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  • 1
    Publication Date: 2021-02-05
    Description: Few studies reported the relation of intestinal microbiome composition and diversity in pediatric patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC). In this cross-sectional study, we selected patients younger than 19 years old from the pediatric gastroenterology and hepatology outpatient clinic of a tertiary hospital to describe the intestinal microbiome of pediatric patients with PSC associated or not to UC. Patients were divided in PSC, PSC+UC, and UC diagnosis. A stool sample was collected from each patient (n=30) and from a healthy relative/neighbor (n=23). The microbiome composition was assessed using MiSeq (Illumina) platform. Differences in microbial composition were found between PSC and PSC+UC groups. The relative abundance of Veillonella and Megasphaera genera were increased depending on patients’ age at diagnosis. Veillonella was also increased in patients who were in an active status of the disease. Both genera were positively correlated to total bilirubin and gamma-glutamyl transferase. As a conclusion, the disease, the age and the disease activity status seem to influence the intestinal microbiome, highlighting the difference of intestinal microbiome profile for patients depending on age at diagnosis. We also showed an increase of Veillonella in patients with PSC and PSC+UC, and a positive correlation of dysbiosis and higher gamma-glutamyl transferase and total bilirubin in PSC+UC patients. Our findings are promising in the diagnosis, prognosis, and future therapeutic perspectives for PSC patients.
    Electronic ISSN: 1664-3224
    Topics: Medicine
    Published by Frontiers Media
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  • 2
    Publication Date: 2021-02-05
    Description: The COVID-19 pandemic has changed individuals' lifestyles to a great extent, particularly in Italy. Although many concerns about it have been highlighted, its impact on children and adolescents has scarcely been examined. The purpose of this study was to explore behavioral consequences and coping strategies related to the pandemic among families in Italy, by focusing on developmental ages from the caregivers' perspective, 3 weeks into quarantine. An exploratory cross-sectional online survey was conducted over 14 days. Google Forms was employed to conduct the survey. Demographic variables and pre-existing Psychological Weaknesses (PsW) were asked. Adults' sleep difficulties (SleepScore) and coping strategies during quarantine were assessed. Behavioral changes related to quarantine of both subjects completing the form (COVIDStress) and their children (when present) were questioned. Of the 6,871 respondents, we selected 6,800 valid questionnaires; 3,245 declared children aged under 18 years of age (caregivers). PsWs were recognizable in 64.9% among non-caregivers and in 61.5% of caregivers, with a mean PsW score of 1.42 ± 1.26 and 1.30 ± 1.25 over 3 points, respectively. The 95.5% of the non-caregivers and the 96.5% of caregivers presented behavioral changes with a mean COVIDStress of 3.85 ± 1.82 and 4.09 ± 1.79 over 8, respectively (p
    Electronic ISSN: 2296-2565
    Topics: Medicine
    Published by Frontiers Media
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  • 3
    Publication Date: 2021-02-05
    Description: Background:Enterococcus faecalis has been commonly considered as one of the major pathogens of the urinary tract infection (UTI) in human host worldwide, whereas the molecular characteristics of E. faecalis clinical isolates from the patients with UTI in China remains seldomly reported. This study aimed to investigate the resistance mechanism, molecular characteristics and risk factors of E. faecalis clinical isolates from patients with UTI in China.Methods: A total of 115 non-duplicated E. faecalis clinical isolates from patients with UTI were retrospectively collected in a tertiary hospital in China and their clinical data was further analyzed. The linezolid and tedizolid susceptibility were determined by agar dilution. The resistance genes, including erm(A), erm(B), erm(C), tet(M), optrA, cfr, cfr(B), poxtA, and MLST-based housekeeping genes were investigated by PCR.Results: In 115 non-duplicated E. faecalis clinical isolates from the patients with UTI in this hospital setting, the frequency of linezolid or tedizolid-resistant/intermediate isolates were 22.61 and 13.04%, respectively, and the frequency of linezolid-resistant/intermediate E. faecalis clinical isolates carrying with erm(A) were 86%. Among the five linezolid-resistant E. faecalis strains found in this study, three optrA-positive isolates and the other two linezolid-resistant strains were G2576U genetic mutations in the V domain of the 23S rRNA genes. The ST clonality analysis indicated that 31.42% (11/35) of ST16 E. faecalis UTI isolates were not susceptible to linezolid. Moreover, the univariable analysis indicated that the high risk factors of linezolid-resistant/intermediate E. faecalis infections involved the indwelling catheter, trachea cannula catheter and the carriage of erm(A) or optrA. Furthermore, the indwelling catheter and trachea cannula catheter were demonstrated as the independent predictors of linezolid-resistant/intermediate E. faecalis strains in patients with UTI by multivariable analysis.Conclusion: Linezolid-resistant/intermediate E. faecalis associated with urinary tract infections of patients in this hospital setting from China might be explained by the high carriage frequency of optrA genes and moreover, indwelling catheter and trachea cannula should be considered as the independent predictors of linezolid-resistant/intermediate E. faecalis infections. The transmission mechanism of linezolid-resistant/intermediate E. faecalis in this hospital setting should be further studied.
    Electronic ISSN: 2296-2565
    Topics: Medicine
    Published by Frontiers Media
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  • 4
    Publication Date: 2021-02-05
    Description: Background: Distinguishing between stroke subtypes and knowing the time of stroke onset are critical in clinical practice. Thrombolysis and thrombectomy are very effective treatments in selected patients with acute ischemic stroke. Neuroimaging helps decide who should be treated and how they should be treated but is expensive, not always available and can have contraindications. These limitations contribute to the under use of these reperfusion therapies.Aim: An alternative approach in acute stroke diagnosis is to identify blood biomarkers which reflect the body's response to the damage caused by the different types of stroke. Specific blood biomarkers capable of differentiating ischemic from hemorrhagic stroke and mimics, identifying large vessel occlusion and capable of predicting stroke onset time would expedite diagnosis and increase eligibility for reperfusion therapies.Summary of Review: To date, measurements of candidate biomarkers have usually occurred beyond the time window for thrombolysis. Nevertheless, some candidate markers of brain tissue damage, particularly the highly abundant glial structural proteins like GFAP and S100β and the matrix protein MMP-9 offer promising results. Grouping of biomarkers in panels can offer additional specificity and sensitivity for ischemic stroke diagnosis. Unbiased “omics” approaches have great potential for biomarker identification because of greater gene, protein, and metabolite coverage but seem unlikely to be the detection methodology of choice because of their inherent cost.Conclusion: To date, despite the evolution of the techniques used in their evaluation, no individual candidate or multimarker panel has proven to have adequate performance for use in an acute clinical setting where decisions about an individual patient are being made. Timing of biomarker measurement, particularly early when decision making is most important, requires urgent and systematic study.
    Electronic ISSN: 1664-2295
    Topics: Medicine
    Published by Frontiers Media
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  • 5
    Publication Date: 2021-02-05
    Description: Powdery mildew (PM), caused by Podosphaera xanthii (Px), is one of the most devastating fungal diseases of melon worldwide. The use of resistant cultivars is considered to be the best and most effective approach to control this disease. In this study, an F2 segregating population derived from a cross between a resistant (wm-6) and a susceptible cultivar (12D-1) of melon was used to map major powdery mildew resistance genes using bulked segregant analysis (BSA), in combination with next-generation sequencing (NGS). A novel quantitative trait locus (QTL) named qCmPMR-12 for resistance to PM on chromosome 12 was identified, which ranged from 22.0 Mb to 22.9 Mb. RNA-Seq analysis indicated that the MELO3C002434 gene encoding an ankyrin repeat-containing protein was considered to be the most likely candidate gene that was associated with resistance to PM. Moreover, 15 polymorphic SNPs around the target area were successfully converted to Kompetitive Allele-Specific PCR (KASP) markers (P 〈 0.0001). The novel QTL and candidate gene identified from this study provide insights into the genetic mechanism of PM resistance in melon, and the tightly linked KASP markers developed in this research can be used for marker-assisted selection (MAS) to improve powdery mildew resistance in melon breeding programs.
    Electronic ISSN: 1664-462X
    Topics: Biology
    Published by Frontiers Media
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  • 6
    Publication Date: 2021-02-05
    Description: We examined the prevalence and transmission of the fosA3 gene among Citrobacter freundii isolates from flowers and the retail environments. We identified 11 fosfomycin-resistant C. freundii strains (〉256 μg/mL) from 270 samples that included petals (n = 7), leaves (n = 2), dust (n = 1) and water (n = 1). These 11 isolates were multidrug-resistant and most were simultaneously resistant to fosfomycin, cefotaxime, ciprofloxacin and amikacin. Consistently, all 11 isolates also possessed blaCTX–M–14, blaCMY–65/122, aac(6’)-Ib-cr, qnrS1, qnrB13/6/38 and rmtB. These fosA3-positive isolates were assigned to two distinct PFGE patterns and one (n = 9) predominated indicating clonal expansion of fosA3-positive isolates across flower markets and shops. Correspondingly, fosA3 was co-transferred with blaCTX–M–14via two plasmid types by conjugation possessing sizes of 110 kb (n = 9) and 260 kb (n = 2). Two representatives were fully sequenced and p12-1 and pS39-1 possessed one and two unclassified replicons, respectively. These plasmids shared a distinctive and conserved backbone in common with fosA3-carrying C. freundii and other Enterobacteriaceae from human and food animals. However, the fosA3-blaCTX–M–14-containing multidrug resistance regions on these untypable plasmids were highly heterogeneous. To the best of our knowledge, this is the first report of fosA3 and blaCTX–M–14 that were present in bacterial contaminants from flower shops and markets. These findings underscore a public health threat posed by untypable and transferable p12-1-like and pS39-1-like plasmids bearing fosA3-blaCTX–M–14 that could circulate among Enterobacteriaceae species and in particular C. freundi in environmental isolates.
    Electronic ISSN: 1664-302X
    Topics: Biology
    Published by Frontiers Media
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  • 7
    Publication Date: 2021-02-05
    Description: Respiratory sinus arrhythmia (RSA) is a form of cardiorespiratory coupling. It is observed as changes in the heart rate in synchrony with the respiration. RSA has been hypothesized to be due to a combination of linear and nonlinear effects. The quantification of the latter, in turn, has been suggested as a biomarker to improve the assessment of several conditions and diseases. In this study, a framework to quantify RSA using support vector machines is presented. The methods are based on multivariate autoregressive models, in which the present samples of the heart rate variability are predicted as combinations of past samples of the respiration. The selection and tuning of a kernel in these models allows to solve the regression problem taking into account only the linear components, or both the linear and the nonlinear ones. The methods are tested in simulated data as well as in a dataset of polysomnographic studies taken from 110 obstructive sleep apnea patients. In the simulation, the methods were able to capture the nonlinear components when a weak cardiorespiratory coupling occurs. When the coupling increases, the nonlinear part of the coupling is not detected and the interaction is found to be of linear nature. The trends observed in the application in real data show that, in the studied dataset, the proposed methods captured a more prominent linear interaction than the nonlinear one.
    Electronic ISSN: 1664-042X
    Topics: Biology
    Published by Frontiers Media
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  • 8
    Publication Date: 2021-02-05
    Description: Background: With the growing momentum for the adoption of machine learning (ML) in medical field, it is likely that reliance on ML for imaging will become routine over the next few years. We have developed a software named BAAD, which uses ML algorithms for the diagnosis of Alzheimer's disease (AD) and prediction of mild cognitive impairment (MCI) progression.Methods: We constructed an algorithm by combining a support vector machine (SVM) to classify and a voxel-based morphometry (VBM) to reduce concerned variables. We grouped progressive MCI and AD as an AD spectrum and trained SVM according to this classification. We randomly selected half from the total 1,314 subjects of AD neuroimaging Initiative (ADNI) from North America for SVM training, and the remaining half were used for validation to fine-tune the model hyperparameters. We created two types of SVMs, one based solely on the brain structure (SVMst), and the other based on both the brain structure and Mini-Mental State Examination score (SVMcog). We compared the model performance with two expert neuroradiologists, and further evaluated it in test datasets involving 519, 592, 69, and 128 subjects from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Aging (AIBL), Japanese ADNI, the Minimal Interval Resonance Imaging in AD (MIDIAD) and the Open Access Series of Imaging Studies (OASIS), respectively.Results: BAAD's SVMs outperformed radiologists for AD diagnosis in a structural magnetic resonance imaging review. The accuracy of the two radiologists was 57.5 and 70.0%, respectively, whereas, that of the SVMst was 90.5%. The diagnostic accuracy of the SVMst and SVMcog in the test datasets ranged from 88.0 to 97.1% and 92.5 to 100%, respectively. The prediction accuracy for MCI progression was 83.0% in SVMst and 85.0% in SVMcog. In the AD spectrum classified by SVMst, 87.1% of the subjects were Aβ positive according to an AV-45 positron emission tomography. Similarly, among MCI patients classified for the AD spectrum, 89.5% of the subjects progressed to AD.Conclusion: Our ML has shown high performance in AD diagnosis and prediction of MCI progression. It outperformed expert radiologists, and is expected to provide support in clinical practice.
    Electronic ISSN: 1664-2295
    Topics: Medicine
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  • 9
    Publication Date: 2021-02-05
    Description: Objectives: Autonomic dysfunction is a common symptom of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis; however, it has been poorly researched. The purpose of this study was to compare the clinical features, tumor occurrence, intensive care unit (ICU) admission, mechanical ventilation, imaging assessment, cerebrospinal fluid examination, disease severity, and immunotherapy in patients with anti-NMDAR encephalitis with or without autonomic dysfunction.Methods: A retrospective study of anti-NMDAR encephalitis patients diagnosed between January 2016 and April 2020 was performed at the First Affiliated Hospital of Zhengzhou University. Patients were divided into two groups according to whether they had autonomic dysfunction, and their clinical features, treatment, and prognosis were compared.Results: A total of 119 patients with anti-NMDAR encephalitis were included in this study. Seventy-three patients (61.3%) had autonomic dysfunction, while the remaining 46 (38.7%) did not. Sinus tachycardia (69.9%) was the autonomic dysfunction with the highest incidence, while the incidences of symptoms including constipation, central hypopnea, and others gradually decreased. Compared to the group without autonomic dysfunction, the prevalence of the main clinical symptoms such as epileptic seizure (P = 0.003), involuntary movement (P = 0.028), and decreased consciousness (P 〈 0.001) were higher in the group with autonomic dysfunction, which also more frequently presented with complications such as pulmonary infection (P 〈 0.001) and abnormal liver function (P = 0.001). Moreover, the rates of ICU admission (P 〈 0.001) and mechanical ventilation (P = 0.001), as well as the modified Rankin scale (mRS) scores at admission (P 〈 0.001), maximum mRS scores during the course of disease (P 〈 0.001), and mRS scores at discharge (P 〈 0.001) were higher in the patients with autonomic dysfunction than in those without. The number of patients in the autonomic dysfunction group who underwent ≥2 immunotherapies was also higher than that in the group without autonomic dysfunction (P 〈 0.001).Conclusion: Sinus tachycardia is the most common type of autonomic dysfunction in anti-NMDAR encephalitis. Compared to patients without autonomic dysfunction, those with autonomic dysfunction had a higher incidence of epilepsy, involuntary movements, decreased consciousness, pulmonary infections, abnormal liver function, ICU admissions, and mechanical ventilation; moreover, the severity of the disease was greater, and their prognosis worse. Therefore, such patients require intensive immunotherapy.
    Electronic ISSN: 1664-2295
    Topics: Medicine
    Published by Frontiers Media
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  • 10
    Publication Date: 2021-02-05
    Description: Glioblastoma multiforme (GBM), the most common malignant brain tumor, universally carries a poor prognosis. Despite aggressive multimodality treatment, the median survival is ~18–20 months, depending on molecular subgroups. A long history of observations suggests antitumor effects of bacterial infections against malignant tumors. The present review summarizes and critically analyzes the clinical data providing evidence for or against the survival benefit of post-operative bacterial infections in GBM patients. Furthermore, we explore the probable underlying mechanism(s) from basic science studies on the topic. There are plausible explanations from immunobiology for the mechanism of the “favorable effect” of bacterial infections in GBM patients. However, available clinical literature does not provide a definitive association between postoperative bacterial infection and prolonged survival in GBM patients. The presently available, single-/multi-center and national database retrospective case-control studies on the topic provide conflicting results. A prospective randomized study on the subject is clearly not possible. Immunobiology literature supports development of genetically modified bacteria as part of multimodal regimen against GBM.
    Electronic ISSN: 1664-2295
    Topics: Medicine
    Published by Frontiers Media
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  • 11
    Publication Date: 2021-02-05
    Description: Recent studies suggest the brain functional connectivity impairment is the early event occurred in case of Alzheimer’s disease (AD) as well as mild cognitive impairment (MCI). We model the brain as a graph based network to study these impairment. In this paper, we present a new diagnosis approach using graph theory based features from functional magnetic resonance (fMR) images to discriminate AD, MCI, and healthy control (HC) subjects using different classification techniques. These techniques include linear support vector machine (LSVM), and regularized extreme learning machine (RELM). We used pairwise Pearson’s correlation-based functional connectivity to construct the brain network. We compare the classification performance of brain network using Alzheimer’s disease neuroimaging initiative (ADNI) datasets. Node2vec graph embedding approach is employed to convert graph features to feature vectors. Experimental results show that the SVM with LASSO feature selection method generates better classification accuracy compared to other classification technique.
    Print ISSN: 1662-4548
    Electronic ISSN: 1662-453X
    Topics: Medicine
    Published by Frontiers Media
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  • 12
    Publication Date: 2021-02-05
    Description: Abnormal autophagy is related to the pathogenesis and clinical symptoms of myelodysplastic syndrome (MDS). However, the effect of autophagy-related genes (ARGs) on the prognosis of MDS remains unclear. Here, we examined the expression profile of 108 patients with MDS from the GSE58831 dataset, and identified 22 genes that were significantly associated with overall survival. Among them, seven ARGs were screened and APIs were calculated for all samples based on the expression of the seven ARGs, and then, MDS patients were categorized into high- and low-risk groups based on the median APIs. The overall survival of patients with high-risk scores based on these seven ARGs was shorter than patients with low-risk scores in both the training cohort (P = 2.851e-06) and the validation cohort (P = 9.265e-03). Additionally, API showed an independent prognostic indicator for survival in the training samples [hazard ratio (HR) = 1.322, 95% confidence interval (CI): 1.158–1.51; P 〈 0.001] and the validation cohort (HR = 1.05, 95% CI: 1–1.1; P 〈 0.01). The area under the receiver operating characteristic curve (AUROC) of API and IPSS were 43.0137 and 66.0274 in the training cohorts and the AUC of the validation cohorts were 41.5361 and 72.0219. Our data indicate these seven ARGs can predict prognosis in patients with MDS and could guide individualized treatment.
    Electronic ISSN: 2234-943X
    Topics: Medicine
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  • 13
    Publication Date: 2021-02-05
    Description: Renal neuroendocrine neoplasms are rare, with descriptions of cases limited to individual reports and small series. The natural history of this group of neuroendocrine neoplasms is poorly understood. In this study, we queried the Surveillance, Epidemiology and End Results (SEER) database over a four-decade period where we identified 166 cases of primary renal neuroendocrine neoplasms. We observed a 5-year overall survival of 50%. On multivariate analysis, survival was influenced by stage, histology, and if surgery was performed. We observed that patients managed by operative management had a greater frequency of localized or regional stage disease as well as a greater frequency of neuroendocrine tumor, grade 1 histology; whereas those managed non-operatively tended to have distant disease and histologies of neuroendocrine carcinoma, NOS and small cell neuroendocrine carcinoma. This is the largest description of patients with renal neuroendocrine neoplasms. Increased survival was observed in patients with earlier stage and favorable histologies.
    Electronic ISSN: 1664-2392
    Topics: Medicine
    Published by Frontiers Media
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  • 14
    Publication Date: 2021-02-04
    Description: Dystonia is a common movement disorder, involving sustained muscle contractions, often resulting in twisting and repetitive movements and abnormal postures. Dystonia may be primary, as the sole feature (isolated) or in combination with other movement disorders (combined dystonia), or as one feature of another neurological process (secondary dystonia). The current hypothesis is that dystonia is a disorder of distributed brain networks, including the basal ganglia, cerebellum, thalamus and the cortex resulting in abnormal neural motor programs. In comparison, functional dystonia (FD) may resemble other forms of dystonia (OD) but has a different pathophysiology, as a subtype of functional movement disorders (FMD). FD is the second most common FMD and amongst the most diagnostically challenging FMD subtypes. Therefore, distinguishing between FD and OD is important, as the management of these disorders is distinct. There are also different pathophysiological underpinnings in FD, with for example evidence of involvement of the right temporoparietal junction in functional movement disorders that is believed to serve as a general comparator of internal predictions/motor intentions with actual motor events resulting in disturbances in self-agency. In this article, we present a comprehensive review across the spectrum of FD, including oromandibular and vocal forms and discuss the history, clinical clues, evidence for adjunctive “laboratory-based” testing, pathophysiological research and prognosis data. We also provide the approach used at the Massachusetts General Hospital Dystonia Center toward the diagnosis, management and treatment of FD. A multidisciplinary approach, including neurology, psychiatry, physical, occupational therapy and speech therapy, and cognitive behavioral psychotherapy approaches are frequently required; pharmacological approaches, including possible targeted use of botulinum toxin injections and inpatient programs are considerations in some patients. Early diagnosis and treatment may help prevent unnecessary investigations and procedures, while facilitating the appropriate management of these highly complex patients, which may help to mitigate frequently poor clinical outcomes.
    Electronic ISSN: 1664-2295
    Topics: Medicine
    Published by Frontiers Media
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  • 15
    Publication Date: 2021-02-05
    Description: Molluscs have evolved the capacity to fabricate a wide variety of shells over their 540+ million-year history. While modern sequencing and proteomic technologies continue to expand the catalog of molluscan shell-forming proteins, a complete functional understanding of how any mollusc constructs its shell remains an ambitious goal. This lack of understanding also constrains our understanding of how evolution has generated a plethora of molluscan shell morphologies. Taking advantage of a previous expression atlas for shell-forming genes in Lymnaea stagnalis, I have characterized the spatial expression patterns of seven shell-forming genes in the terrestrial gastropod Cepaea nemoralis, with the aim of comparing and contrasting their expression patterns between the two species. Four of these genes were selected from a previous proteomic screen of the C. nemoralis shell, two were targeted by bioinformatics criteria designed to identify likely shell-forming gene products, and the final one was a clear homolog of a peroxidase sequence in the L. stagnalis dataset. While the spatial expression patterns of all seven C. nemoralis genes could be recognized as falling into distinct zones within the mantle tissue similar to those established in L. stagnalis, some zones have apparently been modified. These similarities and differences hint at a modularity to the molluscan mantle that may provide a mechanistic explanation as to how evolution has efficiently generated a diversity of molluscan shells.
    Electronic ISSN: 1664-8021
    Topics: Biology , Medicine
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  • 16
    Publication Date: 2021-02-08
    Description: The cellular response to interferon (IFN) is essential for antiviral immunity, IFN-based therapy and IFN-related disease. The plasma membrane (PM) provides a critical interface between the cell and its environment, and is the initial portal of entry for viruses. Nonetheless, the effect of IFN on PM proteins is surprisingly poorly understood, and has not been systematically investigated in primary immune cells. Here, we use multiplexed proteomics to quantify IFNα2a-stimulated PM protein changes in primary human CD14+ monocytes and CD4+ T cells from five donors, quantifying 606 and 482 PM proteins respectively. Comparison of cell surface proteomes revealed a remarkable invariance between donors in the overall composition of the cell surface from each cell type, but a marked donor-to-donor variability in the effects of IFNα2a. Furthermore, whereas only 2.7% of quantified proteins were consistently upregulated by IFNα2a at the surface of CD4+ T cells, 6.8% of proteins were consistently upregulated in primary monocytes, suggesting that the magnitude of the IFNα2a response varies according to cell type. Among these differentially regulated proteins, we found the viral target Endothelin-converting enzyme 1 (ECE1) to be an IFNα2a-stimulated protein exclusively upregulated at the surface of CD4+ T cells. We therefore provide a comprehensive map of the cell surface of IFNα2a-stimulated primary human immune cells, including previously uncharacterized interferon stimulated genes (ISGs) and candidate antiviral factors.
    Electronic ISSN: 1664-3224
    Topics: Medicine
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  • 17
    Publication Date: 2021-02-05
    Description: Single cell RNA sequencing (scRNA-seq) allows quantitative measurement and comparison of gene expression at the resolution of single cells. Ignoring the batch effects and zero inflation of scRNA-seq data, many proposed differentially expressed (DE) methods might generate bias. We propose a method, single cell mixed model score tests (scMMSTs), to efficiently identify DE genes of scRNA-seq data with batch effects using the generalized linear mixed model (GLMM). scMMSTs treat the batch effect as a random effect. For zero inflation, scMMSTs use a weighting strategy to calculate observational weights for counts independently under zero-inflated and zero-truncated distributions. Counts data with calculated weights were subsequently analyzed using weighted GLMMs. The theoretical null distributions of the score statistics were constructed by mixed Chi-square distributions. Intensive simulations and two real datasets were used to compare edgeR-zinbwave, DESeq2-zinbwave, and scMMSTs. Our study demonstrates that scMMSTs, as supplement to standard methods, are advantageous to define DE genes of zero-inflated scRNA-seq data with batch effects.
    Electronic ISSN: 1664-8021
    Topics: Biology , Medicine
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  • 18
    Publication Date: 2021-02-08
    Description: It is widely accepted that infection and immune response incur significant metabolic demands, yet the respective demands of specific immune responses to live pathogens have not been well delineated. It is also established that upon activation, metabolic pathways undergo shifts at the cellular level. However, most studies exploring these issues at the systemic or cellular level have utilized pathogen associated molecular patterns (PAMPs) that model sepsis, or model antigens at isolated time points. Thus, the dynamics of pathogenesis and immune response to a live infection remain largely undocumented. To better quantitate the metabolic demands induced by infection, we utilized a live pathogenic infection model. Mice infected with Listeria monocytogenes were monitored longitudinally over the course of infection through clearance. We measured systemic metabolic phenotype, bacterial load, innate and adaptive immune responses, and cellular metabolic pathways. To further delineate the role of adaptive immunity in the metabolic phenotype, we utilized two doses of bacteria, one that induced both sickness behavior and protective (T cell mediated) immunity, and the other protective immunity alone. We determined that the greatest impact to systemic metabolism occurred during the early immune response, which coincided with the greatest shift in innate cellular metabolism. In contrast, during the time of maximal T cell expansion, systemic metabolism returned to resting state. Taken together, our findings demonstrate that the timing of maximal metabolic demand overlaps with the innate immune response and that when the adaptive response is maximal, the host has returned to relative metabolic homeostasis.
    Electronic ISSN: 1664-3224
    Topics: Medicine
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  • 19
    Publication Date: 2021-02-08
    Description: Rapid proliferation of cancer cells is enabled by favoring aerobic glycolysis over mitochondrial oxidative phosphorylation (OXPHOS). P32 (C1QBP/gC1qR) is essential for mitochondrial protein translation and thus indispensable for OXPHOS activity. It is ubiquitously expressed and directed to the mitochondrial matrix in almost all cell types with an excessive up-regulation of p32 expression reported for tumor tissues. We recently demonstrated high levels of non-mitochondrial p32 to be associated with high-grade colorectal carcinoma. Mutations in human p32 are likely to disrupt proper mitochondrial function giving rise to various diseases including cancer. Hence, we aimed to investigate the impact of the most common single nucleotide polymorphism (SNP) rs56014026 in the coding sequence of p32 on tumor cell metabolism. In silico homology modeling of the resulting p.Thr130Met mutated p32 revealed that the single amino acid substitution potentially induces a strong conformational change in the protein, mainly affecting the mitochondrial targeting sequence (MTS). In vitro experiments confirmed an impaired mitochondrial import of mutated p32-T130M, resulting in reduced OXPHOS activity and a shift towards a low metabolic phenotype. Overexpression of p32-T130M maintained terminal differentiation of a goblet cell-like colorectal cancer cell line compared to p32-wt without affecting cell proliferation. Sanger sequencing of tumor samples from 128 CRC patients identified the heterozygous SNP rs56014026 in two well-differentiated, low proliferating adenocarcinomas, supporting our in vitro data. Together, the SNP rs56014026 reduces metabolic activity and proliferation while promoting differentiation in tumor cells.
    Electronic ISSN: 2234-943X
    Topics: Medicine
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  • 20
    Publication Date: 2021-02-08
    Description: ObjectiveCirculating tumor cells (CTCs) can predict the efficacy of anti-cancer treatments and indicate prognosis. Here we investigate the significance of CTCs in relation to the prediction of treatment efficacy and prognosis in patients with small cell lung cancer (SCLC) who have received prophylactic cranial irradiation (PCI).MethodsCTCs were detected in 20 patients with SCLC before and after PCI using the oHSV1-hTERT-GFP method. The primary endpoints were progression-free survival (PFS) and overall survival (OS).ResultsEleven patients had limited-stage SCLC, and nine had extensive-stage SCLC. All patients completed chemo-radiotherapy and received PCI. The median baseline CTC count before PCI was 12. After PCI, the median CTC count was 4. The median follow-up time for all enrolled patients was 39.2 months. The median PFS and OS were significantly reduced in patients with ≥4 CTCs after PCI compared to those with
    Electronic ISSN: 2234-943X
    Topics: Medicine
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  • 21
    Publication Date: 2021-02-08
    Description: Neuronavigation using pre-operative imaging data for neurosurgical guidance is a ubiquitous tool for the planning and resection of oncologic brain disease. These systems are rendered unreliable when brain shift invalidates the patient-image registration. Our previous review in 2015, Brain shift in neuronavigation of brain tumours: A review offered a new taxonomy, classification system, and a historical perspective on the causes, measurement, and pre- and intra-operative compensation of this phenomenon. Here we present an updated review using the same taxonomy and framework, focused on the developments of intra-operative ultrasound-based brain shift research from 2015 to the present (2020). The review was performed using PubMed to identify articles since 2015 with the specific words and phrases: “Brain shift” AND “Ultrasound”. Since 2015, the rate of publication of intra-operative ultrasound based articles in the context of brain shift has increased from 2–3 per year to 8–10 per year. This efficient and low-cost technology and increasing comfort among clinicians and researchers have allowed unique avenues of development. Since 2015, there has been a trend towards more mathematical advancements in the field which is often validated on publicly available datasets from early intra-operative ultrasound research, and may not give a just representation to the intra-operative imaging landscape in modern image-guided neurosurgery. Focus on vessel-based registration and virtual and augmented reality paradigms have seen traction, offering new perspectives to overcome some of the different pitfalls of ultrasound based technologies. Unfortunately, clinical adaptation and evaluation has not seen as significant of a publication boost. Brain shift continues to be a highly prevalent pitfall in maintaining accuracy throughout oncologic neurosurgical intervention and continues to be an area of active research. Intra-operative ultrasound continues to show promise as an effective, efficient, and low-cost solution for intra-operative accuracy management. A major drawback of the current research landscape is that mathematical tool validation based on retrospective data outpaces prospective clinical evaluations decreasing the strength of the evidence. The need for newer and more publicly available clinical datasets will be instrumental in more reliable validation of these methods that reflect the modern intra-operative imaging in these procedures.
    Electronic ISSN: 2234-943X
    Topics: Medicine
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  • 22
    Publication Date: 2021-02-08
    Description: Peptide receptor radioligand therapy (PRRT) has evolved as an important second-line treatment option in the management of inoperable and metastatic neuroendocrine neoplasms (NEN). Though high radiation doses can be delivered to the tumors, complete remission is still rare. Radiosensitization prior to PRRT is therefore considered to be a promising strategy to improve the treatment effect. In this study, effect and mechanism of mTOR inhibitors were investigated in a comprehensive panel of five NEN cell lines (BON, QGP-1, LCC-18, H727, UMC-11), employing assays for cellular proliferation, clonogenic survival, cell cycle modification and signaling. mTOR inhibition lead to growth arrest with a biphasic concentration-response pattern: a partial response at approximately 1 nM and full response at micromolar concentrations (8–48 µM). All cell lines demonstrated elevated p70S6K phosphorylation yet also increased phosphorylation of counterregulatory Akt. The pulmonary NEN cell line UMC-11 showed the lowest induction of phospho-Akt and strongest growth arrest by mTOR inhibitors. Radiation sensitivity of the cells (50% reduction versus control) was found to range between 4 and 8 Gy. Further, mTOR inhibition was employed together with irradiation to evaluate radiosensitizing effects of this combination treatment. mTOR inhibition was found to radiosensitize all five NEN cells in an additive manner with a moderate overall effect. The radiation-induced G2/M arrest was diminished under combination treatment, leading to an increased G1 arrest. Further investigation involving a suitable animal model as well as radioligand application such as 177Lu-DOTATATE or 177Lu-DOTATOC will have to demonstrate the full potential of this strategy for radiosensitization in NEN.
    Electronic ISSN: 2234-943X
    Topics: Medicine
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  • 23
    Publication Date: 2021-02-08
    Description: UDP-glucuronosyltransferase 1A1 (UGT1A1) is an essential enzyme in mammals that is responsible for detoxification and metabolic clearance of the endogenous toxin bilirubin and a variety of xenobiotics, including some crucial therapeutic drugs. Discovery of potent and safe UGT1A1 inducers will provide an alternative therapy for ameliorating hyperbilirubinaemia and drug-induced hepatoxicity. This study aims to find efficacious UGT1A1 inducer(s) from natural flavonoids, and to reveal the mechanism involved in up-regulating of this key conjugative enzyme by the flavonoid(s) with strong UGT1A1 induction activity. Among all the tested flavonoids, neobavaisoflavone (NBIF) displayed the most potent UGT1A1 induction activity, while its inductive effects were confirmed by both western blot and glucuronidation activity assays. A panel of nuclear receptor reporter assays demonstrated that NBIF activated PPARα and PPARγ in a dose-dependent manner. Meanwhile, we also found that NBIF could up-regulate the expression of PPARα and PPARγ in hepatic cells, suggesting that the induction of UGT1A1 by NBIF was mainly mediated by PPARs. In silico simulations showed that NBIF could stably bind on pocket II of PPARα and PPARγ. Collectively, our results demonstrated that NBIF is a natural inducer of UGT1A1, while this agent induced UGT1A1 mainly via activating and up-regulating PPARα and PPARγ. These findings suggested that NBIF can be used as a promising lead compound for the development of more efficacious UGT1A1 inducers to treat hyperbilirubinaemia and UGT1A1-associated drug toxicities.
    Electronic ISSN: 1663-9812
    Topics: Medicine
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  • 24
    Publication Date: 2021-02-08
    Description: Globally, methamphetamine (MA) is the second most abused drug, with psychotic symptoms being one of the most common adverse effects. Emotional disorders induced by MA abuse have been widely reported both in human and animal models; however, the mechanisms underlying such disorders have not yet been fully elucidated. In this study, a chronic MA administration mouse model was utilized to elucidate the serotonergic pathway involved in MA-induced emotional disorders. After 4 weeks of MA administration, the animals exhibited significantly increased depressive and anxious symptoms. Molecular and morphological evidence showed that chronic MA administration reduced the expression of the 5-hydroxytryptamine (5-HT) rate-limiting enzyme, tryptophan hydroxylase 2, in the dorsal raphe and the concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid in the basolateral amygdala (BLA) nuclei. Alterations in both 5-HT and 5-HT receptor levels occurred simultaneously in BLA; quantitative polymerase chain reaction, western blotting, and fluorescence analysis revealed that the expression of the 5-HT2C receptor (5-HT2CR) increased. Neuropharmacology and virus-mediated silencing strategies confirmed that targeting 5-HT2CR reversed the depressive and anxious behaviors induced by chronic MA administration. In the BLA, 5-HT2CR-positive cells co-localized with GABAergic interneurons. The inactivation of 5-HT2CR ameliorated impaired GABAergic inhibition and decreased BLA activation. Thus, herein, for the first time, we report that the abnormal regulation of 5-HT2CR is involved in the manifestation of emotional disorder-like symptoms induced by chronic MA use. Our study suggests that 5-HT2CR in the BLA is a promising clinical target for the treatment of MA-induced emotional disorders.
    Electronic ISSN: 1663-9812
    Topics: Medicine
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  • 25
    Publication Date: 2021-02-08
    Description: Currently, the main treatment for familial adenomatous polyposis (FAP) is surgery, however, surgery is far from ideal as there are many complications such as uncontrollable bowel movements, pouch inflammation, anastomotic stricture, and secondary fibroids. Therefore, it is necessary to further expand the understanding of FAP and develop new treatments for FAP. The immune microenvironment including immune cells and cytokines, plays an important role in FAP and the progression of FAP to adenocarcinoma, thus it may be a promising treatment for FAP. In the current review, we summarized the recent progress in the immune microenvironment of FAP.
    Electronic ISSN: 2234-943X
    Topics: Medicine
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  • 26
    Publication Date: 2021-02-08
    Description: Macrophages are pivotal in mounting liver inflammatory and tissue repair responses upon hepatic injury, showing remarkable functional plasticity. The molecular mechanisms determining macrophage transition from inflammatory to restorative phenotypes in the damaged liver remain unclear. Using mouse models of acute (APAP) and chronic (CCl4) drug-induced hepatotoxic injury we show that the immune receptor Trem-2 controls phenotypic shifts of liver macrophages and impacts endothelial cell differentiation during tissue recovery. Trem-2 gene ablation led to a delayed re-population of Kupffer cells correlating with deterred resolution of hepatic damage following acute and chronic injury. During tissue recovery, we found that macrophages transitioning to Kupffer cells expressed high levels of Trem-2. Acquisition of the transition phenotype was associated with a unique transcriptomic profile denoting strong responsiveness to oxidative stress and downmodulation of the pro-inflammatory phenotype, which was not observed in absence of Trem-2. During tissue recovery, lack of Trem-2 favored accumulation of a liver-damage associated endothelial cell population (LDECs), whose transcriptional program was compatible with endothelial de-differentiation. Accordingly, LDECs precursor potential is supported by the downregulation of surface endothelial cell markers and by striking in vitro morphological changes towards typical endothelial cells. In conclusion, we found that the dynamics of liver macrophages in response to liver injury are critically controlled by Trem-2 and this regulation is interlinked with the de-differentiation of endothelial cells and heightened liver pathology. We propose that Trem-2 promotes the transition from pro-inflammatory to tissue repair phase by driving the acquisition of restorative properties in phagocytic macrophages.
    Electronic ISSN: 1664-3224
    Topics: Medicine
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  • 27
    Publication Date: 2021-02-08
    Description: For patients suffering with chronic neuropathic pain the need for suitable novel therapies is imperative. Over recent years a contributing factor for the lack of development of new analgesics for neuropathic pain has been the mismatch of primary neuropathic pain assessment endpoints in preclinical vs. clinical trials. Despite continuous forward translation failures across diverse mechanisms, reflexive quantitative sensory testing remains the primary assessment endpoint for neuropathic pain and analgesia in animals. Restricting preclinical evaluation of pain and analgesia to exclusively reflexive outcomes is over simplified and can be argued not clinically relevant due to the continued lack of forward translation and failures in the clinic. The key to developing new analgesic treatments for neuropathic pain therefore lies in the development of clinically relevant endpoints that can translate preclinical animal results to human clinical trials. In this review we discuss this mismatch of primary neuropathic pain assessment endpoints, together with clinical and preclinical evidence that supports how bidirectional research is helping to validate new clinically relevant neuropathic pain assessment endpoints. Ethological behavioral endpoints such as burrowing and facial grimacing and objective measures such as electroencephalography provide improved translatability potential together with currently used quantitative sensory testing endpoints. By tailoring objective and subjective measures of neuropathic pain the translatability of new medicines for patients suffering with neuropathic pain will hopefully be improved.
    Electronic ISSN: 1663-9812
    Topics: Medicine
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  • 28
    Publication Date: 2021-02-08
    Description: Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly throughout the world. Although COVID-19 has a relatively low case severity rate compared to SARS and Middle East Respiratory syndrome it is a major public concern because of its rapid spread and devastating impact on the global economy. Scientists and clinicians are urgently trying to identify drugs to combat the virus with hundreds of clinical trials underway. Current treatments could be divided into two major part: anti-viral agents and host system modulatory agents. On one hand, anti-viral agents focus on virus infection process. Umifenovir blocks virus recognizing host and entry. Remdesivir inhibits virus replication. Chloroquine and hydroxychloroquine involve preventing the whole infection process, including virus transcription and release. On the other hand, host system modulatory agents are associated with regulating the imbalanced inflammatory reaction and biased immune system. Corticosteroid is believed to be commonly used for repressing hyper-inflammation, which is one of the major pathologic mechanisms of COVID-19. Convalescent plasma and neutralizing antibodies provide essential elements for host immune system and create passive immunization. Thrombotic events are at high incidence in COVID-19 patients, thus anti-platelet and anti-coagulation are crucial, as well. Here, we summarized these current or reproposed agents to better understand the mechanisms of agents and give an update of present research situation.
    Electronic ISSN: 1663-9812
    Topics: Medicine
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  • 29
    Publication Date: 2021-02-08
    Description: IntroductionClostridioides difficile is a neglected pathogen in many African countries as it is generally not regarded as one of the major contributors toward the diarrheal disease burden in the continent. However, several studies have suggested that C. difficile infection (CDI) may be underreported in many African settings. The aim of this study was to determine the prevalence of CDI in hospitalized patients, evaluate antimicrobial exposure, and detect toxin and antimicrobial resistance profiles of the isolated C. difficile strains.MethodsIn this cross-sectional study, 333 hospitalized patients with hospital-onset diarrhoea were selected. The stool samples were collected and cultured on cycloserine-cefoxitin egg yolk agar (CCEY). Isolates were presumptively identified by phenotypic characteristics and Gram stain and confirmed by singleplex real-time PCR (qPCR) assays detecting the species-specific tpi gene, toxin A (tcdA) gene, toxin B (tcdB) gene, and the binary toxin (cdtA/cdtB) genes. Confirmed C. difficile isolates were tested against a panel of eight antimicrobials (vancomycin, metronidazole, rifampicin, ciprofloxacin, tetracycline, clindamycin, erythromycin, and ceftriaxone) using E-test strips.ResultsC. difficile was detected in 57 (25%) of diarrheal patients over the age of two, 56 (98.2%) of whom received antimicrobials before the diarrheal episode. Amongst the 71 confirmed isolates, 69 (97.1%) harbored at least one toxin gene. More than half of the toxigenic isolates harbored a truncated tcdA gene. All isolates were sensitive to vancomycin, while three isolates (2.1%) were resistant to metronidazole (MIC 〉32 mg/L). High levels of resistance were observed to rifampicin (65/71, 91.5%), erythromycin (63/71, 88.7%), ciprofloxacin (59/71, 83.1%), clindamycin (57/71, 80.3%), and ceftriaxone (36/71, 50.7.8%). Among the resistant isolates, 61 (85.9%) were multidrug-resistant.ConclusionMultidrug-resistant C. difficile strains were a significant cause of healthcare facility-onset C. difficile infections in patients with prior antimicrobial exposure in this Kenyan hospital.
    Electronic ISSN: 2235-2988
    Topics: Biology , Medicine
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  • 30
    Publication Date: 2021-02-08
    Description: BackgroundTriple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer with poorest clinical outcomes. Patients of childbearing age have a higher probability of TNBC diagnosis, with more demands on maintenance and restoration of physical and psychosocial function. This study aimed to design effective and comprehensive nomograms to predict survival in these patients.MethodsWe used the SEER database to identify patients with TNBC aged between 18 and 45 and randomly classified these patients into a training (n=2,296) and a validation (n=2,297) cohort. Nomograms for estimating overall survival (OS) and breast cancer-specific survival (BCSS) were generated based on multivariate Cox proportional hazards models and competing-risk models in the training cohort. The performances of the nomograms were quantified in the validation cohort using calibration curves, time-dependent receiver operating characteristic (ROC) curves and Harrell’s concordance index (C-index).ResultsA total of 4,593 TNBC patients of childbearing age were enrolled. Four prognostic factors for OS and six for BCSS were identified and incorporated to construct nomograms. In the validation cohort, calibration curves showed excellent agreement between nomogram-predicted and actual survival data. The nomograms also achieved relatively high Harrell’s C-indexes and areas under the time-dependent ROC curves for estimating OS and BCSS in both training and validation cohorts.ConclusionsIndependent prognostic factors were identified, and used to develop nomograms to predict OS and BCSS in childbearing-age patients with TNBC. These models could enable individualized risk estimation and risk-adapted treatment for these patients.
    Electronic ISSN: 2234-943X
    Topics: Medicine
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  • 31
    Publication Date: 2021-02-08
    Description: The deregulation of the MYC family of oncogenes, including c-MYC, MYCN and MYCL occurs in many types of cancers, and is frequently associated with a poor prognosis. The majority of functional studies have focused on c-MYC due to its broad expression profile in human cancers. The existence of highly conserved functional domains between MYCN and c-MYC suggests that MYCN participates in similar activities. MYC encodes a basic helix-loop-helix-leucine zipper (bHLH-LZ) transcription factor (TF) whose central oncogenic role in many human cancers makes it a highly desirable therapeutic target. Historically, as a TF, MYC has been regarded as “undruggable”. Thus, recent efforts focus on investigating methods to indirectly target MYC to achieve anti-tumor effects. This review will primarily summarize the recent progress in understanding the function of MYCN. It will explore efforts at targeting MYCN, including strategies aimed at suppression of MYCN transcription, destabilization of MYCN protein, inhibition of MYCN transcriptional activity, repression of MYCN targets and utilization of MYCN overexpression dependent synthetic lethality.
    Electronic ISSN: 2234-943X
    Topics: Medicine
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  • 32
    Publication Date: 2021-02-08
    Description: Radiotherapy (RT) is an effective method of cancer treatment, but like any other method of cancer treatment, there are inherent limitations. While technological advances and a growing understanding of its biological effects have improved its results dramatically, the use of RT is still limited to certain patient populations and by normal tissue toxicities. The harmful side effects of treating patients with radiation can offset its therapy benefits, limiting its use in certain cases. Phyto, or plant-based, medicines offer a way to add to radiation treatment, while also protecting patients from its toxic side effects. Phytomedicines such as cannabinoids (CBD) and bitter melon extract have demonstrated therapeutic properties, including the ability to activate apoptotic death in cancer cells, diminish tumor progression, and generally decrease the incidence of several cancer types. In addition, herbal drugs have been shown to be powerful antioxidants with the ability to decrease toxicity of RT without the adverse side effects found in synthetic drugs. Furthermore, a number of phytomedicines have been shown to mitigate hypoxic conditions within the tumor microenvironment, creating a more radiosensitive disease and preventing tumorigenesis. The purpose of this article is to examine the merits and demerits of employing phytomedicines during RT. Results from studies that have tested the effects of combining radiotherapy with supplemental herbal treatment are discussed along with perspectives on where additional research is needed to advance “Phytoradiotherapy”. Overall, experimental evidence points to the fact that phytomedicines have significant potential to enhance RT, with need for cross-disciplinary collaborations to establish optimal dosing combinations with evidence-base for clinical translation.
    Electronic ISSN: 2234-943X
    Topics: Medicine
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  • 33
    Publication Date: 2021-02-08
    Description: Aim: To investigate the relationship between cytokines associated with innate immune cell activation and brain injury and outcome in infants with NE compared to neonatal controls.Methods: Serum and CSF biomarkers associated with activated neutrophils and monocytes [Interleukin-8 (IL-8) and Granulocyte-Macrophage-Colony-Stimulating-Factor (GM-CSF)] were serially measured using duplex immunoassays on days 1, 3 and 7 in term newborns with NE and controls. Results were compared to grade of encephalopathy, seizures, MRI brain imaging, mortality and Bayley Score of Infant and Toddler Development (Bayley-III) at 2 years of age.Results: Ninety-four infants had serum samples collected with 34 CSF samples. NE Grade II/III was significantly associated with elevated on day 2 serum IL-8. Mortality was best predicted by elevated day 1 IL-8. GM-CSF was initially elevated on day 1 and abnormal MRI imaging was associated with decreased day 2 GM-CSF. Elevated GM-CSF at day of life 6–7 correlated negatively with composite cognitive, language and motor Bayley-III scores at 2 years.Conclusion: Moderate or severe NE and mortality was associated with elevated IL-8. Day 2 GM-CSF could predict abnormal MRI results in NE and Bayley-III. Therefore, these cytokines are altered in NE and may predict early outcomes and further implicate inflammatory processes in NE.
    Electronic ISSN: 2296-2360
    Topics: Medicine
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  • 34
    Publication Date: 2021-02-09
    Description: Thyroid cancers (TC) have increasingly been detected following advances in diagnostic methods. Risk stratification guided by refined information becomes a crucial step toward the goal of personalized medicine. The diagnosis of TC mainly relies on imaging analysis, but visual examination may not reveal much information and not enable comprehensive analysis. Artificial intelligence (AI) is a technology used to extract and quantify key image information by simulating complex human functions. This latent, precise information contributes to stratify TC on the distinct risk and drives tailored management to transit from the surface (population-based) to a point (individual-based). In this review, we started with several challenges regarding personalized care in TC, for example, inconsistent rating ability of ultrasound physicians, uncertainty in cytopathological diagnosis, difficulty in discriminating follicular neoplasms, and inaccurate prognostication. We then analyzed and summarized the advances of AI to extract and analyze morphological, textural, and molecular features to reveal the ground truth of TC. Consequently, their combination with AI technology will make individual medical strategies possible.
    Electronic ISSN: 2234-943X
    Topics: Medicine
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  • 35
    Publication Date: 2021-02-09
    Description: PurposeDyslipidemia has been frequently reported and associated with increased cardiovascular risk in patients with Cushing’s disease (CD). Few studies are available regarding the relationships between lipid abnormalities and other preoperative metabolic comorbidities in CD, and the data on alterations of the lipid profile after surgery is quite variable. We aimed to investigate the associations between hyperlipidemia and other baseline metabolic and hormonal parameters and the impact of surgical remission on lipid metabolism in patients with CD.MethodsThis retrospective study included 104 patients diagnosed with CD. Baseline hormonal and metabolic parameters were compared between the hyperlipidemia (HLP) group and non-hyperlipidemia (NLP) group, and their relationships with hyperlipidemia at diagnosis were evaluated. Alterations in lipid profiles after surgical remission of CD were evaluated in 65 patients with available follow-up data.ResultsUpon baseline, logistic regression analysis showed that impaired glucose metabolism (IGM) (OR=4.68, 95%CI:1.38–15.91) and morning cortisol levels (per 10 μg/dl change) (OR=1.81, 95%CI:1.11–2.95) are both independent risk factors of preoperative occurrence of hyperlipidemia in patients with CD. The baseline triglyceride (TG) level was positively correlated with systolic blood pressure (SBP) (r=0.297, p=0.003). Lipid abnormalities had improvement but may persist after surgical remission, and the persisted hyperlipidemia is associated with higher baseline total cholesterol (TC) levels (r=0.505, p=0.033).ConclusionsPersistence of post-surgery hyperlipidemia is associated with severe baseline lipid abnormalities. Surgical remission with concomitant control of impaired glucose metabolism at diagnosis may have significant implications for controlling hyperlipidemia and reducing cardiovascular risk in CD.
    Electronic ISSN: 1664-2392
    Topics: Medicine
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  • 36
    Publication Date: 2021-02-09
    Description: The existing computational models used to estimate motion sickness are incapable of describing the fact that the predictability of motion patterns affects motion sickness. Therefore, the present study proposes a computational model to describe the effect of the predictability of dynamics or the pattern of motion stimuli on motion sickness. In the proposed model, a submodel – in which a recursive Gaussian process regression is used to represent human features of online learning and future prediction of motion dynamics – is combined with a conventional model of motion sickness based on an observer theory. A simulation experiment was conducted in which the proposed model predicted motion sickness caused by a 900 s horizontal movement. The movement was composed of a 9 m repetitive back-and-forth movement pattern with a pause. Regarding the motion condition, the direction and timing of the motion were varied as follows: (a) Predictable motion (M_P): the direction of the motion and duration of the pause were set to 8 s; (b) Motion with unpredicted direction (M_dU): the pause duration was fixed as in (M_P), but the motion direction was randomly determined; (c) Motion with unpredicted timing (M_tU): the motion direction was fixed as in (M_P), but the pause duration was randomly selected from 4 to 12 s. The results obtained using the proposed model demonstrated that the predicted motion sickness incidence for (M_P) was smaller than those for (M_dU) and (M_tU) and no considerable difference was found between M_dU and M_tU. This tendency agrees with the sickness patterns observed in a previous experimental study in which the human participants were subject to motion conditions similar to those used in our simulations. Moreover, no significant differences were found in the predicted motion sickness incidences at different conditions when the conventional model was used.
    Electronic ISSN: 1662-5137
    Topics: Medicine
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  • 37
    Publication Date: 2021-02-09
    Description: Background: Pruritus is a frequent adverse event during the use of immune checkpoint inhibitors (ICIs), with a frequency estimated to be between 11 and 47%. The underlying causes remain poorly understood.Objectives: The main goal was to search for putative causes of pruritus occurring in patients treated with ICIs for melanomas and cutaneous carcinomas. Other objectives were to assess the association between the occurrence of pruritus and survival and between the occurrence of pruritus and other adverse events.Methods: A monocentric retrospective descriptive study was performed using data for patients treated with ICIs (nivolumab, pembrolizumab, ipilimumab, and cemiplimab) between August 2010 and November 2019.Results: A total of 181 patients were included (mean age: 69 years). Pruritus was reported by 25 patients (13.8%). We were able to determine three subgroups of pruritus causes under ICI use: pruritus directly related to immunotherapy, pruritus indirectly related through other pruritus-inducing side effects and pruritus unrelated to ICIs. In 6/25 patients, no more specific cause of pruritus was found at the onset of pruritus or in their backgrounds, other than ICI use.Limitations: The study has some limitations due to unicentric and retrospective design.Conclusion: Pruritus was found in 25/181 patients in this series; only in 6/25 patients no potential cause other than ICI could be found, and pruritus was not associated with differences in survival.
    Electronic ISSN: 2296-858X
    Topics: Medicine
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  • 38
    Publication Date: 2021-02-09
    Electronic ISSN: 2234-943X
    Topics: Medicine
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  • 39
    Publication Date: 2021-02-09
    Description: Context: There is an ongoing debate on the optimal management of patent ductus arteriosus (PDA) in preterm infants. Identifying subgroup of infants who would benefit from pharmacological treatment might help.Objective: To investigate the modulating effect of the differences in methodological quality, the rate of open-label treatment, and patient characteristics on relevant outcome measures in randomized controlled trials (RCTs).Data Sources: Electronic database search between 1950 and May 2020.Study Selection: RCTs that assessed pharmacological treatment compared to placebo/no treatment.Data Extraction: Data is extracted following the PRISMA guidelines. Outcome measures were failure to ductal closure, surgical ligation, incidence of necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, periventricular leukomalacia, intraventricular hemorrhage (IVH) grade ≥3, retinopathy of prematurity and mortality.Results: Forty-seven studies were eligible. The incidence of IVH grade ≥3 was lower in the treated infants compared to the placebo/no treatment (RR 0.77, 95% CI 0.64–0.94) and in the subgroups of infants with either a gestational age
    Electronic ISSN: 2296-2360
    Topics: Medicine
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  • 40
    Publication Date: 2021-02-09
    Description: Diaporthe species are associated with Citrus as endophytes, pathogens, and saprobes worldwide. However, little is known about Diaporthe as endophytes in Citrus grandis in China. In this study, 24 endophytic Diaporthe isolates were obtained from cultivated C. grandis cv. “Tomentosa” in Huazhou, Guangdong Province in 2019. The nuclear ribosomal internal transcribed spacer (ITS), partial sequences of translation elongation factor 1-α (tef1), β-tubulin (tub2), and partial calmodulin (cal) gene regions were sequenced and employed to construct phylogenetic trees. Based on morphology and combined multigene phylogeny, eleven Diaporthe species were identified including two new species, Diaporthe endocitricola and D. guangdongensis. These are the first report of D. apiculata, D. aquatica, D. arecae, D. biconispora, D. limonicola, D. masirevicii, D. passifloricola, D. perseae, and D. sennae on C. grandis. This study provides the first intensive study of endophytic Diaporthe species on C. grandis cv. tomentosa in China. These results will improve the current knowledge of Diaporthe species associated with C. grandis. The results obtained in this study will also help to understand the potential pathogens and biocontrol agents and to develop a platform in disease management.
    Electronic ISSN: 1664-302X
    Topics: Biology
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  • 41
    Publication Date: 2021-02-09
    Description: Background: Carbon dioxide (CO2) insufflation during gastrointestinal (GI) endoscopic procedures has gained popularity in adults. However, its utility in pediatric patients is not known. The current review aimed to compare the efficacy of CO2 vs. air insufflation for GI endoscopic procedures in pediatric patients.Methods: The electronic databases of PubMed, Embase, Scopus, and CENTRAL were searched from the inception of databases to 15th August 2020.Results: All randomized controlled trials (RCTs) comparing CO2 vs. air insufflation for GI endoscopic procedures in pediatric patients were eligible for inclusion. Five RCTs were identified. Pooled analysis of data from 226 patients in the CO2 group and 224 patients in the air group revealed that patients receiving CO2 insufflation were at a lower odds of experiencing postoperative pain as compared to those undergoing the procedure with air (OR: 0.40; 95% CI: 0.19, 0.87; I2 = 62%; p = 0.02). Descriptive analysis indicated no difference in the two groups for abdominal distention after the procedure. Two trials reported elevated CO2 in the study group but without any pulmonary complications. Bloating was reported by two studies and both reported significantly less bloating in the CO2 group.Conclusion: Our study indicates that the incidence of pain may be reduced with the use of CO2 insufflation in pediatric GI endoscopies without a significant risk of adverse events. However, current evidence is from a limited number of trials and not strong to recommend a routine of CO2 in pediatric gastroenterology practice. Further high-quality RCTs are required to supplement current evidence.
    Electronic ISSN: 2296-2360
    Topics: Medicine
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  • 42
    Publication Date: 2021-02-09
    Description: The genus Brassica includes oil crops, vegetables, condiments, fodder crops, and ornamental plants. Brassica species underwent a whole genome triplication event after speciation between ancestral species of Brassica and closely related genera including Arabidopsis thaliana. Diploid species such as Brassica rapa and Brassica oleracea have three copies of genes orthologous to each A. thaliana gene, although deletion in one or two of the three homologs has occurred in some genes. The floral transition is one of the crucial events in a plant’s life history, and time of flowering is an important agricultural trait. There is a variation in flowering time within species of the genus Brassica, and this variation is largely dependent on a difference in vernalization requirements. In Brassica, like in A. thaliana, the key gene of vernalization is FLOWERING LOCUS C (FLC). In Brassica species, the vernalization response including the repression of FLC expression by cold treatment and the enrichment of the repressive histone modification tri-methylated histone H3 lysine 27 (H3K27me3) at the FLC locus is similar to A. thaliana. B. rapa and B. oleracea each have four paralogs of FLC, and the allotetraploid species, Brassica napus, has nine paralogs. The increased number of paralogs makes the role of FLC in vernalization more complicated; in a single plant, paralogs vary in the expression level of FLC before and after vernalization. There is also variation in FLC expression levels between accessions. In this review, we focus on the regulatory circuits of the vernalization response of FLC expression in the genus Brassica.
    Electronic ISSN: 1664-462X
    Topics: Biology
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  • 43
    Publication Date: 2021-02-09
    Description: The increase of blood pressure is accompanied by the changes in the morphology and function of vascular endothelial cells. Vascular endothelial injury and hypertension actually interact as both cause and effect. A large number of studies have proved that inflammation plays a significant role in the occurrence and development of hypertension, but the potential mechanism between inflammation and hypertensive endothelial injury is still ambiguous. The purpose of this study was to explore the association between the activation of NLRP3 inflammasome and hypertensive endothelial damage, and to demonstrate the protective effect of sinapine thiocyanate (ST) on endothelia in hypertension. The expression of NLRP3 gene was silenced by tail vein injection of adeno-associated virus (AAVs) in spontaneously hypertensive rats (SHRs), indicating that activation of NLRP3 inflammasome accelerated hypertensive endothelial injury. ST not only protected vascular endothelial function in SHRs by inhibiting the activation of NLRP3 inflammasome and the expression of related inflammatory mediators, but also improved AngII-induced huvec injury. In summary, our results show that alleviative NLRP3 inflammasome activation attenuates hypertensive endothelial damage and ST ameliorates vascular endothelial dysfunction in hypertension via inhibiting activation of the NLRP3 inflammasome.
    Electronic ISSN: 1663-9812
    Topics: Medicine
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  • 44
    Publication Date: 2021-02-09
    Description: Caladenia fulva G.W. Carr (Tawny Spider-orchid) is a terrestrial Australian endangered orchid confined to contiguous reserves in open woodland in Victoria, Australia. Natural recruitment is poor and no confirmed pollinator has been observed in the last 30 years. Polymorphic variation in flower color complicates plans for artificial pollination, seed collection and ex situ propagation for augmentation or re-introduction. DNA sequencing showed that there was no distinction among color variants in the nuclear ribosomal internal transcribed spacer (ITS) region and the chloroplast trnT-trnF and matK regions. Also, authentic specimens of both C. fulva and Caladenia reticulata from the reserves clustered along with these variants, suggesting free interbreeding. Artificial cross-pollination in situ and assessment of seed viability further suggested that no fertility barriers existed among color variants. Natural fruit set was 15% of the population and was proportional to numbers of the different flower colors but varied with orchid patch within the population. Color modeling on spectral data suggested that a hymenopteran pollinator could discriminate visually among color variants. The similarity in fruiting success, however, suggests that flower color polymorphism may avoid pollinator habituation to specific non-rewarding flower colors. The retention of large brightly colored flowers suggests that C. fulva has maintained attractiveness to foraging insects rather than evolving to match a scarce unreliable hymenopteran sexual pollinator. These results suggest that C. fulva should be recognized as encompassing plants with these multiple flower colors, and artificial pollination should use all variants to conserve the biodiversity of the extant population.
    Electronic ISSN: 1664-462X
    Topics: Biology
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  • 45
    Publication Date: 2021-02-09
    Description: Asymptomatic/subclinical gonococcal infections in females continue to be prevalent within the general population, thus emerging as a global health problem. However, the reasons for these clinical manifestations are unknown. Our group had previously found out that in females, asymptomatic gonococcal infections correlate with higher serum progesterone (P4) levels and lower IL-1β levels in cervical secretions. We used murine infection model and THP-1 cells to determine whether P4 exerts anti-inflammatory effects on gonococcal infections. In the murine infection model, P4 (1 mg/day) inhibited the inflammatory effects induced by gonococcal infections which led to decreased neutrophil infiltration, reduced polymorphonuclear neutrophils (PMNs) numbers, IL-1β, TNF-α, and IL-6 levels in vaginal secretions. In addition, P4 down-regulated the mRNA and protein levels of NLRP3, associated with lower mRNA levels of pro-IL-1β, repressed caspase-1 activity in genital tissues and THP-1 cells. Moreover, P4 suppressed the phosphorylation levels of NF-κB and attenuated Neisseria gonorrhoeae (N. gonorrhoeae, gonococci or GC)-induced ROS generation. This is consistent with the two signals required for activation of the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome. In conclusion, our result shows that P4 suppresses the gonococci induced-inflammation, especially through the NLRP3 inflammasome pathway, and partially explains the pathogenesis of asymptomatic GC infection in women.
    Electronic ISSN: 1664-302X
    Topics: Biology
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  • 46
    Publication Date: 2021-02-09
    Description: Squamous cell carcinoma (SCC) is the second most common skin cancer worldwide and, despite the relatively easy visualization of the tumor in the clinic, a sizeable number of SCC patients are diagnosed at advanced stages with local invasion and distant metastatic lesions. In the last decade, immunotherapy has emerged as the fourth pillar in cancer therapy via the targeting of immune checkpoint molecules such as programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). FDA-approved monoclonal antibodies directed against these immune targets have provide survival benefit in a growing list of cancer types. Currently, there are two immunotherapy drugs available for cutaneous SCC: cemiplimab and pembrolizumab; both monoclonal antibodies (mAb) that block PD-1 thereby promoting T-cell activation and/or function. However, the success rate of these checkpoint inhibitors currently remains around 50%, which means that half of the patients with advanced SCC experience no benefit from this treatment. This review will highlight the mechanisms by which the immune checkpoint molecules regulate the tumor microenvironment (TME), as well as the ongoing clinical trials that are employing single or combinatory therapeutic approaches for SCC immunotherapy. We also discuss the regulation of additional pathways that might promote superior therapeutic efficacy, and consequently provide increased survival for those patients that do not benefit from the current checkpoint inhibitor therapies.
    Electronic ISSN: 2296-634X
    Topics: Biology
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  • 47
    Publication Date: 2021-02-09
    Description: Sphingolipids are a class of essential lipids, functioning as both cell membrane constituents and signaling messengers. In the sphingolipid metabolic network, ceramides serve as the central hub that is hydrolyzed to sphingosine, followed by phosphorylation to sphingosine 1-phosphate (S1P) by sphingosine kinase (SphK). SphK is regarded as a “switch” of the sphingolipid rheostat, as it catalyzes the conversion of ceramide/sphingosine to S1P, which often exhibit opposing biological roles in the cell. Besides, SphK is an important signaling enzyme that has been implicated in the regulation of a wide variety of biological functions. In recent years, an increasing body of evidence has suggested a critical role of SphK in type 2 diabetes mellitus (T2D), although a certain level of controversy remains. Herein, we review recent findings related to SphK in the field of T2D research with a focus on peripheral insulin resistance and pancreatic β-cell failure. It is expected that a comprehensive understanding of the role of SphK and the associated sphingolipids in T2D will help to identify druggable targets for future anti-diabetes therapy.
    Electronic ISSN: 1664-2392
    Topics: Medicine
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  • 48
    Publication Date: 2021-02-09
    Description: Tropical storms and hurricanes (collectively hereafter, tropical cyclones) are among the most destructive forces in nature. These threats are of particular concern to human populations and ecosystems of coastal areas of the southeastern United States, most especially in the State of Florida. This review begins with an overview of the effects of tropical cyclones on Florida’s most conspicuous terrestrial ecosystem—longleaf pine. Environmental factors leading to tropical cyclogenesis will also be reviewed, with a specific focus on (1) landfall history in Florida, and (2) the potential relationship between climate change and the frequency/intensity of tropical cyclones in the North Atlantic Ocean. Given its geographical distribution, it is not surprising that longleaf pine has long been impacted by tropical cyclones of the North Atlantic. Tropical cyclones are formed from a complex combination of meteorological conditions, driven initially by the release of excess heat from the surface waters of the ocean, along with an unstable atmosphere comprising air temperatures decreasing and wind speeds increasing with altitude. Among the coastal counties from Texas to Maine, those of Florida have experienced by far the highest frequency of tropical cyclones, especially the southern tip of peninsular Florida, with its most populous county (Miami-Dade) receiving 25 hits from 1900 to 2010, second only to Monroe County (32 hits) during that period. Frequencies of all categories of cyclones have increased significantly from 1850 to the present. Cyclone frequencies were significantly correlated with increases in air and ocean temperatures, both of which have increased over the past, suggesting a causal relationship with anthropogenic climate change. Of future concern is how increases in frequencies and intensities of tropical cyclones will negatively affect the structure and function of these ecologically and economically important longleaf pine ecosystems.
    Electronic ISSN: 2296-701X
    Topics: Biology
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  • 49
    Publication Date: 2021-02-09
    Description: The bulk of plant biomass is comprised of plant cell walls, which are complex polymeric networks, composed of diverse polysaccharides, proteins, polyphenolics, and hydroxyproline-rich glycoproteins (HRGPs). Glycosyltransferases (GTs) work together to synthesize the saccharide components of the plant cell wall. The Arabidopsis thaliana fucosyltransferases (FUTs), AtFUT4, and AtFUT6, are members of the plant-specific GT family 37 (GT37). AtFUT4 and AtFUT6 transfer fucose (Fuc) onto arabinose (Ara) residues of arabinogalactan (AG) proteins (AGPs) and have been postulated to be non-redundant AGP-specific FUTs. AtFUT4 and AtFUT6 were recombinantly expressed in mammalian HEK293 cells and purified for biochemical analysis. We report an updated understanding on the specificities of AtFUT4 and AtFUT6 that are involved in the synthesis of wall localized AGPs. Our findings suggest that they are selective enzymes that can utilize various arabinogalactan (AG)-like and non-AG-like oligosaccharide acceptors, and only require a free, terminal arabinofuranose. We also report with GUS promoter-reporter gene studies that AtFUT4 and AtFUT6 gene expression is sub-localized in different parts of developing A. thaliana roots.
    Electronic ISSN: 1664-462X
    Topics: Biology
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  • 50
  • 51
    Publication Date: 2021-02-09
    Description: Background: The aim of this study is to evaluate the pharmacoeconomic profile of adding enzalutamide to first-line treatment for metastatic, hormone-sensitive prostate cancer (mHSPC) from the US and Chinese payers' perspectives.Materials and Methods: A Markov model with three health states: progression-free survival (PFS), progressive disease (PD), and death, was constructed. All patients were assumed to enter the model in the PFS state and transit according to the transition structure. Efficacy data were derived from the ENZAMET trial and Weibull distribution curves were modeled to fit the survival curves. Costs in the model included cost of drugs, best-supportive care (BSC), follow-up, tests, and adverse events (AEs)-related treatments. The primary endpoint of the study was incremental cost-effectiveness ratio (ICER). In addition, the impact of several key parameters on the results of the cost-effectiveness analysis was tested with one-way sensitivity analyses and probabilistic sensitivity analyses.Results: Overall, ICERs were $430,933.95/QALY and $225,444.74/QALY of addition of enzalutamide to androgen deprivation therapy (ADT) vs. ADT from the US and Chinese payers' perspective, respectively. The most influential factors were the utility for the PFS state and the cost of enzalutamide. At the willingness-to-pay (WTP) thresholds of $100,000.00/QALY in the US and $28,988.40/QALY in China, the probability of adding enzalutamide to first-line treatment being a cost-effective option for mHSPC was 0%.Conclusions: Based on the data from the ENZAMET trial and the current price of enzalutamide, adding enzalutamide to first-line treatment is not cost-effective for patients with mHSPC from the US and Chinse payers' perspectives.
    Electronic ISSN: 2296-2565
    Topics: Medicine
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  • 52
    Publication Date: 2021-02-09
    Description: Intimate partner violence (IPV) affects individuals and families from all backgrounds, regardless of their ethnicity, socio-economic status, sexual orientation, or religion. Pregnancy and childbirth could be a time of vulnerability to violence because of changes in physical, emotional, social, and economic demands and needs. Prevalence of IPV against women during the perinatal period is increasingly researched and documented. However, evidence on IPV prevalence among intimate partners as well as on the course of IPV over the perinatal period is scarce. The purpose of this review was to provide a narrative synthesis of the existing literature regarding the prevalence estimates of IPV among intimate partners over the perinatal period. Through this review, we also gained better insight into associated factors, as well as the various forms of IPV. Of the 766 studies assessing prevalence estimates identified, 86 were included, where 80 studies focused on unidirectional IPV (i.e., perpetrated by men against women) and six studies investigated bidirectional IPV (i.e., IPV perpetrated by both partners). Most of the included studies reported lower overall prevalence rates for unidirectional IPV postpartum (range: 2–58%) compared to pregnancy (range: 1.5–66.9%). Psychological violence was found to be the most prevalent form of violence during the entire perinatal period. Studies on bidirectional IPV mostly reported women's perpetration to be almost as high as that of their partner or even higher, yet their findings need to be interpreted with caution. In addition, our results also highlighted the associated factors of IPV among partners, in which they were assimilated into a multi-level ecological model and were analyzed through an intersectional framework. Based on our findings, IPV is found to be highly prevalent during the entire perinatal period and in populations suffering from social inequalities. Further research exploring not only the occurrence, but also the motivations and the context of the bidirectionality of IPV during the perinatal period may facilitate better understanding of the detrimental consequences on partners and their families, as well as the development of effective intervention strategies. Public health prevention approaches intervening at optimal times during the perinatal period are also needed.
    Electronic ISSN: 1664-0640
    Topics: Medicine
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  • 53
    Publication Date: 2021-02-05
    Description: Introduction: Lung cancer is the deadliest and most prevalent cancer worldwide. Lung cancer treatments have different characteristics and are associated with a range of benefits and side effects for patients. Such differences may raise uncertainty among drug developers, regulators, payers, and clinicians regarding the value of these treatment effects to patients. The value of conducting patient preference studies (using qualitative and/or quantitative methods) for benefits and side effects of different treatment options has been recognized by healthcare stakeholders, such as drug developers, regulators, health technology assessment bodies, and clinicians. However, evidence-based guidelines on how and when to conduct and use these studies in drug decision-making are lacking. As part of the Innovative Medicines Initiative PREFER project, we developed a protocol for a qualitative study that aims to understand which treatment characteristics are most important to lung cancer patients and to develop attributes and levels for inclusion in a subsequent quantitative preference survey.Methods: The study protocol specifies a four-phased approach: (i) a scoping literature review of published literature, (ii) four focus group discussions with stage III and IV Non-Small Cell Lung Cancer patients, (iii) two nominal group discussions with stage III and IV Non-Small Cell Lung Cancer patients, and (iv) multi-stakeholder discussions involving clinicians and preference experts.Discussion: This protocol outlines methodological and practical steps as to how qualitative research can be applied to identify and develop attributes and levels for inclusion in patient preference studies aiming to inform decisions across the drug life cycle. The results of this study are intended to inform a subsequent quantitative preference survey that assesses patient trade-offs regarding lung cancer treatment options. This protocol may assist researchers, drug developers, and decision-makers in designing qualitative studies to understand which treatment aspects are most valued by patients in drug development, regulation, and reimbursement.
    Electronic ISSN: 2296-2565
    Topics: Medicine
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  • 54
    Publication Date: 2021-02-09
    Description: Purpose of ReviewIn this review, we summarize ethnic/race- and age-related variation in AMH and discuss the underpinnings behind these differences.Recent findingsAnti-mullerian hormone (AMH) has become a widely used method of ovarian reserve testing over the last 15 years. Numerous studies have shown substantial ethnic/race and age-related differences. When compared to age-matched Caucasian women, AMH levels tend to be lower in black and Hispanic women. Chinese women tend to have significantly greater AMH levels prior to age 25 than Caucasian women. When considering subpopulations within ethnicities, at least one study noted lower AMH levels among Maya women compared to other Hispanic women. Age exhibits a positive trend with AMH up until at least 25 years of age with a consistent decline after 34 years of age extending to menopause.SummaryAMH levels are highly variable among ethnicities and race with higher age-matched levels typically seen in Caucasian women. Age does not exhibit a consistent linear relationship with AMH, but a consistent decline is seen starting in the third decade of life and proceeding to menopause.
    Electronic ISSN: 1664-2392
    Topics: Medicine
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  • 55
    Publication Date: 2021-02-09
    Description: Objectives: Prediction of aortic hemodynamics after aortic valve replacement (AVR) could help optimize treatment planning and improve outcomes. This study aims to demonstrate an approach to predict postoperative maximum velocity, maximum pressure gradient, secondary flow degree (SFD), and normalized flow displacement (NFD) in patients receiving biological AVR.Methods: Virtual AVR was performed for 10 patients, who received actual AVR with a biological prosthesis. The virtual AVRs used only preoperative anatomical and 4D flow MRI data. Subsequently, computational fluid dynamics (CFD) simulations were performed and the abovementioned hemodynamic parameters compared between postoperative 4D flow MRI data and CFD results.Results: For maximum velocities and pressure gradients, postoperative 4D flow MRI data and CFD results were strongly correlated (R2 = 0.75 and R2 = 0.81) with low root mean square error (0.21 m/s and 3.8 mmHg). SFD and NFD were moderately and weakly correlated at R2 = 0.44 and R2 = 0.20, respectively. Flow visualization through streamlines indicates good qualitative agreement between 4D flow MRI data and CFD results in most cases.Conclusion: The approach presented here seems suitable to estimate postoperative maximum velocity and pressure gradient in patients receiving biological AVR, using only preoperative MRI data. The workflow can be performed in a reasonable time frame and offers a method to estimate postoperative valve prosthesis performance and to identify patients at risk of patient-prosthesis mismatch preoperatively. Novel parameters, such as SFD and NFD, appear to be more sensitive, and estimation seems harder. Further workflow optimization and validation of results seems warranted.
    Electronic ISSN: 2297-055X
    Topics: Medicine
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  • 56
    Publication Date: 2021-02-09
    Description: Purpose: To evaluate serum S100 protein at hospital admission and after 48 h in early neuroprognostication of comatose survivors of out-of-hospital cardiac arrest (OHCA).Methods: The study included 48 consecutive patients after OHCA, who survived for at least 72 h after the event. The patients were divided based on their best cerebral performance category (CPC) achieved over a 30 day follow-up period: favorable neurological outcome (CPC 1–2) vs. unfavorable neurological outcome (CPC 3–4). Predictors of an unfavorable neurological outcome were identified by multivariable regression analysis. Analysis of the receiver operating characteristic curve (ROC) was used to determine the cut-off value for S100, having a 0% false-positive prediction rate.Results: Of the 48 patients, 30 (63%) had a favorable and 18 (38%) had an unfavorable neurological outcome. Eleven patients (23%) died over the 30 day follow-up. Increased S100 levels at 48 h after OHCA, but not the baseline S100 levels, were independently associated with unfavorable neurological outcome, with an area under the ROC curve of 0.85 (confidence interval 0.74–0.96). A 48 h S100 value ≥0.37 μg/L had a specificity of 100% and sensitivity of 39% in predicting an unfavorable 30 day neurological outcome.Conclusion: This study showed that S100 values assessed 48 h after an OHCA could independently predict an unfavorable neurological outcome at 30 days.
    Electronic ISSN: 2297-055X
    Topics: Medicine
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  • 57
    Publication Date: 2021-02-09
    Description: Background: Patients with vestibular schwannoma that show residual peripheral-vestibular function before surgery may experience sudden and substantial vestibular loss of function after surgical resection. To alleviate the sudden loss of peripheral-vestibular function after vestibular-schwannoma (VS) resection, pre-surgical intratympanic gentamicin application was proposed.Objective: We hypothesized that this approach allows for a controlled reduction of peripheral-vestibular function before surgery but that resulting peripheral-vestibular deficits may be canal-specific with anterior-canal sparing as observed previously in systemic gentamicin application.Methods: Thirty-four patients (age-range = 27–70 y) with unilateral VS (size = 2–50 mm) were included in this retrospective single-center trial. The angular vestibulo-ocular reflex (aVOR) was quantified before and after (29.7 ± 18.7 d, mean ± 1SD) a single or two sequential intratympanic gentamicin applications by use of video-head-impulse testing. Both aVOR gains, cumulative saccadic amplitudes, and overall aVOR function were retrieved. Statistical analysis was done using a generalized linear model.Results: At baseline, loss of function of the horizontal (20/34) and posterior (21/34) canal was significantly (p 〈 0.001) more frequent than that of the anterior canal (5/34). After gentamicin application, loss of function of the horizontal (32/34) or posterior (31/34) canal remained significantly (p ≤ 0.003) more frequent than that of the anterior canal (18/34). For all ipsilesional canals, significant aVOR-gain reductions and cumulative-saccadic-amplitude increases were noted after gentamicin. For the horizontal canal, loss of function was significantly larger (increase in cumulative-saccadic-amplitude: 1.6 ± 2.0 vs. 0.8 ± 1.2, p = 0.007) or showed a trend to larger changes (decrease in aVOR-gain: 0.24 ± 0.22 vs. 0.13 ± 0.29, p = 0.069) than for the anterior canal.Conclusions: Intratympanic gentamicin application resulted in a substantial reduction in peripheral-vestibular function in all three ipsilesional canals. Relative sparing of anterior-canal function noted at baseline was preserved after gentamicin treatment. Thus, pre-surgical intratympanic gentamicin is a suitable preparatory procedure for reducing the drop in peripheral-vestibular function after VS-resection. The reasons for relative sparing of the anterior canal remain unclear.
    Electronic ISSN: 1664-2295
    Topics: Medicine
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  • 58
    Publication Date: 2021-02-09
    Description: Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a leading cause of death worldwide. Despite decades of research, there is still much to be uncovered regarding the immune response to Mtb infection. Here, we summarize the current knowledge on anti-Mtb immunity, with a spotlight on immune cell amino acid metabolism. Specifically, we discuss L-arginine and L-tryptophan, focusing on their requirements, regulatory roles, and potential use as adjunctive therapy in TB patients. By continuing to uncover the immune cell contribution during Mtb infection and how amino acid utilization regulates their functions, it is anticipated that novel host-directed therapies may be developed and/or refined, helping to eradicate TB.
    Electronic ISSN: 1664-3224
    Topics: Medicine
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  • 59
    Publication Date: 2021-02-09
    Description: Acute kidney injury (AKI) has been associated with deleterious impacts on a variety of body systems. While AKI is often accompanied by dysregulation of mineral metabolism—including alterations in calcium, phosphate, vitamin D, parathyroid hormone, fibroblast growth factor 23, and klotho—its direct effects on the skeletal system of children and adolescents remain largely unexplored. In this review, the pathophysiology of dysregulated mineral metabolism in AKI and its potential effects on skeletal health are discussed, including data associating AKI with fracture risk.
    Electronic ISSN: 2296-2360
    Topics: Medicine
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  • 60
    Publication Date: 2021-02-09
    Description: Background: Providing endovascular treatment (EVT) access for acute ischemic stroke (AIS) is a challenge in Latin America. Even though the Mexican Endovascular Reperfusion Registry (MERR) and the RESILIENT trial have demonstrated the feasibility of EVT of AIS in Latin America, the MERR has uncovered potential challenges to delivering EVT to AIS patients.Aim: To identify the perceived barriers to access EVT for AIS in Mexico.Methods: We surveyed endovascular neurologists in Mexico. The survey addressed the situation of thrombectomy in the country and the infrastructure and resources available in the participants' institutions. The questionnaire inquired about costs, barriers, and challenges to accessing EVT for AIS, emphasizing the prices and availability of medical devices needed for EVT.Results: We analyzed data from 21 hospitals. The most extreme identified barriers to access EVT were the lack of health coverage for EVT in the National Health System, the cost of the medical supplies for EVT, and inadequate knowledge of stroke symptoms in the general population. The median cost for EVT was USD 20,000 (IQR 7,500–20,000). From this amount, 60% (IQR 50–70%) corresponded to the costs involved with medical devices. EVT carried additional out-of-pocket costs in 90% of the hospitals, and in 57%, the costs exceed USD $10,000.Conclusion: Efforts at all government levels and society are required to tackle these barriers. An increase in and efficient use of public funding for EVT coverage and the deployment of continuous and targeted stroke education campaigns could reduce inequities in EVT access in Mexico.
    Electronic ISSN: 1664-2295
    Topics: Medicine
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  • 61
    Publication Date: 2021-02-09
    Description: Synaptic transmission is controlled by re-uptake systems that reduce transmitter concentrations in the synaptic cleft and recycle the transmitter into presynaptic terminals. The re-uptake systems are thought to ensure cytosolic concentrations in the terminals that are sufficient for reloading empty synaptic vesicles (SVs). Genetic deletion of glycine transporter 2 (GlyT2) results in severely disrupted inhibitory neurotransmission and ultimately to death. Here we investigated the role of GlyT2 at inhibitory glycinergic synapses in the mammalian auditory brainstem. These synapses are tuned for resilience, reliability, and precision, even during sustained high-frequency stimulation when endocytosis and refilling of SVs probably contribute substantially to efficient replenishment of the readily releasable pool (RRP). Such robust synapses are formed between MNTB and LSO neurons (medial nucleus of the trapezoid body, lateral superior olive). By means of patch-clamp recordings, we assessed the synaptic performance in controls, in GlyT2 knockout mice (KOs), and upon acute pharmacological GlyT2 blockade. Via computational modeling, we calculated the reoccupation rate of empty release sites and RRP replenishment kinetics during 60-s challenge and 60-s recovery periods. Control MNTB-LSO inputs maintained high fidelity neurotransmission at 50 Hz for 60 s and recovered very efficiently from synaptic depression. During 'marathon-experiments' (30,600 stimuli in 20 min), RRP replenishment accumulated to 1,260-fold. In contrast, KO inputs featured severe impairments. For example, the input number was reduced to ~1 (vs. ~4 in controls), implying massive functional degeneration of the MNTB-LSO microcircuit and a role of GlyT2 during synapse maturation. Surprisingly, neurotransmission did not collapse completely in KOs as inputs still replenished their small RRP 80-fold upon 50 Hz | 60 s challenge. However, they totally failed to do so for extended periods. Upon acute pharmacological GlyT2 inactivation, synaptic performance remained robust, in stark contrast to KOs. RRP replenishment was 865-fold in marathon-experiments, only ~1/3 lower than in controls. Collectively, our empirical and modeling results demonstrate that GlyT2 re-uptake activity is not the dominant factor in the SV recycling pathway that imparts indefatigability to MNTB-LSO synapses. We postulate that additional glycine sources, possibly the antiporter Asc-1, contribute to RRP replenishment at these high-fidelity brainstem synapses.
    Electronic ISSN: 1663-3563
    Topics: Medicine
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  • 62
    Publication Date: 2021-02-09
    Description: The world’s most endangered small cetaceans are found in countries many miles from Sarasota Bay and its common bottlenose dolphins (Tursiops truncatus). Information on the ecology and threats to many of these endangered cetaceans is often far more limited than that on bottlenose dolphins, with the IUCN Red Data List describing many species as “data deficient.” In many developing nations where these rare species occur, resources for research and monitoring are scant, and logistical challenges further limit research into marine mammal health and population status and their threats. The Sarasota Dolphin Research Program (SDRP) has tackled this problem by using the bottlenose dolphin as a model for cetacean species in other parts of the world and using its resources to assist scientists working with more endangered species of cetacean. The celebration of 50 years of study by the SDRP exemplifies how using long-term data on known individuals can advance the fields of cetacean behavior, ecology, life history, physiology, toxicology, and medicine, all providing information for informing certain conservation actions. The Sarasota team has used their work to inform conservation policy both home and abroad.
    Electronic ISSN: 2296-7745
    Topics: Biology
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  • 63
    Publication Date: 2021-02-09
    Description: Transient receptor potential vanilloid subtype 2 (TRPV2) channel is a polymodal receptor regulating neuronal development, cardiac function, immunity and oncogenesis. The activity of TRPV2 is regulated by the molecular interactions in the subplasmalemmel signaling complex. Here by yeast two-hybrid screening of a cDNA library of mouse dorsal root ganglia (DRG) and patch clamp electrophysiology, we identified that flotillin-1, the lipid raft-associated protein, interacts with TRPV2 channel and regulates its function. The interaction between TRPV2 and flotillin-1 was validated through co-immuoprecipitation in situ using endogenous DRG neurons and the recombinant expression model in HEK 293T cells. Fluorescent imaging and bimolecular fluorescence complementation (BiFC) further revealed that flotillin-1 and TRPV2 formed a functional complex on the cell membrane. The presence of flotillin-1 enhanced the whole-cell current density of TRPV2 via increasing its surface expression levels. Using site-specific mapping, we also uncovered that the SPFH (stomatin, prohibitin, flotillin, and HflK/C) domain of flotillin-1 interacted with TRPV2 N-termini and transmembrane domains 1–4, respectively. Our findings therefore demonstrate that flotillin-1 is a key element in TRPV2 signaling complex and modulates its cellular response.
    Electronic ISSN: 2296-634X
    Topics: Biology
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  • 64
    Publication Date: 2021-02-09
    Description: Background: To evaluate the efficacy, safety and tolerability of methylphenidate (MPH) for cognitive function in older patients with mild cognitive impairment (MCI).Methods: Male and female subjects aged 65 years and older with a clinical diagnosis MCI were included in an exploratory randomized, double-blind, placebo-controlled trial. Eligible subjects were assigned to either treatment with immediate-release MPH or placebo. The active compound was administered in an increasing-dose stepwise fashion, namely 10 mg MPH on day 1, 20 mg on day 2, and 30 mg on day 3. Subjects remained under observation for 4 h following drug administration and were monitored for changes in blood pressure and for adverse events. Cognitive outcome measures included the Montreal Cognitive Assessment (MoCA) and the Neurotrax Mindstreams computerized cognitive assessment battery.Results: Of 17 subjects enrolled, 15 subjects completed the study, 7 in the active MPH group and 8 in the placebo group. The average age of the participants was 76.1 ± 6.6 years and 10 (66.7%) were men. Following the final dose a significant benefit on memory (predominantly non-verbal memory) was found in the MPH group. While 12 adverse events were reported, they were all rated as mild to moderate.Conclusions: Our finding of modest beneficial effects of MPH on memory tests in older subjects with MCI in this exploratory study is of interest and should be investigated in further studies.
    Electronic ISSN: 2296-858X
    Topics: Medicine
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  • 65
    Publication Date: 2021-02-09
    Description: Objective: The emergence of carbapenem-resistant gram-negative bacteria (CR-GNB) has brought great challenges to clinical anti-infection treatment around the world. Polymyxins are often considered as the last line of defense in the treatment of CR-GNB infections. In this study, we explored the microbiological efficacy of Polymyxin B (PMB) on different CR-GNB infections as well as the factors influencing microbiological efficacy.Methods: CR-GNB infected patients with PMB-based regimens were enrolled. Clinical and microbiological data were collected from the medical electronic record system of the Second Xiangya hospital. The efficacy of PMB on different CR-GNB was evaluated by the clearance rate at 7-days and within the course of treatment, as well as the 30-day mortality rate.Results: A total of 294 CR-GNB infected patients were enrolled: 154 CR-Acinetobacter baumannii (CRAB), 55 CR-Klebsiella pneumoniae (CRKP), and 85 CR-Pseudomonas aeruginosa (CRPA). The CRAB group had the highest 7-day bacterial clearance rate [(CRAB: 39.0%) vs. (CRKP: 29.4%) vs. (CRPA: 14.5%), P = 0.003] and total bacterial clearance rate [(CRAB: 49.0%) vs. (CRKP: 39.8%) vs. (CRPA: 18.2%), P 〈 0.001] among the three groups, while the bacterial clearance rate of the CRPA group was the lowest. Multivariate logistic regression showed that the differences among the three groups were multiple CR-GNB infections (P = 0.004), respiratory infections (P = 0.001), PMB resistance (P 〈 0.001), and the combination of tigecycline (P 〈 0.001). Binary logistic regression showed that multiple CR-GNB infection [(7-day bacterial clearance: P = 0.004) & (total bacterial clearance: P = 0.011)] and bacterial species [(7-day bacterial clearance: P 〈 0.001) & (total bacterial clearance: P 〈 0.001)] were independent risk factors for microbiological efficacy.Conclusion: PMB exhibited differential microbiological efficacy on different types of CR-GNB infections; it had the best effect on CRAB, followed by CRKP and CRPA. Multiple CR-GNB infections and bacterial species were independent risk factors for microbiological efficacy.
    Electronic ISSN: 2296-858X
    Topics: Medicine
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  • 66
    Publication Date: 2021-02-09
    Description: Nanosecond pulsed electric fields (nsPEFs) have emerged as a novel and effective strategy for the non-surgical and minimally invasive removal of tumors. However, the effects of nsPEFs treatment on the tumor immune microenvironment remain unknown. In this study, the changes in the morphology and function of pancreatic cancer cells after nsPEFs were assessed and the modifications in the immune profile in pancreatic cancer models were investigated. To this end, electrodes were inserted with different parameters applied to ablate the targeted tumor tissues. Tumor development was found to be inhibited, with decreased volumes post-nsPEFs treatment compared with control tumors (P 〈 0.05). Hematoxylin and eosin staining showed morphological changes in pancreatic cancer cells, Ki-67 staining confirmed the effects of nsPEFs on tumor growth, and caspase-3 staining indicated that nsPEFs caused apoptosis in the early stages after treatment. Three days after nsPEFs, positron emission tomography demonstrated little residual metabolic activity compared with the control group. Gene expression profiling identified significant changes in immune-related pathways. After treatment with nsPEFs, CD8+ T lymphocytes increased. We showed that nsPEFs led to a significant decrease in immune suppressive cells, including myeloid derived suppressor cells, T regulatory cells, and tumor-associated macrophages. In addition, the levels of TNF-α and IL-1β increased (P 〈 0.05), while the level of IL-6 was decreased (P 〈 0.05). NsPEFs alleviated the immunosuppressive components in pancreatic cancer stroma, including hyaluronic acid and fibroblast activation protein-α. Our data demonstrate that tumor growth can be effectively inhibited by nsPEFs in vivo. NsPEFs significantly altered the infiltration of immune cells and triggered immune response.
    Electronic ISSN: 2234-943X
    Topics: Medicine
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  • 67
    Publication Date: 2021-02-09
    Description: We report phylogenetic and mutational analysis by NGS of six SARS-CoV-2 strains from patients flying from Bangladesh to Italy (July 2020). Data suggest that no further circulation of such imported strains occurred in Italy, stating the efficacy of early screening at the point of entry and supporting the importance of molecular epidemiology in monitoring the efficacy of control measures.
    Electronic ISSN: 1664-8021
    Topics: Biology , Medicine
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  • 68
    Publication Date: 2021-02-09
    Description: MicroRNAs (miRNAs) that belong to non-coding RNAs are verified to be closely associated with several complicated biological processes and human diseases. In this study, we proposed a novel model that was Similarity Network Fusion and Inductive Matrix Completion for miRNA-Disease Association Prediction (SNFIMCMDA). We applied inductive matrix completion (IMC) method to acquire possible associations between miRNAs and diseases, which also could obtain corresponding correlation scores. IMC was performed based on the verified connections of miRNA–disease, miRNA similarity, and disease similarity. In addition, miRNA similarity and disease similarity were calculated by similarity network fusion, which could masterly integrate multiple data types to obtain target data. We integrated miRNA functional similarity and Gaussian interaction profile kernel similarity by similarity network fusion to obtain miRNA similarity. Similarly, disease similarity was integrated in this way. To indicate the utility and effectiveness of SNFIMCMDA, we both applied global leave-one-out cross-validation and five-fold cross-validation to validate our model. Furthermore, case studies on three significant human diseases were also implemented to prove the effectiveness of SNFIMCMDA. The results demonstrated that SNFIMCMDA was effective for prediction of possible associations of miRNA–disease.
    Electronic ISSN: 2296-634X
    Topics: Biology
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  • 69
    Publication Date: 2021-02-09
    Description: Proper targeting of the urate and xenobiotic transporter ATP-binding transporter subfamily G member 2 (ABCG2) to the plasma membrane (PM) is essential for its normal function. The naturally occurring Q141K and M71V polymorphisms in ABCG2, associated with gout and hyperuricemia, affect the cellular routing of the transporter, rather than its transport function. The cellular localization of ABCG2 variants was formerly studied by immunolabeling, which provides information only on the steady-state distribution of the protein, leaving the dynamics of its cellular routing unexplored. In the present study, we assessed in detail the trafficking of the wild-type, M71V-, and Q141K-ABCG2 variants from the endoplasmic reticulum (ER) to the cell surface using a dynamic approach, the so-called Retention Using Selective Hooks (RUSH) system. This method also allowed us to study the kinetics of glycosylation of these variants. We found that the fraction of Q141K- and M71V-ABCG2 that passes the ER quality control system is only partially targeted to the PM; a subfraction is immobile and retained in the ER. Surprisingly, the transit of these variants through the Golgi apparatus (either the appearance or the exit) was unaffected; however, their PM delivery beyond the Golgi was delayed. In addition to identifying the specific defects in the trafficking of these ABCG2 variants, our study provides a novel experimental tool for studying the effect of drugs that potentially promote the cell surface delivery of mutant or polymorphic ABCG2 variants with impaired trafficking.
    Electronic ISSN: 2296-634X
    Topics: Biology
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  • 70
    Publication Date: 2021-02-09
    Description: Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus that causes Rift Valley fever (RVF), a zoonotic disease of wild and domestic ruminants, causing serious economic losses and a threat to human health that could be controlled by vaccination. Though RVF vaccines are available for livestock, no RVF vaccines have been licensed for veterinary use in non-endemic countries nor for human populations in RVF risk areas. In a recent work, we showed that favipiravir, a promising drug with antiviral activity against a number of RNA viruses, led to the extinction of RVFV from infected cell cultures. Nevertheless, certain drug concentrations allowed the recovery of a virus variant showing increased resistance to favipiravir. In this work, we characterized this novel resistant variant both at genomic and phenotypic level in vitro and in vivo. Interestingly, the resistant virus displayed reduced growth rates in C6/36 insect cells but not in mammalian cell lines, and was highly attenuated but still immunogenic in vivo. Some amino acid substitutions were identified in the viral RNA-dependent RNA-polymerase (RdRp) gene and in the virus encoded type I-interferon (IFN-I) antagonist NSs gene, in catalytic core motifs and nuclear localization associated positions, respectively. These data may help to characterize novel potential virulence markers, offering additional strategies for further safety improvements of RVF live attenuated vaccine candidates.
    Electronic ISSN: 1664-302X
    Topics: Biology
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  • 71
    Publication Date: 2021-02-09
    Description: Several studies have demonstrated that severe tricuspid regurgitation (TR) has a significant negative impact on morbidity and mortality. Nowadays, several therapeutic options to treat TR are available and patients at high surgical risk can also be treated with transcatheter procedures. For the management of patients with TR, an accurate assessment of the tricuspid valve and its surrounding structures is therefore of crucial importance and has gained significant interest in the medical community. Different imaging modalities can provide detailed information on the tricuspid valve apparatus, right ventricle, right atrium, and coronary circulation which are fundamental to define the timing and anatomic suitability of surgical and percutaneous procedures. The present review illustrates the role of 2D and 3D echocardiography, cardiac magnetic resonance, and multidetector row computed tomography for the assessment of the tricuspid valve and right heart with a particular focus on the data needed for planning and guiding interventional procedures.
    Electronic ISSN: 2297-055X
    Topics: Medicine
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  • 72
    Publication Date: 2021-02-09
    Description: Cellular senescence due to telomere dysfunction has been hypothesized to play a role in age-associated diseases including idiopathic pulmonary fibrosis (IPF). It has been postulated that paracrine mediators originating from senescent alveolar epithelia signal to surrounding mesenchymal cells and contribute to disease pathogenesis. However, murine models of telomere-induced alveolar epithelial senescence fail to display the canonical senescence-associated secretory phenotype (SASP) that is observed in senescent human cells. In an effort to understand human-specific responses to telomere dysfunction, we modeled telomere dysfunction-induced senescence in a human alveolar epithelial cell line. We hypothesized that this system would enable us to probe for differences in transcriptional and proteomic senescence pathways in vitro and to identify novel secreted protein (secretome) changes that potentially contribute to the pathogenesis of IPF. Following induction of telomere dysfunction, a robust senescence phenotype was observed. RNA-seq analysis of the senescent cells revealed the SASP and comparisons to previous murine data highlighted differences in response to telomere dysfunction. We conducted a proteomic analysis of the senescent cells using a novel biotin ligase capable of labeling secreted proteins. Candidate biomarkers selected from our transcriptional and secretome data were then evaluated in IPF and control patient plasma. Four novel proteins were found to be differentially expressed between the patient groups: stanniocalcin-1, contactin-1, tenascin C, and total inhibin. Our data show that human telomere-induced, alveolar epithelial senescence results in a transcriptional SASP that is distinct from that seen in analogous murine cells. Our findings suggest that studies in animal models should be carefully validated given the possibility of species-specific responses to telomere dysfunction. We also describe a pragmatic approach for the study of the consequences of telomere-induced alveolar epithelial cell senescence in humans.
    Electronic ISSN: 2296-858X
    Topics: Medicine
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  • 73
    Publication Date: 2021-02-09
    Description: Renal fibrosis is considered as the final pathway of all types of kidney diseases, which can lead to the progressive loss of kidney functions and eventually renal failure. The mechanisms behind are diversified, in which the mammalian target of rapamycin (mTOR) pathway is one of the most important regulatory pathways that accounts for the disease. Several processes that are regulated by the mTOR pathway, such as autophagy, epithelial-mesenchymal transition (EMT), and endoplasmic reticulum (ER) stress, are tightly associated with renal fibrosis. In this study, we have reported that the expression of tripartite motif-containing (TRIM) protein 6, a member of TRIM family protein, was highly expressed in renal fibrosis patients and positively correlated with the severity of renal fibrosis. In our established in vitro and in vivo renal fibrosis models, its expression was upregulated by the Angiotensin II-induced nuclear translocation of nuclear factor-κB (NF-κB) p50 and p65. In HK2 cells, the expression of TRIM6 promoted the ubiquitination of tuberous sclerosis proteins (TSC) 1 and 2, two negative regulators of the mTORC1 pathway. Moreover, the knockdown of TRIM6 was found efficient for alleviating renal fibrosis and inhibiting the downstream processes of EMT and ER in both HK2 cells and 5/6-nephrectomized rats. Clinically, the level of TRIM6, TSC1/2, and NF-κB p50 was found closely related to renal fibrosis. As a result, we have presented the first study on the role of TRIM6 in the mTORC1 pathway in renal fibrosis models and our findings suggested that TRIM6 may be a potential target for the treatment of renal fibrosis.
    Electronic ISSN: 2296-634X
    Topics: Biology
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  • 74
    Publication Date: 2021-02-09
    Description: Renal involvement is frequent in COVID-19 (4–37%). This study evaluated the incidence and risk factors of acute kidney injury (AKI) in hospitalized patients with COVID-19.Methodology: This study represents a prospective cohort in a public and tertiary university hospital in São Paulo, Brazil, during the first 90 days of the COVID-19 pandemic, with patients followed up until the clinical outcome (discharge or death).Results: There were 101 patients hospitalized with COVID-19, of which 51.9% were admitted to the intensive care unit (ICU). The overall AKI incidence was 50%; 36.8% had hematuria or proteinuria (66.6% of those with AKI), 10.2% had rhabdomyolysis, and mortality was 36.6%. Of the ICU patients, AKI occurred in 77.3% and the mortality was 65.4%. The mean time for the AKI diagnosis was 6 ± 2 days, and Kidney Disease Improving Global Outcomes (KDIGO) stage 3 AKI was the most frequent (58.9%). Acute renal replacement therapy was indicated in 61.5% of patients. The factors associated with AKI were obesity [odds ratio (OR) 1.98, 95% confidence interval (CI) 1.04–2.76, p 〈 0.05] and the APACHE II score (OR 1.97, 95% CI 1.08–2.64, p 〈 0.05). Mortality was higher in the elderly (OR 1.03, 95% CI 1.01–1.66, p 〈 0.05), in those with the highest APACHE II score (OR 1.08, 95% CI 1.02–1.98, p 〈 0.05), and in the presence of KDIGO stage 3 AKI (OR 1.11, 95% CI 1.05–2.57, p 〈 0.05).Conclusion: AKI associated with severe COVID-19 in this Brazilian cohort was more frequent than Chinese, European, and North American data, and the risk factors associated with its development were obesity and higher APACHE II scores. Mortality was high, mainly in elderly patients, in those with a more severe disease manifestation, and in those who developed KDIGO stage 3 AKI.
    Electronic ISSN: 2296-858X
    Topics: Medicine
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  • 75
    Publication Date: 2021-02-09
    Description: The neural crest cell (NCC) is a multipotent progenitor cell population that is sensitive to ethanol and is implicated in the Fetal Alcohol Spectrum Disorders (FASD). Studies have shown that sulforaphane (SFN) can prevent ethanol-induced apoptosis in NCCs. This study aims to investigate whether ethanol exposure can induce apoptosis in human NCCs (hNCCs) through epigenetically suppressing the expression of anti-apoptotic genes and whether SFN can restore the expression of anti-apoptotic genes and prevent apoptosis in ethanol-exposed hNCCs. We found that ethanol exposure resulted in a significant increase in the expression of DNMT3a and the activity of DNMTs. SFN treatment diminished the ethanol-induced upregulation of DNMT3a and dramatically reduced the activity of DNMTs in ethanol-exposed hNCCs. We also found that ethanol exposure induced hypermethylation at the promoter regions of two inhibitor of apoptosis proteins (IAP), NAIP and XIAP, in hNCCs, which were prevented by co-treatment with SFN. SFN treatment also significantly diminished ethanol-induced downregulation of NAIP and XIAP in hNCCs. The knockdown of DNMT3a significantly enhanced the effects of SFN on preventing the ethanol-induced repression of NAIP and XIAP and apoptosis in hNCCs. These results demonstrate that SFN can prevent ethanol-induced apoptosis in hNCCs by preventing ethanol-induced hypermethylation at the promoter regions of the genes encoding the IAP proteins and diminishing ethanol-induced repression of NAIP and XIAP through modulating DNMT3a expression and DNMT activity.
    Electronic ISSN: 2296-634X
    Topics: Biology
    Published by Frontiers Media