bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of liquid hog manure applications on antibiotic resistance genes concentration in soil and drainage water in field crops
Authors: Larouche Élodie , Généreux Mylène , Tremblay Marie-Ève , Rhouma Mohamed , Gasser Marc-Olivier , Quessy Sylvain , Côté Caroline
Published: April 2020

Agricultural practices such as manure applications could contribute to the spread of antibiotic resistance genes (ARGs) within the environment. Our objective was to assess the impact of certain fertilization methods (mineral or manure) and tillage practices (reduced or conventional) on the presence of ARGs and bacteria in soil and drainage water under wheat and grain corn crops. Targeted ARGs tet(T), sul1, and blaCTX-M-1 in liquid hog manure, soil, and water samples were quantified by qPCR. Conventional PCR was used to detect mcr-1 and mcr-2. ARGs in control plots were detected despite the absence of manure, representing an environmental reservoir of resistant microorganisms. The manure application rate higher than 39 m3/ha increased tet(T) and sul1 gene concentrations in soil for more than 180 days. Tillage practices had no impact on ARG concentrations in soil and water samples. The blaCTX-M-1 gene was only detected in seven water samples in 2016, but no link was established with the treatments. The mcr-1 and mcr-2 genes were not detected in all tested samples. This study demonstrated that tet(T) and sul1 gene concentrations increased in soil after liquid hog manure application as well as in drainage water in the next weeks.
Benefits of mixed grass–legume pastures and pasture rejuvenation using bloat-free legumes in western Canada: a review
Authors: Khatiwada B. , Acharya S.N. , Larney F.J. , Lupwayi N.Z. , Smith E.G. , Islam M.A. , Thomas J.E.
Published: April 2020

Forage mixtures containing legume out-yield monocultures, fix atmospheric nitrogen, and have lower carbon footprints. However, evidence-based information on creating forage mixtures by direct seeding legumes into existing pastures is limited, and information on bloat-free legumes is nonexistent. Traditionally, pastures requiring improvement in western Canada were fully replaced by breaking up the old stand and reseeding. With new and improved forage cultivars, better seeding equipment, and increased knowledge about pasture management, there is a growing interest among producers in rejuvenating pastures instead of replacing them. Pasture rejuvenation refers to the improvement in biomass productivity and (or) nutritional quality of existing pasture without removing the existing vegetation. This can be done through fertilizer application, which is generally expensive and causes negative environmental impacts. Amelioration of compacted pastureland via mechanical aeration is short-lived and can lead to weed problems. As an alternative, direct seeding of productive, nutritive and bloat-free legume species into existing pasture is an attractive option for pasture rejuvenation. For high performance grazing systems, identification of suitable bloat-free legumes and methods for direct seeding into old grass and legume stands will be essential strategies. This review includes information on the benefits of mixed pastures and seeks possible methods of introducing bloat-free forage legumes into existing pastures in western Canada for rapid improvement in productivity and quality while positively influencing animal, soil, and environmental health.
Analysis of Bose–Einstein correlation at 7 TeV by LHCb collaboration based on stochastic approach
Authors: Mizoguchi Takuya , Biyajima Minoru
Published: April 2020

The Bose–Einstein correlation (BEC) in forward region [Formula: see text] measured at 7 TeV in the Large Hadron Collider (LHC) by the LHCb collaboration is analyzed using two conventional formulas of different types named CF[Formula: see text] and CF[Formula: see text]. The first formula is well known and contains the degree of coherence [Formula: see text] and the exchange function [Formula: see text] from the BE statistics. The second formula is an extended formula (CF[Formula: see text]) that contains the second degree of coherence [Formula: see text] and the second exchange function [Formula: see text] in addition to CF[Formula: see text]. To examine the physical meaning of the parameters estimated by CF[Formula: see text], we analyze the LHCb BEC data by using a stochastic approach of the three-negative binomial distribution and the three-generalized Glauber–Lachs formula. Our results reveal that the BEC at 7 TeV consisted of three activity intervals defined by the multiplicity [Formula: see text] ([8, 18], [19, 35], and [36, 96]) can be well explained by CF[Formula: see text].
Small molecule inhibition of gut microbial choline trimethylamine lyase activity alters host cholesterol and bile acid metabolism
Authors: Pathak Preeti , Helsley Robert N. , Brown Amanda L. , Buffa Jennifer A. , Choucair Ibrahim , Nemet Ina , Gogonea Camelia Baleanu , Gogonea Valentin , Wang Zeneng , Garcia-Garcia Jose Carlos , Cai Lei , Temel Ryan , Sangwan Naseer , Hazen Stanley L. , Brown J. Mark
Published: April 2020

The gut microbe-dependent metabolite trimethylamine- N-oxide (TMAO) has been strongly associated with cardiovascular mortality, prompting drug discovery efforts to identify points of therapeutic intervention within the microbe-host TMAO pathway. Recently, mechanism-based small molecule inhibitors of the major bacterial trimethylamine (TMA) lyase enzymes have been developed, and these drugs show efficacy as anti-atherothrombotic agents. The novel findings of this study are that small molecule TMA lyase inhibition results in beneficial reorganization of host cholesterol and bile acid metabolism. This study confirms previous observations that the gut microbial TMAO pathway is intimately linked to host cholesterol and bile acid metabolism and provides further rationale for the development of small molecule choline TMA lyase inhibitors for the treatment of cardiometabolic disorders.
Role of the Epigenome in Heart Failure
Authors: Papait Roberto , Serio Simone , Condorelli Gianluigi
Published: April 2020

Gene expression is needed for the maintenance of heart function under normal conditions and in response to stress. Each cell type of the heart has a specific program controlling transcription. Different types of stress induce modifications of these programs and, if prolonged, can lead to altered cardiac phenotype and, eventually, to heart failure. The transcriptional status of a gene is regulated by the epigenome, a complex network of DNA and histone modifications. Until a few years ago, our understanding of the role of the epigenome in heart disease was limited to that played by histone deacetylation. But over the last decade, the consequences for the maintenance of homeostasis in the heart and for the development of cardiac hypertrophy of a number of other modifications, including DNA methylation and hydroxymethylation, histone methylation and acetylation, and changes in chromatin architecture, have become better understood. Indeed, it is now clear that many levels of regulation contribute to defining the epigenetic landscape required for correct cardiomyocyte function, and that their perturbation is responsible for cardiac hypertrophy and fibrosis. Here, we review these aspects and draw a picture of what epigenetic modification may imply at the therapeutic level for heart failure.
Glial Connexins and Pannexins in the Healthy and Diseased Brain
Authors: Giaume Christian , Naus Christian C. , Sáez Juan C. , Leybaert Luc
Published: April 2020

Over the past several decades a large amount of data have established that glial cells, the main cell population in the brain, dynamically interact with neurons and thus impact their activity and survival. One typical feature of glia is their marked expression of several connexins, the membrane proteins forming intercellular gap junction channels and hemichannels. Pannexins, which have a tetraspan membrane topology as connexins, are also detected in glial cells. Here, we review the evidence that connexin and pannexin channels are actively involved in dynamic and metabolic neuroglial interactions in physiological as well as in pathological situations. These features of neuroglial interactions open the way to identify novel non-neuronal aspects that allow for a better understanding of behavior and information processing performed by neurons. This will also complement the “neurocentric” view by facilitating the development of glia-targeted therapeutic strategies in brain disease.
Correlation between Fracture Morphology and Microstructural Evolution during Long-Term Aging of EK61 Superalloy
Authors: Huang Jin , Xu Guohua , Qin Heyong , Zheng Lei
Published: April 2020

Microstructural evolutions of EK61 superalloy during long-term aging until 1000 h at 700°C and 750°C, respectively, are studied by combination of Scanning Electron Microscope (SEM) and Transmission Electron Microscope (TEM). Impact fracture morphologies after aging for different time are observed by the SEM. The microstructure is found to be relatively stable during aging at 700°C, and the fracture morphologies are characterized by transgranular fracture. At 750°C, the coarsening of γ′ phase leads the reduction of the quantity of dimples, the chainization of carbides on grain boundaries leads to intergranular fracture, and the netting of η phases within grains leads to the formation of lamellar cleavage steps. It is obvious that the destabilization of precipitated phases affects fracture morphology significantly. The relationship between fracture morphology and the microstructure promotes the evaluation of service reliability of EK61 superalloy.
Multiple Solutions for Ellipticpx,qx-Kirchhoff-Type Potential Systems in Unbounded Domains
Authors: Chems Eddine Nabil , El Hachimi Abderrahmane
Published: April 2020

In this paper, we establish the existence of at least three weak solutions for a parametric double eigenvalue quasi-linear ellipticpx,qx-Kirchhoff-type potential system. Our approach is based on a variational method, and a three critical point theorem is obtained by Bonano and Marano.
Research on Intelligent Guidance Optimal Path of Shared Car Charging in the IOT Environment
Authors: Sun Yuefang , Jin Kangkang , Guo Zhaozhuang , Zhang Chen , Wang Hao
Published: April 2020

In recent years, with the improvement of Internet of Things (IOT) technology, a “shared” service concept has appeared in people’s life. In the limited available resources, it is of great value to study the optimal path of charging pile selection for shared cars. With the help of Internet of Things technology and through analyzing the collected data, this paper introduces three path optimization methods, the Dijkstra algorithm, heuristic algorithm A∗, and improved particle swarm optimization (PSO) algorithm; establishes relevant convergence conditions; and takes the actual path cost as the criterion to judge the optimal path. In addition, this paper studies the optimal path from the shared car to the charging pile. Through the simulation experiment, the results show that compared with the traditional optimal path algorithm, the improved particle swarm optimization algorithm has strong parallelism and better search effect for optimal path selection in the case of large number of traffic path nodes and complex paths, which fully reflects the performance advantage of the algorithm.
Tolerability of Palmitoylethanolamide in a Pediatric Population Suffering from Migraine: A Pilot Study
Authors: Papetti Laura , Sforza Giorgia , Tullo Giulia , Alaimo di Loro Pierfrancesco , Moavero Romina , Ursitti Fabiana , Ferilli Michela Ada Noris , Tarantino Samuela , Vigevano Federico , Valeriani Massimiliano
Published: April 2020

Background. Palmitoylethanolamide (PEA) is emerging as a new therapeutic approach in pain and inflammatory conditions, and it has been evaluated in studies on various painful diseases. The aim of this open-label study was to evaluate the efficacy of ultramicronized PEA (umPEA) in the prophylactic treatment of migraine. Methods. The study included 70 patients with mean age of 10.3 ± 2.7 (24.5% M and 75.5% F). All patients had a diagnosis of migraine without aura (ICHD 3 criteria) and received umPEA (600 mg/day orally) for three months. We compared the attack frequency (AF) and attack intensity at baseline and after three months. Patients were asked to classify the intensity of the attack with a value ranging from 1 to 3, where 1 means mild attack, 2 moderate, and 3 severe attack. Results. Nine patients discontinued treatment before the target time of 12 weeks. After 3 months of treatment with umPEA, the headache frequency was reduced by >50% per month in 63.9% patients. The number of monthly attacks at T1 decreased significantly compared with the baseline assessment (from 13.9 ± 7.5 SD of T0 to 6.5 ± 5.9 SD of T1; p<0.001). The mean intensity of the attacks dropped from 1.67 ± 0.6 (T0) to 1.16 ± 0.5 (T1) (p<0.001), and the percentage of patients with severe attacks decreased after treatment (from 8.2% to 1.6%; p<0.05). The monthly assumptions of drugs for the attack reduced from 9.5 ± 4.4 to 4.9 ± 2.5 (p<0.001). Only one patient developed mild side effects (nausea and floating). Conclusions. Our preliminary data show that umPEA administered for three month reduces pain intensity and the number of attacks per month in pediatric patients with migraine. Although the small number of patients and the lack of control group do not allow us to consider these initial results as definitely reliable, they encourage us to expand the sample.
Systematic Elucidation of the Potential Mechanisms of Core Chinese Materia Medicas in Treating Liver Cancer Based on Network Pharmacology
Authors: Wu Zhulin , Yang Lina , He Li , Wang Lianan , Peng Lisheng
Published: April 2020

Objective. In this study, the data mining method was used to screen the core Chinese materia medicas (CCMMs) against primary liver cancer (PLC), and the potential mechanisms of CCMMs in treating PLC were analyzed based on network pharmacology. Methods. Traditional Chinese medicine (TCM) prescriptions for treating PLC were obtained from a famous TCM doctor in Shenzhen, China. According to the data mining technique, the TCM Inheritance Support System (TCMISS) was applied to excavate the CCMMs in the prescriptions. Then, bioactive ingredients and corresponding targets of CCMMs were collected using three different TCM online databases, and target genes of PLC were obtained from GeneCards and OMIM. Afterwards, common targets of CCMMs and PLC were screened. Furthermore, a network of CCMMs bioactive ingredients and common target gene was constructed by Cytoscape 3.7.1, and gene ontology (GO) and signaling pathways analyses were performed to explain the mechanism of CCMMs in treating PLC. Besides, protein‐protein interaction (PPI) analysis was used to identify key target genes of CCMMs, and the prognostic value of key target genes was verified using survival analysis. Results. A total of 15 high‐frequency Chinese materia medica combinations were found, and CCMMs (including Paeoniae Radix Alba, Radix Bupleuri, Macrocephalae Rhizoma, Coicis Semen, Poria, and Curcumae Radix) were identified by TCMISS. A total of 40 bioactive ingredients (e.g., quercetin, kaempferol, and naringenin) of CCMMs were obtained, and 202 common target genes of CCMMs and PLC were screened. GO analysis indicated that biological processes of CCMMs were mainly involved in response to drug, response to ethanol, etc. Pathway analysis demonstrated that CCMMs exerted its antitumor effects by acting on multiple signaling pathways, including PI3K‐Akt, TNF, and MAPK pathways. Also, some key target genes of CCMMs were determined by PPI analysis, and four genes (MAPK3, VEGFA, EGF, and EGFR) were found to be correlated with survival in PLC patients. Conclusion. Based on data mining and network pharmacology methods, our results showed that the therapeutic effect of CCMMs on PLC may be realized by acting on multitargets and multipathways related to the occurrence and development of PLC.
Melatonin Attenuates Calcium Deposition from Vascular Smooth Muscle Cells by Activating Mitochondrial Fusion and Mitophagy via an AMPK/OPA1 Signaling Pathway
Authors: Chen Wei Ren , Zhou Yu Jie , Yang Jia Qi , Liu Fang , Wu Xue Ping , Sha Yuan
Published: April 2020

Mitochondrial fusion/mitophagy plays a role in cardiovascular calcification. Melatonin has been shown to protect against cardiovascular disease. This study sought to explore whether melatonin attenuates vascular calcification by regulating mitochondrial fusion/mitophagy via the AMP-activated protein kinase/optic atrophy 1 (AMPK/OPA1) signaling pathway. The effects of melatonin on vascular calcification were investigated in vascular smooth muscle cells (VSMCs). Calcium deposits were visualized by Alizarin Red S staining, while calcium content and alkaline phosphatase (ALP) activity were used to evaluate osteogenic differentiation. Western blots were used to measure expression of runt-related transcription factor 2 (Runx2), mitofusin 2 (Mfn2), mito-light chain 3 (mito-LC3) II, and cleaved caspase 3. Melatonin markedly reduced calcium deposition and ALP activity. Runx2 and cleaved caspase 3 were downregulated in response to melatonin, whereas Mfn2 and mito-LC3II were enhanced and accompanied by decreased mitochondrial superoxide levels. Melatonin also maintained mitochondrial function and promoted mitochondrial fusion/mitophagy via the OPA1 pathway. However, OPA1 deletion abolished the protective effects of melatonin on VSMC calcification. Melatonin treatment significantly increased p-AMPK and OPA1 protein expression, whereas treatment with compound C ablated the observed benefits of melatonin treatment. Collectively, our results demonstrate that melatonin protects VSMCs against calcification by promoting mitochondrial fusion/mitophagy via the AMPK/OPA1 pathway.
Epigenetic Mechanisms in the Neurodevelopmental Theory of Depression
Authors: Talarowska Monika
Published: April 2020

The genome (genes), epigenome, and environment work together from the earliest stages of human life to produce a phenotype of human health or disease. Epigenetic modifications, including among other things: DNA methylation, modifications of histones and chromatin structure, as well as functions of noncoding RNA, are coresponsible for specific patterns of gene expression. This refers also to mental disorders, including depressive disorders. Early childhood experiences accompanied by severe stressors (considered a risk factor for depression in adult life) are linked with changes in gene expression. They include genes involved in a response to stress (hypothalamic-pituitary-adrenal axis, HPA), associated with autonomic nervous system hyperactivity and with cortical, and subcortical processes of neuroplasticity and neurodegeneration. These are, among others: gene encoding glucocorticoid receptor, FK506 binding protein 5 gene (FKBP5), gene encoding arginine vasopressin and oestrogen receptor alpha, 5-hydroxy-tryptamine transporter gene (SLC6A4), and gene encoding brain-derived neurotrophic factor. How about personality? Can the experiences unique to every human being, the history of his or her development and gene-environment interactions, through epigenetic mechanisms, shape the features of our personality? Can we pass on these features to future generations? Hence, is the risk of depression inherent in our biological nature? Can we change our destiny?
Near-Field HF-RFID and CMA-Based Circularly Polarized Far-Field UHF-RFID Integrated Tag Antenna
Authors: Sakonkanapong Arnon , Phongcharoenpanich Chuwong
Published: April 2020

This research proposes an integrated high-frequency (HF) and ultrahigh-frequency (UHF) passive radio frequency identification (RFID) tag antenna for near-field (13.56 MHz) and far-field (920–925 MHz) communication. This tag antenna is advantageous for the applications with lossy material in the near-field communication and mitigates polarization loss in the far-field communications. The HF-RFID tag antenna is of square spiral structure, and the circularly polarized UHF-RFID structure consists of a square loop radiator with cascading loop feeding and shorted stub. The structure of HF-RFID tag antenna situated inside the circularly polarized UHF-RFID tag can avoid the significant effect of the near-field magnetic coupling from the square loop. The UHF-RFID tag antenna is realized by using characteristic mode analysis for wideband circular polarization. The HF-RFID structure is conjugate-matched with NXP NT3H2111 chip, and the UHF-RFID structure is conjugate-matched with NXP G2X chip. Simulations were carried out, and an antenna prototype was fabricated. The experimental results reveal that the radiation pattern of UHF-RFID tag antenna is bidirectional with a gain of 0.31 dBic. The impedance bandwidth covers the frequency range of 903–944 MHz, and the axial ratio in boresight direction at 922.5 MHz is 1.67 dB, with the axial ratio bandwidth over 863–938 MHz. The maximum near-field and far-field reading ranges are 4.9 cm and 8.7 m. The proposed integrated dual-band passive tag antenna is operationally ideal for HF-RFID and UHF-RFID applications.
The Effect of Art Therapy in Women with Gynecologic Cancer: A Systematic Review
Authors: Fu Wenjing , Huang Yan , Liu Xing , Ren Jianhua , Zhang Mengqin
Published: April 2020

Objectives. The purpose of this study was to evaluate the evidence of art therapy on the psychological outcome, quality of life (QOL), and cancer‐related symptoms in women with gynecological cancer. Methods. A systematic literature search was conducted. The randomized controlled trials, quasiexperimental studies, case reports, and qualitative studies were all included. Result. 1,587 articles were retrieved. A total of 9 articles met the inclusion criteria. The existing studies provided initial evidence to suggest that art therapy may benefit gynecological cancer patients with respect to improving psychological outcome and QOL, reducing fatigue related to cancer, and improving subjective overall health condition. However, the quality of the current evidence limits the efficacy of these findings. Conclusion. Research on art therapy of gynecologic cancer patients is insufficient. We cannot draw the conclusion that art therapy benefits gynecological cancer patients in the psychological outcome, QOL, and cancer‐related symptoms. More rigorous research is needed.
(‐)‐cis‐Carveol, a Natural Compound, Improves β‐Amyloid‐Peptide 1‐42‐Induced Memory Impairment and Oxidative Stress in the Rat Hippocampus
Authors: Hritcu Lucian , Boiangiu Razvan Stefan , de Morais Mayara Castro , de Sousa Damião Pergentino
Published: April 2020

Alzheimer’s disease (AD) could be considered a multifactorial neurodegenerative disorder characterized by the accumulation of the β‐amyloid‐peptide (Aβ) within the brain leading to cognitive deficits, oxidative stress, and neuroinflammation. The present work was carried out to investigate the neuroprotective effect of (‐)‐cis‐carveol (1% and 3%, for 21 days) against the β‐amyloid‐peptide 1‐42‐ (Aβ1‐42‐) induced AD. Twenty‐five rats were divided into five groups (n = 5/group): the first group—control (sham‐operated); the second group—Aβ1‐42 (1 mM) that received donepezil treatment (5 mg/kg, as the positive reference drug in the Y‐maze and the radial arm maze tests); the third group—Aβ1‐42 (1 mM); the fourth and fifth groups—Aβ1‐42 (1 mM) that received (‐)‐cis‐carveol treatment groups (1% and 3%). The results of this study demonstrated that (‐)‐cis‐carveol improved Aβ1‐42‐induced memory deficits examined by using Y‐maze and radial arm maze in vivo tests. Also, the biochemical analyses of the hippocampus homogenates showed that (‐)‐cis‐carveol reduced hippocampal oxidative stress caused by Aβ1‐42. Our results suggested that the use of (‐)‐cis‐carveol may be suitable for decreasing AD‐related symptoms.
A Bayesian Approach to Competing Risks Model with Masked Causes of Failure and Incomplete Failure Times
Authors: Yousif Yosra , Elfaki Faiz A. M. , Hrairi Meftah , Adegboye Oyelola A.
Published: April 2020

We present a Bayesian approach for analysis of competing risks survival data with masked causes of failure. This approach is often used to assess the impact of covariates on the hazard functions when the failure time is exactly observed for some subjects but only known to lie in an interval of time for the remaining subjects. Such data, known as partly interval-censored data, usually result from periodic inspection in production engineering. In this study, Dirichlet and Gamma processes are assumed as priors for masking probabilities and baseline hazards. Markov chain Monte Carlo (MCMC) technique is employed for the implementation of the Bayesian approach. The effectiveness of the proposed approach is illustrated with simulated and production engineering applications.
The Inhibition of P-Selectin Reduced Severe Acute Lung Injury in Immunocompromised Mice
Authors: Liu Yang , Xiang Du , Gao Fang , Yao Hanlin , Ye Qifa , Wang Yanfeng
Published: April 2020

In an immunocompetent host, excess infiltration of immune cells in the lung is a key factor in infection-induced severe acute lung injury. Kidney transplant patients are immunocompromised by the use of immunosuppressive drugs. Immune cell infiltration in the lung in a renal transplant recipient suffering from pulmonary infection is significantly less than that in an immunocompetent host; however, the extent of lung injury in renal transplant patients is more serious than that in immunocompetent hosts. Therefore, we explored the role of platelet activation in a Klebsiella pneumoniae-induced lung injury model with P-selectin gene knockout mice or wild-type mice. Our study suggested that the inhibition of platelets reduced severe acute lung injury and increased survival after acute lung infection in mice. In addition, P-selectin expression on the surface of platelets in mice increased after administration of immunosuppressive drugs, and the extent of lung injury induced by infection decreased in P-selectin gene knockout mice. In conclusion, p-selectin plays a key role in severe acute lung injury in immunocompromised mice by reducing platelet activation and inflammatory processes.
Cancer Incidence Projections in Northern Ireland to 2040
Authors: Donnelly David W. , Anderson Lesley A. , Gavin Anna
Published: April 2020

Background:

Data on historic trends and estimates of future cancer incidence are essential if cancer services are to be adequately resourced in future years.

Methods:

Age-standardized incidence rates (ASIR) for all cancers combined and 19 common cancers diagnosed during 1993–2017 were determined by sex, year of diagnosis, and age. Data were fitted using an age–period–cohort model, which was used to predict rates in future years up to 2040. These were combined with population projections to provide estimates of the future case number.

Results:

Compared with the annual average in 2013–2017, for all cancers (excluding nonmelanoma skin) ASIRs are expected by 2040 to fall 9% among males and rise 12% among females, while the number of cases diagnosed is projected to increase by 45% for males and 58% for females. Case volume is projected to rise for all cancer types except for cervical and stomach cancer, with the annual number of cases diagnosed projected to more than double among males for melanoma, liver, and kidney cancers, and among females for liver, pancreatic, and lung cancers.

Conclusions:

Increased numbers of cancer cases is projected, due primarily to projected increases in the number of people aged 60 years and over.

Impact:

Projected increases will significantly impact the health services which diagnose and treat cancer. However, while population growth is primarily responsible, reduction of exposure to cancer risk factors, especially tobacco use, obesity, alcohol consumption, and UV radiation, could attenuate the predicted increase in cancer cases.
Modeling the Balance of Benefits and Harms of Cervical Cancer Screening with Cytology and Human Papillomavirus Testing
Authors: Malagón Talía , Mayrand Marie-Hélène , Ogilvie Gina , Gotlieb Walter H. , Blake Jennifer , Bouchard Céline , Franco Eduardo L. , Kulasingam Shalini
Published: April 2020

Background:

Benefits of screening should outweigh its potential harms. We compared various metrics to assess the balance of benefits and harms of cervical cancer screening.

Methods:

We used a cervical cancer natural history Markov model calibrated to the Canadian context to simulate 100,000 unvaccinated women over a lifetime of screening with either cytology every 3 years or human papillomavirus (HPV) testing every 5 years. We estimated the balance of benefits and harms attributable to screening using various metrics, including colposcopies/life-year gained, and net lifetime quality-adjusted life-years (QALY) gained, a measure integrating women's health preferences. We present the average (minimum–maximum) model predictions.

Results:

Cytology-based screening led to 1,319,854 screening tests, 30,395 colposcopies, 13,504 life-years gained over a lifetime, 98 screening tests/life-year gained, 2.3 (1.6–3.3) colposcopies/life-year gained, and a net lifetime gain of 10,735 QALY (5,040–17,797). HPV-based screening with cytology triage in the same population would lead to 698,250 screening tests, 73,296 colposcopies, 15,066 life-years gained over a lifetime, 46 screening tests/life-year gained, 4.9 colposcopies/life-year gained (2.9–11.1), and a net lifetime gain of 11,690 QALY (4,409–18,742). HPV-based screening was predicted to prevent more cancers, but also incur more screening harms than cytology-based screening.

Conclusions:

Metrics using colposcopies as the main harm outcome favored cytology-based screening, whereas metrics based on screening tests and health preferences tended to favor HPV-based screening strategies.

Impact:

Whether HPV-based screening will improve the balance between benefits and harms of cervical cancer screening depends on how the balance between benefits and harms is assessed.
Dendritic Cells, the T-cell-inflamed Tumor Microenvironment, and Immunotherapy Treatment Response
Authors: Garris Christopher S. , Luke Jason J.
Published: April 2020

The development of the most successful cancer immunotherapies in solid tumors, immune-checkpoint blockade, has focused on factors regulating T-cell activation. Until recently, the field has maintained a predominately T-cell centric view of immunotherapy, leaving aside the impact of innate immunity and especially myeloid cells. Dendritic cells (DC) are dominant partners of T cells, necessary for initiation of adaptive immune responses. Emerging evidence supports a broader role for DCs in tumors including the maintenance and support of effector functions during T-cell responses. This relationship is evidenced by the association of activated DCs with immune-checkpoint blockade responses and transcriptional analysis of responding tumors demonstrating the presence of type I IFN transcripts and DC relevant chemokines. T-cell-inflamed tumors preferentially respond to immunotherapies compared with non–T-cell-inflamed tumors and this model suggests a potentially modifiable spectrum of tumor microenvironmental immunity. Although host and commensal factors may limit the T-cell-inflamed phenotype, tumor cell intrinsic factors are gaining prominence as therapeutic targets. For example, tumor WNT/β-catenin signaling inhibits production of chemokine gradients and blocking DC recruitment to tumors. Conversely, mechanisms of innate immune nucleic acid sensing, normally operative during pathogen response, may enhance DC accumulation and make tumors more susceptible to cancer immunotherapy. Elucidating mechanisms whereby DCs infiltrate and become activated within tumors may provide new opportunities for therapeutic intervention. Conceptually, this would facilitate conversion of non–T-cell-inflamed to T-cell-inflamed states or overcome secondary resistance mechanisms in T-cell-inflamed tumors, expanding the proportion of patients who benefit from cancer immunotherapy.
The Immunosuppressive Niche of Soft-Tissue Sarcomas is Sustained by Tumor-Associated Macrophages and Characterized by Intratumoral Tertiary Lymphoid Structures
Authors: Chen Lingling , Oke Teniola , Siegel Nicholas , Cojocaru Gady , Tam Ada J. , Blosser Richard L. , Swailes Jessica , Ligon John A. , Lebid Andriana , Morris Carol , Levin Adam , Rhee Daniel S. , Johnston Fabian M. , Greer Jonathan B. , Meyer Christian F. , Ladle Brian H. , Thompson Elizabeth D. , Montgomery Elizabeth A. , Choi Woonyoung , McConkey David J. , Anders Robert A. , Pardoll Drew M. , Llosa Nicolas J.
Published: April 2020

Purpose:

Clinical trials with immune checkpoint inhibition in sarcomas have demonstrated minimal response. Here, we interrogated the tumor microenvironment (TME) of two contrasting soft-tissue sarcomas (STS), rhabdomyosarcomas and undifferentiated pleomorphic sarcomas (UPS), with differing genetic underpinnings and responses to immune checkpoint inhibition to understand the mechanisms that lead to response.

Experimental Design:

Utilizing fresh and formalin-fixed, paraffin-embedded tissue from patients diagnosed with UPS and rhabdomyosarcomas, we dissected the TME by using IHC, flow cytometry, and comparative transcriptomic studies.

Results:

Our results demonstrated both STS subtypes to be dominated by tumor-associated macrophages and infiltrated with immune cells that localized near the tumor vasculature. Both subtypes had similar T-cell densities, however, their in situ distribution diverged. UPS specimens demonstrated diffuse intratumoral infiltration of T cells, while rhabdomyosarcomas samples revealed intratumoral T cells that clustered with B cells near perivascular beds, forming tertiary lymphoid structures (TLS). T cells in UPS specimens were comprised of abundant CD8+ T cells exhibiting high PD-1 expression, which might represent the tumor reactive repertoire. In rhabdomyosarcomas, T cells were limited to TLS, but expressed immune checkpoints and immunomodulatory molecules which, if appropriately targeted, could help unleash T cells into the rest of the tumor tissue.

Conclusions:

Our work in STS revealed an immunosuppressive TME dominated by myeloid cells, which may be overcome with activation of T cells that traffic into the tumor. In rhabdomyosarcomas, targeting T cells found within TLS may be key to achieve antitumor response.
Impact of DNA Damage Response and Repair (DDR) Gene Mutations on Efficacy of PD-(L)1 Immune Checkpoint Inhibition in Non–Small Cell Lung Cancer
Authors: Ricciuti Biagio , Recondo Gonzalo , Spurr Liam F. , Li Yvonne Y. , Lamberti Giuseppe , Venkatraman Deepti , Umeton Renato , Cherniack Andrew D. , Nishino Mizuki , Sholl Lynette M. , Shapiro Geoffrey I. , Awad Mark M. , Cheng Michael L.
Published: April 2020

Purpose:

DNA damage response and repair (DDR) gene alterations are associated with increased tumor-infiltrating lymphocytes, higher genomic instability, and higher tumor mutational burden (TMB) in cancer. Whether DDR alterations are associated with clinical outcomes to programmed death ligand 1 [PD-(L)1] blockade in non–small cell lung cancer (NSCLC) is unknown.

Experimental Design:

Tumors from patients treated with PD-(L)1 inhibitors were analyzed using targeted next-generation sequencing (NGS). Cancers were categorized on the basis of the presence or absence of deleterious mutations across a panel of 53 DDR genes. Clinical outcomes to PD-(L)1 inhibitors were evaluated according to DDR mutation status.

Results:

Of 266 patients with successful NGS who received PD-(L)1 inhibitors, 132 (49.6%) were identified as having deleterious DDR mutations (DDR-positive). DDR-positive and DDR-negative groups were similar in terms of baseline clinicopathologic characteristics. The median TMB was significantly higher in the DDR-positive group compared with the DDR-negative group (12.1 vs. 7.6 mutations/megabase; P < 0.001). Compared with DDR-negative patients (N = 134), DDR-positive patients had a significantly higher objective response rate (30.3% vs. 17.2%; P = 0.01), longer median progression-free survival [PFS; 5.4 vs. 2.2 months; HR, 0.58 (95% confidence interval (CI), 0.45–0.76); P < 0.001], and longer median overall survival [OS; 18.8 vs. 9.9 months; HR, 0.57 (95% CI, 0.42–0.77); P < 0.001] with PD-(L)1 therapy. After adjusting for PD-L1, TMB, performance status, tobacco use, and line of therapy, DDR-positive status was associated with a significantly longer PFS [HR, 0.68 (95% CI, 0.51–0.92); P = 0.01] and OS [HR, 0.60 (95% CI, 0.43–0.85); P = 0.004] in multivariate analysis.

Conclusions:

Deleterious DDR mutations are frequent in NSCLC and are associated with improved clinical outcomes in patients with NSCLC treated with PD-(L)1 blockade.
Therapeutic Efficacy of Immune Stimulatory Thymidine Kinase and fms-like Tyrosine Kinase 3 Ligand (TK/Flt3L) Gene Therapy in a Mouse Model of High-Grade Brainstem Glioma
Authors: Mendez Flor , Kadiyala Padma , Nunez Felipe J. , Carney Stephen , Nunez Fernando M. , Gauss Jessica C. , Ravindran Ramya , Pawar Sheeba , Edwards Marta , Garcia-Fabiani Maria Belen , Haase Santiago , Lowenstein Pedro R. , Castro Maria G.
Published: April 2020

Purpose:

Diffuse intrinsic pontine glioma (DIPG) bears a dismal prognosis. A genetically engineered brainstem glioma model harboring the recurrent DIPG mutation, Activin A receptor type I (ACVR1)-G328V (mACVR1), was developed for testing an immune-stimulatory gene therapy.

Experimental Design:

We utilized the Sleeping Beauty transposase system to generate an endogenous mouse model of mACVR1 brainstem glioma. Histology was used to characterize and validate the model. We performed RNA-sequencing analysis on neurospheres harboring mACVR1. mACVR1 neurospheres were implanted into the pons of immune-competent mice to test the therapeutic efficacy and toxicity of immune-stimulatory gene therapy using adenoviruses expressing thymidine kinase (TK) and fms-like tyrosine kinase 3 ligand (Flt3L). mACVR1 neurospheres expressing the surrogate tumor antigen ovalbumin were generated to investigate whether TK/Flt3L treatment induces the recruitment of tumor antigen–specific T cells.

Results:

Histologic analysis of mACVR1 tumors indicates that they are localized in the brainstem and have increased downstream signaling of bone morphogenetic pathway as demonstrated by increased phospho-smad1/5 and Id1 levels. Transcriptome analysis of mACVR1 neurosphere identified an increase in the TGFβ signaling pathway and the regulation of cell differentiation. Adenoviral delivery of TK/Flt3L in mice bearing brainstem gliomas resulted in antitumor immunity, recruitment of antitumor-specific T cells, and increased median survival (MS).

Conclusions:

This study provides insights into the phenotype and function of the tumor immune microenvironment in a mouse model of brainstem glioma harboring mACVR1. Immune-stimulatory gene therapy targeting the hosts' antitumor immune response inhibits tumor progression and increases MS of mice bearing mACVR1 tumors.
Neonatal Resuscitation Where the Mother Has a Suspected or Confirmed Novel Coronavirus (SARS-CoV-2) Infection: Suggestion for a Pragmatic Action Plan
Authors: Trevisanuto Daniele , Moschino Laura , Doglioni Nicoletta , Roehr Charles Christoph , Gervasi Maria Teresa , Baraldi Eugenio
Published: April 2020

Coronavirus disease 2019 (COVID-19), caused by the novel SARS-CoV-2 virus, is rapidly spreading across the world. As the number of infections increases, those of infected pregnant women and children will rise as well. Controversy exists whether COVID-19 can be transmitted in utero and lead to disease in the newborn. As this chance cannot be ruled out, strict instructions for the management of mothers and newborn infants are mandatory. This perspective aims to be a practical support tool for the planning of delivery and neonatal resuscitation of infants born by mothers with suspected or confirmed COVID-19 infection.
Late Effects of Parasellar Lesion Treatment: Hypogonadism and Infertility
Authors: Sbardella Emilia , Minnetti Marianna , Pofi Riccardo , Cozzolino Alessia , Greco Ermanno , Gianfrilli Daniele , Isidori Andrea M.
Published: April 2020

Central hypogonadism, also defined as hypogonadotropic hypogonadism, is a recognized complication of hypothalamic-pituitary-gonadal axis damage following treatment of sellar and parasellar masses. In addition to radiotherapy and surgery, CTLA4-blocking antibodies and alkylating agents such as temozolomide can also lead to hypogonadism, through different mechanisms. Central hypogonadism in boys and girls may lead to pubertal delay or arrest, impairing full development of the genitalia and secondary sexual characteristics. Alternatively, cranial irradiation or ectopic hormone production may instead cause early puberty, affecting hypothalamic control of the gonadostat. Given the reproductive risks, discussion of fertility preservation options and referral to reproductive specialists before treatment is essential. Steroid hormone replacement can interfere with other replacement therapies and may require specific dose adjustments. Adequate gonadotropin stimulation therapy may enable patients to restore gametogenesis and conceive spontaneously. When assisted reproductive technology is needed, protocols must be tailored to account for possible long-term gonadotropin insufficiency prior to stimulation. The aim of this review was to provide an overview of the risk factors for hypogonadism and infertility in patients treated for parasellar lesions and to give a summary of the current recommendations for management and follow-up of these dysfunctions in such patients. We have also briefly summarized evidence on the physiological role of pituitary hormones during pregnancy, focusing on the management of pituitary deficiencies.
Management of Endophthalmitis with and without Topical Antibiotics: A Case-Control Study
Authors: Dave Vivek Pravin , Pathengay Avinash , Nishant Kumar , Reddy Venkata Shubakar , Pappuru Rajeev Reddy , Das Taraprasad
Published: April 2020

Purpose: The aim of this study was to compare the management outcome of endophthalmitis with and without the use of topical antibiotics. Methods: A retrospective comparative chart review of 2 cohorts of endophthalmitis (other than those associated with open-globe injury, keratitis, or wound site infection), one managed with topical antibiotics (TA group) and one without (NTA group), was performed. Results: The study included a total of 270 eyes of 270 patients. Of these, 169 eyes were in the TA group and 101 were in the NTA group. Post-cataract surgery was the most common etiology, accounting for 81.06 and 78.2% of cases, respectively (p = 0.57). A favorable functional outcome at the last visit was seen in 37.5 and 39.6% of eyes (p = 0.73), and a favorable anatomic outcome was noted in 61.2 and 49.5% of eyes (p = 0.06), respectively. The median follow-up was 3.5 and 9 months, respectively (p < 0.0001). Susceptibilities to the common antibiotics used (vancomycin, ceftazidime, and amikacin) were comparable, with the exception of imipenem, for which the susceptibility noted was 95 and 66%, respectively (p = 0.01). Culture positivity in the TA group was seen in 72 out of 169 eyes (42.6%), while in the NTA group it was seen in 98 out of 101 eyes (97.02%; p < 0.0001). Conclusion: Topical antibiotics do not give any added advantage in the management of endophthalmitis otherwise being treated with intravitreal antibiotics and standard vitrectomy techniques.
Pesquisas em design, gestão e tecnologia de Têxtil e Moda: volume 8
Authors:   Universidade de São Paulo. Escola de Artes, Ciências e Humanidades, Italiano Isabel Cristina , Marcicano João Paulo ,   Universidade de São Paulo. Escola de Artes, Ciências e Humanidades, Ramos Júlia BaruqueJúlia Baruque ,   Universidade de São Paulo. Escola de Artes, Ciências e Humanidades, Held Maria Sílvia Barros De ,   Universidade de São Paulo. Escola de Artes, Ciências e Humanidades, Sanches Regina Aparecida ,   Universidade de São Paulo. Escola de Artes, Ciências e Humanidades
Published: April 2020

O presente volume é parte da coleção "Pesquisas em Design, Gestão e Tecnologia de Têxtil", tendo como principal objetivo contribuir para o desenvolvimento cientifico, tecnológico, social, cultural e artístico em Têxtil e Moda. Esse trabalho, somado aos volumes anteriores, vem se tornando importante veículo de divulgação do desenvolvimento e dos resultados de pesquisas na área, a partir de trabalhos desenvolvidos em nível de pós-graduação no Brasil e no exterior. A coleção apresenta métodos e abordagens interdisciplinares e inovadores, com potencial de utilização tanto no âmbito acadêmico e de pesquisa quanto fora deles.
A New Role for the Aldosterone/Mineralocorticoid Receptor Pathway in the Development of Mitral Valve Prolapse
Authors: Ibarrola Jaime , Garcia-Peña Amaia , Matilla Lara , Bonnard Benjamin , Sádaba Rafael , Arrieta Vanessa , Alvarez Virginia , Fernández-Celis Amaya , Gainza Alicia , Navarro Adela , Alvarez de la Rosa Diego , Rossignol Patrick , Jaisser Frederic , López-Andrés Natalia
Published: April 2020

Rationale:

Mitral valve prolapse (MVP) is one of the most common valvular disorders. However, the molecular and cellular mechanisms involved in fibromyxomatous changes in the mitral leaflet tissue have not been elucidated. Aldosterone (Aldo) promotes fibrosis in myocardium, and MR (mineralocorticoid receptor) antagonists (MRAs) improve cardiac function by decreasing cardiac fibrosis.

Objective:

We investigated the role of the Aldo/MR in the fibromyxomatous modifications associated with MVP.

Methods and Results:

Aldo enhanced valvular interstitial cell activation markers and induced endothelial-mesenchymal transition in valvular endothelial cells, resulting in increased proteoglycan secretion. MRA blocked all the above effects. Cytokine arrays showed CT-1 (cardiotrophin-1) to be a mediator of Aldo-induced valvular interstitial cell activation and proteoglycan secretion and CD (cluster of differentiation) 14 to be a mediator of Aldo-induced endothelial-mesenchymal transition and proteoglycan secretion in valvular endothelial cells. In an experimental mouse model of MVP generated by nordexfenfluramine administration, MRA treatment reduced mitral valve thickness and proteoglycan content. Endothelial-specific MR deletion prevented fibromyxomatous changes induced by nordexfenfluramine administration. Moreover, proteoglycan expression was slightly lower in the mitral valves of MVP patients treated with MRA.

Conclusions:

These findings demonstrate, for the first time, that the Aldo/MR pathway regulates the phenotypic, molecular, and histological changes of valvular interstitial cells and valvular endothelial cells associated with MVP development. MRA treatment appears to be a promising option to reduce fibromyxomatous alterations in MVP.