1 in the ASD group, compared to the control group. One of the CpG in LINE-1 (GenBank accession no.X58075, nucleotide position 329) was the main responsible for such reduction, highly significant in the ASD subgroup of children with AMR (p < 0.05). Furthermore, we detected higher NCAM1 methylation levels in ASD children, compared to healthy children (p < 0.001). The data, moreover, showed higher NGF methylation levels in the AMR subgroup, compared to the control group and the ANMR subgroup. These results are consistent with our prior study, in which lower plasma levels of NCAM1 and higher levels of NGF were found in the ANMR subgroup, compared to the subgroup that comprised neurotypically developing children.

Conclusions: We have provided new clues about the epigenetic changes that occur in ASD, and suggest two potential epigenetic biomarkers that would facilitate the diagnosis of the disorder. We similarly present with evidence of a clear differentiation in DNA methylation between the ASD subgroups, with or without mental regression.
The Effect of Ellagic Acid on Hepatic Lipid Metabolism and Antioxidant Activity in Mice
Authors: Xu Qiuying , Li Shuwei , Tang Wenjie , Yan Jiayou , Wei Xiaolan , Zhou Mengjia , Diao Hui
Published: October 2021

Accumulating evidence has demonstrated that the imbalance of lipid metabolism and antioxidant capacity leads to damage to liver. The present study aimed to investigate the effects of ellagic acid (EA), a phenolic compound, on hepatic lipid metabolism and antioxidant activity in mice. In our study, 24 C57BL/6J mice were divided into three groups: (1) control (CON); (2) basal diet+0.1% EA (EA1); and (3) basal diet+0.3% EA (EA2). After the 14-day experiment, the liver was sampled for analysis. The results showed that 0.3% EA administration increased the liver weight. Total cholesterol and low-density lipoprotein cholesterol activities decreased and high-density lipoprotein cholesterol activity increased by EA supplementation. Meanwhile, dietary supplementation with EA dose-dependently decreased the acetyl-CoA carboxylase protein abundance and increased the phospho-hormone-sensitive lipase, carnitine palmitoyltransferase 1B, and peroxisome proliferator-activated receptor alpha protein abundances. Moreover, EA supplementation reduced the malonaldehyde concentration and increased the superoxide dismutase and catalase concentrations. The protein abundances of phospho-nuclear factor-E2-related factor 2, heme oxygenase-1, and NAD(P)H: quinone oxidoreductase 1 increased by EA supplementation in a dose-dependent manner. Taken together, EA supplementation promoted the lipid metabolism and antioxidant capacity to maintain the liver health in mice.
Genomic Informed Breeding Strategies for Strawberry Yield and Fruit Quality Traits
Authors: Cockerton Helen M. , Karlström Amanda , Johnson Abigail W. , Li Bo , Stavridou Eleftheria , Hopson Katie J. , Whitehouse Adam B. , Harrison Richard J.
Published: October 2021

Over the last two centuries, breeders have drastically modified the fruit quality of strawberries through artificial selection. However, there remains significant variation in quality across germplasm with scope for further improvements to be made. We reported extensive phenotyping of fruit quality and yield traits in a multi-parental strawberry population to allow genomic prediction and quantitative trait nucleotide (QTN) identification, thereby enabling the description of genetic architecture to inform the efficacy of implementing advanced breeding strategies. A negative relationship (r= −0.21) between total soluble sugar content and class one yield was identified, indicating a trade-off between these two essential traits. This result highlighted an established dilemma for strawberry breeders and a need to uncouple the relationship, particularly under June-bearing, protected production systems comparable to this study. A large effect of quantitative trait nucleotide was associated with perceived acidity and pH whereas multiple loci were associated with firmness. Therefore, we recommended the implementation of both marker assisted selection (MAS) and genomic prediction to capture the observed variation respectively. Furthermore, we identified a large effect locus associated with a 10% increase in the number of class one fruit and a further 10 QTN which, when combined, are associated with a 27% increase in the number of marketable strawberries. Ultimately, our results suggested that the best method to improve strawberry yield is through selecting parental lines based upon the number of marketable fruits produced per plant. Not only were strawberry number metrics less influenced by environmental fluctuations, but they had a larger additive genetic component when compared with mass traits. As such, selecting using “number” traits should lead to faster genetic gain.
Genome-Wide Association Study Identifies Genomic Regions for Important Morpho-Agronomic Traits in Mesoamerican Common Bean
Authors: Delfini Jessica , Moda-Cirino Vânia , dos Santos Neto José , Zeffa Douglas Mariani , Nogueira Alison Fernando , Ribeiro Luriam Aparecida Brandão , Ruas Paulo Maurício , Gepts Paul , Gonçalves Leandro Simões Azeredo
Published: October 2021

The population growth trend in recent decades has resulted in continuing efforts to guarantee food security in which leguminous plants, such as the common bean (Phaseolus vulgaris L.), play a particularly important role as they are relatively cheap and have high nutritional value. To meet this demand for food, the main target for genetic improvement programs is to increase productivity, which is a complex quantitative trait influenced by many component traits. This research aims to identify Quantitative Trait Nucleotides (QTNs) associated with productivity and its components using multi-locus genome-wide association studies. Ten morpho-agronomic traits [plant height (PH), first pod insertion height (FPIH), number of nodules (NN), pod length (PL), total number of pods per plant (NPP), number of locules per pod (LP), number of seeds per pod (SP), total seed weight per plant (TSW), 100-seed weight (W100), and grain yield (YLD)] were evaluated in four environments for 178 Mesoamerican common bean domesticated accessions belonging to the Brazilian Diversity Panel. In order to identify stable QTNs, only those identified by multiple methods (mrMLM, FASTmrMLM, pLARmEB, and ISIS EM-BLASSO) or in multiple environments were selected. Among the identified QTNs, 64 were detected at least thrice by different methods or in different environments, and 39 showed significant phenotypic differences between their corresponding alleles. The alleles that positively increased the corresponding traits, except PH (for which lower values are desired), were considered favorable alleles. The most influenced trait by the accumulation of favorable alleles was PH, showing a 51.7% reduction, while NN, TSW, YLD, FPIH, and NPP increased between 18 and 34%. Identifying QTNs in several environments (four environments and overall adjusted mean) and by multiple methods reinforces the reliability of the associations obtained and the importance of conducting these studies in multiple environments. Using these QTNs through molecular techniques for genetic improvement, such as marker-assisted selection or genomic selection, can be a strategy to increase common bean production.
Predicting Crime and Other Uses of Neural Networks in Police Decision Making
Authors: Walczak Steven
Published: October 2021

Neural networks are a machine learning method that excel in solving classification and forecasting problems. They have also been shown to be a useful tool for working with big data oriented environments such as law enforcement. This article reviews and examines existing research on the utilization of neural networks for forecasting crime and other police decision making problem solving. Neural network models to predict specific types of crime using location and time information and to predict a crime’s location when given the crime and time of day are developed to demonstrate the application of neural networks to police decision making. The neural network crime prediction models utilize geo-spatiality to provide immediate information on crimes to enhance law enforcement decision making. The neural network models are able to predict the type of crime being committed 16.4% of the time for 27 different types of crime or 27.1% of the time when similar crimes are grouped into seven categories of crime. The location prediction neural networks are able to predict the zip code location or adjacent location 31.2% of the time.
Using the Intervention Mapping Approach to Develop a Mental Health Intervention: A Case Study on Improving the Reporting Standards for Developing Psychological Interventions
Authors: van Agteren Joep , Iasiello Matthew , Ali Kathina , Fassnacht Daniel B. , Furber Gareth , Woodyatt Lydia , Howard Alexis , Kyrios Michael
Published: October 2021

Replicating or distilling information from psychological interventions reported in the scientific literature is hindered by inadequate reporting, despite the existence of various methodologies to guide study reporting and intervention development. This article provides an in-depth explanation of the scientific development process for a mental health intervention, and by doing so illustrates how intervention development methodologies can be used to improve development reporting standards of interventions. Intervention development was guided by the Intervention Mapping approach and the Theoretical Domains Framework. It relied on an extensive literature review, input from a multi-disciplinary group of stakeholders and the learnings from projects on similar psychological interventions. The developed programme, called the “Be Well Plan”, focuses on self-exploration to determine key motivators, resources and challenges to improve mental health outcomes. The programme contains an online assessment to build awareness about one’s mental health status. In combination with the exploration of different evidence-based mental health activities from various therapeutic backgrounds, the programme teaches individuals to create a personalised mental health and wellbeing plan. The use of best-practice intervention development frameworks and evidence-based behavioural change techniques aims to ensure optimal intervention impact, while reporting on the development process provides researchers and other stakeholders with an ability to scientifically interrogate and replicate similar psychological interventions.
Online Learning Satisfaction During COVID-19 Pandemic Among Chinese University Students: The Serial Mediation Model
Authors: She Long , Ma Lan , Jan Anbareen , Sharif Nia Hamid , Rahmatpour Pardis
Published: October 2021

The aim of this study was to investigate the relationship between interaction and online learning satisfaction, whether this relationship is mediated by academic self-efficacy and student engagement among Chinese university students during the COVID-19 pandemic. A serial mediation model was developed to examine the proposed relationship. This study employed a cross-sectional, questionnaire-based research design. A sample of 1,504 Chinese university students (Mage=19.89years, SDage=1.93) from five provinces in China completed an online survey questionnaire from December 2020 to January 2021 to respond to questions on demographic characteristics and items to measure the variables in the research model. The partial least squares structural equation modeling was used to assess the measurement model and proposed serial mediation model. Data were analyzed using SmartPLS software version 3.3.2. The results of the measurement model showed good reliability and validity for all constructs. The results of the structural model and hypothesis testing showed that all hypotheses were supported in this study. Particularly, there was a significant positive relationship between interaction and online learning satisfaction (Q1), interaction and academic self-efficacy (Q2), academic self-efficacy and student engagement (Q3), and the student engagement and online learning satisfaction (Q4). In addition, the results showed that academic self-efficacy and student engagement serial mediated the relationship between interaction and online learning satisfaction (Q5). The serial mediation model explained 34.6% of the variance of online learning satisfaction. The findings shed light on the underlying mechanisms that explain students’ online learning satisfaction during the COVID-19 pandemic. Universities and policymakers need to make better decisions that ultimately could lead to students’ academic outcomes and achievement.
Middle-Aged and Older African Americans' Information Use During the COVID-19 Pandemic: An Interview Study
Authors: Tang Lu , York Felicia N. , Zou Wenxue
Published: October 2021

African Americans in the United States have been disproportionately affected by the COVID-19 pandemic in infection and mortality rates. This study examined how middle-aged and older African American individuals accessed and evaluated the information about COVID-19. Semi-structured interviews with 20 individuals (age: 41–72) were conducted during the first stay-at-home advisory period in late March and early April 2020. The phronetic iterative approach was used for data analysis. We found that these individuals primarily relied on information scanning based on their routine media consumption to acquire information about COVID-19 and seldom actively searched for information outside of their regular media use. Individuals used several strategies to assess the quality of the information they received, including checking source credibility, comparing multiple sources, fact-checking, and praying. These findings could inform media and governmental agencies' future health communication efforts to disseminate information about the COVID-19 pandemic and future infectious disease outbreaks among the African American communities.
Effect of Immersive Virtual Reality on Pain and Anxiety at a Veterans Affairs Health Care Facility
Authors: Rawlins Caitlin R. , Veigulis Zachary , Hebert Catherine , Curtin Catherine , Osborne Thomas F.
Published: October 2021

Objectives: The primary objective of this evaluation is to determine the impact of virtual reality (VR) distraction on acute and chronic pain in Veterans within the Veterans Affairs Health Care System (VA). A secondary objective is to determine the impact of VR on the experience of stress and anxiety in Veterans utilizing VR for the indication of pain. A third objective is to develop an understanding of the Veteran experience of using VR in a healthcare setting.

Methods: This prospective, pretest-posttest mixed methods assessment was performed at a VA medical center from August 30, 2019 to November 23, 2020. VR experiences lasted between 10 and 30 min utilizing an immersive head-mounted display with multiple, autonomously chosen virtual environments. Qualitative data was collected concurrently to provide context to quantitative measures which included pain scores and stress/anxiety levels. Data from 79 participants was included in this analysis. Data included pre- and post-VR session Defense and Veterans Pain Rating Scale and stress/anxiety levels.

Results: Results for the cohort demonstrated a statistically significant decrease in pain intensity (p <0 .001) with an average 12% decrease in pain levels and an 92% reduction in anxiety for those in concurrent pain.

Conclusion: VR as a non-pharmacological adjunct or alternative modality, appears to be a viable option for improving pain management and reducing anxiety in Veteran populations across various age ranges, and levels of acuity and chronicity. VR was found to be an effective distraction from pain, a pleasurable experience for the majority, and opened the door to other non-pharmacological modalities in a Veteran population.
Studying the Activity of Leaf-Litter Fauna: A Small World to Discover
Authors: Ruiz-Lupión Dolores , Gavín-Centol María Pilar , Moya-Laraño Jordi
Published: October 2021

Hundreds of thousands of little creatures live in soils. Some eat live plants, live animals, or both. Others, called decomposers, consume dead plants, and the waste of other living beings (their feces and their dead bodies), and transform them into food for plants. The health of soils depends largely on the presence of decomposers, and thus it is necessary to study how these creatures may be affected by climate change. To this end, we built a new type of traps to catch live soil animals, which we called cul-de-sac and basket traps. Here, we show how these traps are better for studying animal activity (how much they move in the soil) compared to the most used devices to date, pitfall traps. Comparatively, our traps capture more active animals and prevent predators from killing prey inside, which will improve the accuracy of future studies all over the world.
Long-Term Observation and Treatment of Epithelioid Haemangioendothelioma of the Mediastinum: A Case Report
Authors: Zhi Qiuli , Ma Zhoupeng , Lin Guansheng , Pan Jiangfeng , Chen Bingye
Published: October 2021

Epithelioid haemangioendothelioma is a rare angiogenic tumour originating from vascular endothelial or pre-endothelial cells, and it can occur anywhere in the body, such as the liver, lung, bone, spleen, lymph nodes, parotid gland, and thyroid. In the fifth revision of the WHO classification, epithelioid haemangioendothelioma (EHE) was described as a malignant vascular neoplasm composed of epithelioid endothelial cells, distinct from epithelioid angiosarcoma. We, herein, report one patient with EHE of the left upper mediastinum who underwent resection and radiotherapy during the first therapeutic process. Multiple metastases occurred in the thoracic vertebrae 6 years later, and resection and multiple radiotherapies were performed. The condition of the patient remained stable at the last review in October 2020, and it has been more than 8 years since her first admission. The reasonable “take-away” lessons from the case are active treatment and prolonged surveillance.
Examining the Effects of Diet Composition, Soluble Fiber, and Species on Total Fecal Excretion of Bile Acids: A Meta-Analysis
Authors: Pezzali Julia Guazzelli , Shoveller Anna K. , Ellis Jennifer
Published: October 2021

Bile acids (BA) are produced in the liver and conjugated with glycine or taurine before being released into the small intestine to aid with lipid digestion. However, excessive BA losses through feces can occur due to several dietary factors that in turn require greater production of BA by the liver due to a reduction in BA recycling. Consequently, net utilization of taurine and/or glycine is increased. To quantify this impact, we conducted a meta-analysis to investigate the effect of soluble fiber, diet composition, and species on fecal excretion of BA. After a systematic review of the literature, twelve studies met all inclusion criteria. Dietary carbohydrate, protein, fat, cellulose, cholesterol, soluble fiber and animal species were tested as independent variables. Mixed models were developed treating study as a random effect, and fixed effect variables were retained atP< 0.05 significance and where collinearity was absent between multiple X variables. A total of ten studies comprised of four species [(rat = 5), hamster (n= 1), guinea pig (n= 3) and dog (n= 1)], and 30 observations were evaluated in the final models after outlier removal. Model evaluation was based on the corrected Akaike Information Criteria, the concordance correlation coefficient and the root mean square prediction error. Three base models were developed, examining carbohydrate, protein and fat impacts separately. The best fitting models included the fixed effect of species and the interaction between soluble fiber (yes/no) and dietary carbohydrate, protein or fat (%, as-fed). Increased concentrations of dietary protein and fat resulted in greater fecal excretion of BA (P< 0.05). Conversely, increasing levels of dietary carbohydrate led to lower excretions of BA (P< 0.05). Increased dietary soluble fiber containing ingredients resulted in greater excretion of BA in all models (P< 0.05). Rats had greater excretion of BA compared to hamsters and guinea pigs (P< 0.05) in all models, and also compared to dogs (P< 0.05) in the carbohydrate model. The findings from this meta-analysis indicate that not only soluble fiber, but also increasing levels of dietary fat and protein may result in greater fecal excretion of BA, potentially altering taurine and/or glycine metabolism and affecting the need for diet delivery of these AA.
Mechanical Property Comparison of Ni–Cr–Mo Alloys Fabricated via One Conventional and Two New Digital Manufacturing Techniques
Authors: Yang Kyung-Ran , Hanawa Takao , Kwon Tae-Yub , Min Bong-Ki , Hong Min-Ho
Published: October 2021

This study compared the microstructures and mechanical properties of nickel–chromium–molybdenum (Ni–Cr–Mo) alloys prepared from a single alloy with an identical composition using two new digital processes (selective laser melting (SLM) and soft metal milling (SMM)) and conventional lost-wax casting (LWC). Disc specimens were used to study the microstructures via various analytical methods, while dumbbell-shaped specimens were subjected to tension to determine the mechanical properties (n = 6). The SLM and SMM alloys showed a higher number of large and small pores, respectively, than the LWC alloy. A face-centered cubic (γ)-phased matrix was indexed for all three resultant alloys. The SLM and SMM alloys also showed more homogeneously distributed elements and finer grains (in particular, ultrafine grains in the SLM alloy) when compared to the LWC alloy. Meanwhile, the LWC alloy showed a statistically higher yield strength than the other two alloys (p < 0.001). Notwithstanding, all three resultant Ni–Cr–Mo alloys satisfied the ISO 22674 standard criteria for type 5 materials (yield strength: >500 MPa; percentage elongation: >2%; and elastic modulus: >150 GPa).
Experimental Study on the Influence of TiN/AlTiN PVD Layer on the Surface Characteristics of Hot Work Tool Steel
Authors: Bitay Enikő , Tóth László , Kovács Tünde Anna , Nyikes Zoltán , Gergely Attila Levente
Published: October 2021

It is desirable to improve tool steel wear resistance to produce pieces with precise dimensions and increase the lifetime of tools. The aim of this work was to modify the surface of 1.2344 (X40CrMoV5-1) hot work tool steel to improve the wear properties. Surface modification was achieved in three steps: first, hardening was applied, followed by plasma nitridation and, finally, physical vapor deposition (PVD) was employed to produce a TiN/AlTiN multilayer coating. The microhardness and the wear coefficient of the surfaces were measured. PVD coating showed the highest hardness value, 2938 HV0.01, whereas plasma nitridation followed by PVD resulted in 2679 HV0.01. The surface modification resulted in an increase in surface roughness in all cases compared to the hardened sample. However, the wear coefficient showed a significant decrease for the surface treated samples. The lowest wear coefficient of K = 1.47 × 10−10 mm3/Nm, which is a magnitude lower than the reference hardened sample (K = 6.32 × 10−9 mm3/Nm), was achieved employing both plasma nitridation and PVD. The results confirm that the use of a combined surface modification of plasma nitridation and PVD significantly improve the wear resistance of the treated samples.
Model for Cryogenic Flashing LNG Leak
Authors: Lim Boon How , Ng Eddie Yin Kwee
Published: October 2021

The growth of liquefied natural gas (LNG)’s importance for curbing greenhouse gas emissions has increased the interest in understanding LNG’s risks, particularly regarding small-diameter leaks (<25 mm). Recently, INERIS performed a series of pressurized LNG release experiments for orifice sizes of up to 9 mm. Based on INERIS findings and the Isenthalpic Homogeneous Equilibrium Model (HEM), this paper created a leak model for flashing LNG leak. The leak model consists of nine equations and quantifies leak parameters for risk assessment. One potential use of this leak model is providing an equivalent leak boundary condition for computational fluid dynamic (CFD) simulation to predict gas dispersion. Using the leak model as input, FLACS gas dispersion simulation was carried out for one INERIS experiment leak case. Compared to TR56, the Singapore safety guideline for LNG bunkering, the dispersion result does not contradict the expected plume reach. Further validation with risk analysis tools and actual experiments is needed to confirm that the leak model is fit for use.
TBX2 Drives Neuroendocrine Prostate Cancer through Exosome-Mediated Repression of miR-200c-3p
Authors: Patel Girijesh , Dutta Sayanika , Mahmud Syed Mosharaf , Ramachandran Sabarish , Sharma Monica , Rajamanickam Venkatesh , Ganapathy Vadivel , DeGraff David , Pruitt Kevin , Tripathi Manisha , Nandana Srinivas
Published: October 2021

Deciphering the mechanisms that drive transdifferentiation to neuroendocrine prostate cancer (NEPC) is crucial to identifying novel therapeutic strategies against this lethal and aggressive subtype of advanced prostate cancer (PCa). Further, the role played by exosomal microRNAs (miRs) in mediating signaling mechanisms that propagate the NEPC phenotype remains largely elusive. The unbiased differential miR expression profiling of human PCa cells genetically modulated for TBX2 expression led to the identification of miR-200c-3p. Our findings have unraveled the TBX2/miR-200c-3p/SOX2/N-MYC signaling axis in NEPC transdifferentiation. Mechanistically, we found that: (1) TBX2 binds to the promoter and represses the expression of miR-200c-3p, a miR reported to be lost in castrate resistant prostate cancer (CRPC), and (2) the repression of miR-200c-3p results in the increased expression of its targets SOX2 and N-MYC. In addition, the rescue of mir-200c-3p in the context of TBX2 blockade revealed that miR-200c-3p is the critical intermediary effector in TBX2 regulation of SOX2 and N-MYC. Further, our studies show that in addition to the intracellular mode, TBX2/miR-200c-3p/SOX2/N-MYC signaling can promote NEPC transdifferentiation via exosome-mediated intercellular mechanism, an increasingly recognized and key mode of propagation of the NEPC phenotype.
ACKR4 in Tumor Cells Regulates Dendritic Cell Migration to Tumor-Draining Lymph Nodes and T-Cell Priming
Authors: Wangmo Dechen , Premsrirut Prem K. , Yuan Ce , Morris William S. , Zhao Xianda , Subramanian Subbaya
Published: October 2021

Colorectal cancer (CRC) is one of the most common malignancies in both morbidity and mortality. Immune checkpoint blockade (ICB) treatments have been successful in a portion of mismatch repair-deficient (dMMR) CRC patients but have failed in mismatch repair-proficient (pMMR) CRC patients. Atypical Chemokine Receptor 4 (ACKR4) is implicated in regulating dendritic cell (DC) migration. However, the roles of ACKR4 in CRC development and anti-tumor immunoregulation are not known. By analyzing human CRC tissues, transgenic animals, and genetically modified CRC cells lines, our study revealed an important function of ACKR4 in maintaining CRC immune response. Loss of ACKR4 in CRC is associated with poor immune infiltration in the tumor microenvironment. More importantly, loss of ACKR4 in CRC tumor cells, rather than stromal cells, restrains the DC migration and antigen presentation to the tumor-draining lymph nodes (TdLNs). Moreover, tumors with ACKR4 knockdown become less sensitive to immune checkpoint blockade. Finally, we identified that microRNA miR-552 negatively regulates ACKR4 expression in human CRC. Taken together, our studies identified a novel and crucial mechanism for the maintenance of the DC-mediated T-cell priming in the TdLNs. These new findings demonstrate a novel mechanism leading to immunosuppression and ICB treatment resistance in CRC.
Aberrant Signaling Pathways in Sinonasal Intestinal-Type Adenocarcinoma
Authors: Riobello Cristina , Sánchez-Fernández Paula , Cabal Virginia N. , García-Marín Rocío , Suárez-Fernández Laura , Vivanco Blanca , Blanco-Lorenzo Verónica , Álvarez Marcos César , López Fernando , Llorente José Luis , Hermsen Mario A.
Published: October 2021

Sinonasal intestinal-type adenocarcinoma (ITAC) is strongly related to occupational exposure to wood and leather dust, however, little is known on the genetic alterations involved in tumor development and progression. The aim of this study was to identify tumorigenic signaling pathways affected by gene mutations and their relation to clinical features. We applied whole exome sequencing of 120 cancer-related genes in 50 ITACs and analyzed the signaling activity of four specific pathways frequently affected by mutations. Genes involved in DNA damage response showed somatic mutations in 30% of cases, including four tumors that also harbored germline mutations. Genes in Wnt, MAPK and PI3K pathways harbored mutations in 20%, 20% and 24% of cases, respectively. Mutations and copy number gains in receptor tyrosine kinases possibly affecting MAPK and PI3K pathways occurred in 44% of cases. Expression of key pathway proteins showed no correlation to mutations in these pathways, except for nuclear β-catenin and APC/CTNNB1 mutation. No specific gene mutation, mutated pathway, nor pathway activity level showed correlation to clinical data or survival. In addition, a similar mutational profile was observed among histological subtypes. The wide spectrum of gene mutations suggests that ITAC is a genetically heterogeneous without specific characterizing gene mutations.
MET Amplification in Non-Small Cell Lung Cancer (NSCLC)—A Consecutive Evaluation Using Next-Generation Sequencing (NGS) in a Real-World Setting
Authors: Schubart Christoph , Stöhr Robert , Tögel Lars , Fuchs Florian , Sirbu Horia , Seitz Gerhard , Seggewiss-Bernhardt Ruth , Leistner Rumo , Sterlacci William , Vieth Michael , Seidl Christoph , Mugler Michael , Kapp Markus , Hohenforst-Schmidt Wolfgang , Hartmann Arndt , Haller Florian , Erber Ramona
Published: October 2021

In non-small cell lung cancer (NSCLC), approximately 1–3% of cases harbor an increased gene copy number (GCN) of the MET gene. This alteration can be due to de novo amplification of the MET gene or can represent a secondary resistance mechanism in response to targeted therapies. To date, the gold standard method to evaluate the GCN of MET is fluorescence in situ hybridization (FISH). However, next-generation sequencing (NGS) is becoming more relevant to optimize therapy by revealing the mutational profile of each NSCLC. Using evaluable n = 205 NSCLC cases of a consecutive cohort, this study addressed the question of whether an amplicon based NGS assay can completely replace the FISH method regarding the classification of MET GCN status. Out of the 205 evaluable cases, only n = 9 cases (43.7%) of n = 16 high-level MET amplified cases assessed by FISH were classified as amplified by NGS. Cases harboring a MET GCN > 10 showed the best concordance when comparing FISH versus NGS (80%). This study confirms that an amplicon-based NGS assessment of the MET GCN detects high-level MET amplified cases harboring a MET GCN > 10 but fails to detect the various facets of MET gene amplification in the context of a therapy-induced resistance mechanism.
Anticipating EGFR Targeting in Early Stages of Lung Cancer: Leave No Stone Unturned
Authors: Belluomini Lorenzo , Riva Silvia Teresa , Simbolo Michele , Nocini Riccardo , Trestini Ilaria , Avancini Alice , Tregnago Daniela , Ferrara Miriam Grazia , Caldart Alberto , Dodi Alessandra , Caliò Anna , Bria Emilio , Scarpa Aldo , Milella Michele , Menis Jessica , Pilotto Sara
Published: October 2021

Background: The current treatment landscape of early stage lung cancer is rapidly evolving, particularly in EGFR mutant non-small cell lung cancer (NSCLC), where target therapy is moving to early stages. In the current review, we collected the available data exploring the impact of EGFR targeting in both neoadjuvant and adjuvant settings, underlying lights and shadows and discussing the existing open issues. Methods: We performed a comprehensive search using PubMed and the proceedings of major international meetings to identify neoadjuvant/adjuvant trials with EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. Results: Limited data are available so far about the activity/efficacy of neoadjuvant TKIs in EGFR mutant NSCLC, with only modest downstaging and pathological complete response rates reported. Differently, the ADAURA trial already proposed osimertinib as a potential new standard of care in resected NSCLC harboring an activating EGFR mutation. Conclusion: Anticipating targeted therapy to early stage EGFR mutant NSCLC presents great opportunities but also meaningful challenges in the current therapeutic/diagnostic pathway of lung cancer care. Appropriate endpoint(s) selection for clinical trials, disease progression management, patients’ and treatment selection, as well as need to address the feasibility of molecular profiling anticipation, represent crucial issues to face before innovation can move to early stages.
Personalized First-Line Treatment of Metastatic Pancreatic Neuroendocrine Carcinoma Facilitated by Liquid Biopsy and Computational Decision Support
Authors: Szkukalek Judita , Dóczi Róbert , Dirner Anna , Boldizsár Ákos , Varga Ágnes , Déri Júlia , Lakatos Dóra , Tihanyi Dóra , Vodicska Barbara , Schwáb Richárd , Pajkos Gábor , Várkondi Edit , Vályi-Nagy István , Valtinyi Dorottya , Nagy Zsuzsanna , Peták István
Published: October 2021

Background: We present the case of a 50-year-old female whose metastatic pancreatic neuroendocrine tumor (pNET) diagnosis was delayed by the COVID-19 pandemic. The patient was in critical condition at the time of diagnosis due to the extensive tumor burden and failing liver functions. The clinical dilemma was to choose between two registered first-line molecularly-targeted agents (MTAs), sunitinib or everolimus, or to use chemotherapy to quickly reduce tumor burden. Methods: Cell-free DNA (cfDNA) from liquid biopsy was analyzed by next generation sequencing (NGS) using a comprehensive 591-gene panel. Next, a computational method, digital drug-assignment (DDA) was deployed for rapid clinical decision support. Results: NGS analysis identified 38 genetic alterations. DDA identified 6 potential drivers, 24 targets, and 79 MTAs. Everolimus was chosen for first-line therapy based on supporting molecular evidence and the highest DDA ranking among therapies registered in this tumor type. The patient’s general condition and liver functions rapidly improved, and CT control revealed partial response in the lymph nodes and stable disease elsewhere. Conclusion: Deployment of precision oncology using liquid biopsy, comprehensive molecular profiling, and DDA make personalized first-line therapy of advanced pNET feasible in clinical settings.
QiBAM: Approximate Sub-String Index Search on Quantum Accelerators Applied to DNA Read Alignment
Authors: Sarkar Aritra , Al-Ars Zaid , Almudever Carmen G. , Bertels Koen L. M.
Published: October 2021

With small-scale quantum processors transitioning from experimental physics labs to industrial products, these processors in a few years are expected to scale up and be more robust for efficiently computing important algorithms in various fields. In this paper, we propose a quantum algorithm to address the challenging field of data processing for genome sequence reconstruction. This research describes an architecture-aware implementation of a quantum algorithm for sub-sequence alignment. A new algorithm named QiBAM (quantum indexed bidirectional associative memory) is proposed, which uses approximate pattern-matching based on Hamming distances. QiBAM extends the Grover’s search algorithm in two ways, allowing: (1) approximate matches needed for read errors in genomics, and (2) a distributed search for multiple solutions over the quantum encoding of DNA sequences. This approach gives a quadratic speedup over the classical algorithm. A full implementation of the algorithm is provided and verified using the OpenQL compiler and QX Simulator framework. Our implementation represents a first exploration towards a full-stack quantum accelerated genome sequencing pipeline design.
An Effective Multi-Task Two-Stage Network with the Cross-Scale Training Strategy for Multi-Scale Image Super Resolution
Authors: Yang Jucheng , Wei Feng , Bai Yaxin , Zuo Meiran , Sun Xiao , Chen Yarui
Published: October 2021

Convolutional neural networks and the per-pixel loss function have shown their potential to be the best combination for super-resolving severely degraded images. However, there are still challenges, such as the massive number of parameters requiring prohibitive memory and vast computing and storage resources as well as time-consuming training and testing. What is more, the per-pixel loss measured by L2 and the Peak Signal-to-Noise Ratio do not correlate well with human perception of image quality, since L2 simply does not capture the intricate characteristics of human visual systems. To address these issues, we propose an effective two-stage hourglass network with multi-task co-optimization, which enables the entire network to focus on training and testing time and inherent image patterns such as local luminance, contrast, structure and data distribution. Moreover, to avoid overwhelming memory overheads, our model is capable of performing real-time single image multi-scale super-resolution, so it is memory-friendly, meaning that memory space is utilized efficiently. In addition, in order to best use the underlying structure and perception of image quality and the intermediate estimates during the inference process, we introduce a cross-scale training strategy with 2×, 3× and 4× image super-resolution. This effective multi-task two-stage network with the cross-scale strategy for multi-scale image super-resolution is named EMTCM. Quantitative and qualitative experiment results show that the proposed EMTCM network outperforms state-of-the-art methods in recovering high-quality images.
The Legal Governance of Oil and Gas in Europe: An Indicator Analysis of the Implementation of the Hydrocarbons Directive
Authors: Hámor Tamás , Bódis Katalin , Hámor-Vidó Mária
Published: October 2021

Hydrocarbons are traditional subjects to European Union (EU) law (“acquis communitaire”). A short historical review reveals that quasi all aspects of upstream and downstream segments are covered by the legislation. The results of applied information extraction and elaborated quantitative analysis indicate that the intensity of legislation making correlates with global drivers such as oil price booms, and technology developments such as extraction of unconventional hydrocarbons by hydraulic fracturing. A quarter of a century after the Hydrocarbons Directive was published and transposed by Member States (MS), data allow us to make a semi-quantitative assessment on the implementation, the major drivers of governments’ publication activity, and the impact on the oil and gas production. Another specific relevance of this study is on non-energy minerals management of the EU, whether the introduction of similar competitive bidding rules would induce a greater interest of investors, and the enhanced competition could bring more benefits to the states by the rejuvenation of the critical minerals extractive sector. The preliminary findings show that in some MS there is a positive correlation between the concession call publication activity and hydrocarbons production. To confirm these conclusions the analysis of an extended dataset including exploration data, investments, and social impacts is needed in order to screen the effect of global market trends, the exhaustion of domestic geological reserves, and the different policy environments.
An Anti-Fluctuation Compensator Design and Its Control Strategy for Wind Farm System
Authors: Gu Feng-Chang , Chen Hung-Cheng
Published: October 2021

Large-scale wind farms in commercial operations have demonstrated growing influence on the stability of an electricity network and the power quality thereof. Variations in the output power of large-scale wind farms cause voltage fluctuations in the corresponding electrical networks. To achieve low-voltage ride-through capability in a doubly fed induction generator (DFIG) during a fault event, this study proposes a real-time reactive power control strategy for effective DFIG application and a static synchronous compensator (STATCOM) for reactive power compensation. Mathematic models were developed for the DFIG and STATCOM, followed by the development of an indirect control scheme for the STATCOM based on decoupling dual-loop current control. Moreover, a real-world case study on a commercial wind farm comprising 23 DFIGs was conducted. The voltage regulation performance of the proposed reactive power control scheme against a fault event was also simulated. The simulation results revealed that enhanced fault ride-through capability and prompt recovery of the output voltage provided by a wind turbine generator could be achieved using the DFIG along with the STATCOM in the event of a three-phase short-circuit fault.
Energy-Efficient IoT e-Health Using Artificial Intelligence Model with Homomorphic Secret Sharing
Authors: Rehman Amjad , Saba Tanzila , Haseeb Khalid , Larabi Marie-Sainte Souad , Lloret Jaime
Published: October 2021

Internet of Things (IoT) is a developing technology for supporting heterogeneous physical objects into smart things and improving the individuals living using wireless communication systems. Recently, many smart healthcare systems are based on the Internet of Medical Things (IoMT) to collect and analyze the data for infectious diseases, i.e., body fever, flu, COVID-19, shortness of breath, etc. with the least operation cost. However, the most important research challenges in such applications are storing the medical data on a secured cloud and make the disease diagnosis system more energy efficient. Additionally, the rapid explosion of IoMT technology has involved many cyber-criminals and continuous attempts to compromise medical devices with information loss and generating bogus certificates. Thus, the increase in modern technologies for healthcare applications based on IoMT, securing health data, and offering trusted communication against intruders is gaining much research attention. Therefore, this study aims to propose an energy-efficient IoT e-health model using artificial intelligence with homomorphic secret sharing, which aims to increase the maintainability of disease diagnosis systems and support trustworthy communication with the integration of the medical cloud. The proposed model is analyzed and proved its significance against relevant systems.
Compound Heterozygote of Point Mutation and Chromosomal Microdeletion Involving OTUD6B Coinciding with ZMIZ1 Variant in Syndromic Intellectual Disability
Authors: Phetthong Tim , Khongkrapan Arthaporn , Jinawath Natini , Seo Go-Hun , Wattanasirichaigoon Duangrurdee
Published: October 2021

The OTUD6B and ZMIZ1 genes were recently identified as causes of syndromic intellectual disability (ID) with shared phenotypes of facial dysmorphism, distal limb anomalies, and seizure disorders. OTUD6B- and ZMIZ1-related ID are inherited in autosomal recessive and autosomal dominant patterns, respectively. We report a 5-year-old girl with developmental delay, facial phenotypes resembling Williams syndrome, and cardiac defects. The patient also had terminal broadening of the fingers and polydactyly. Cytogenomic microarray (CMA), whole exome sequencing (WES), and mRNA analysis were performed. The CMA showed a paternally inherited 0.118 Mb deletion of 8q21.3, chr8:92084087–92202189, with OTUD6B involved. The WES identified a hemizygous OTUD6B variant, c.873delA (p.Lys291AsnfsTer3). The mother was heterozygous for this allele. The WES also demonstrated a heterozygous ZMIZ1 variant, c.1491 + 2T > C, in the patient and her father. This ZMIZ1 variant yielded exon 14 skipping, as evidenced by mRNA study. We suggest that Williams syndrome-like phenotypes, namely, periorbital edema, hanging cheek, and long and smooth philtrum represent expanded phenotypes of OTUD6B-related ID. Our data expand the genotypic spectrum of OTUD6B- and ZMIZ1-related disorders. This is the first reported case of a compound heterozygote featuring point mutation, chromosomal microdeletion of OTUD6B, and the unique event of OTUD6B, coupled with ZMIZ1 variants.