Miracle-dz/UniFAR-FTUs huggingface dataset:
Transient Elastography Measurements of Spleen Stiffness as a Predictor of Clinically Significant Varices in Children

Objectives: Investigate the use of spleen stiffness measurements (SSMs), measured by transient elastography (TE), for the prediction of clinically significant varices (CSV) in children with portal hypertension. Methods: This observational cohort study included children selected for endoscopy, as per department protocol, between September 2015 and June 2016. Those included underwent single TE FibroScan for liver stiffness measurements and SSM. Clinical and laboratory data were collected and variceal prediction scores were calculated at time of elastography. Results: In total 67 children (32 boys) underwent TE. Fifty-two children (25 boys) had chronic liver disease (CLD), 15 (7 boys) portal vein thrombosis (PVT). In all children SSM was the best predictor of CSV+ve, with an optimal cut-off value of 38.0 kPa (area under the receiver operator curve [AUROC] = 0.92, sensitivity = 89%, specificity = 82%, P < 0.01). In the CLD group SSM was also the best predictor, with an optimal cut-off value of 38.05 kPa (AUROC = 0.90, sensitivity = 84%, specificity = 87%, P < 0.01). In the PVT group only SSM was predictive of CSV+ve, with an optimal cut-off value of 16.8 kPa (AUROC = 1.00, sensitivity = 100%, specificity = 100%, P < 0.001). For the prediction of GI bleeding (n = 6), liver stiffness measurement performed the best, with an optimal cut-off value of 34.3 kPa (AUROC = 0.84, sensitivity of 80%, specificity of 88%, P = 0.01). Conclusions: SSM was the greatest predictor of CSV+ve in the whole cohort, and individual CLD and PVT groups. SSM could be used as a noninvasive screening tool for children with portal hypertension to stratify the risk of having CSV.
Targeting HPV16 DNA using CRISPR/Cas inhibits anal cancer growth in vivo

Aim: The goal of this study was to determine if a single AAV vector, encoding Cas9 and guide RNAs specific for the HPV16 E6 and E7 genes, could inhibit the growth of an HPV16-induced tumor in vivo. Materials & methods: We grew HPV16+, patient-derived anal cancer explants in immunodeficient mice and then challenged these by injection of AAV-based vectors encoding Cas9 and control or HPV16-specific guide RNAs. Results & conclusion: We observed a significant and selective reduction in tumor growth when the HPV16 E6 and E7 genes were targeted using Cas9. These studies provide proof of principle for the hypothesis that CRISPR/Cas has the potential to be used to selectively treat HPV-induced tumors in humans.
New Digital Plug and Imaging Sensor for a Proton Therapy Monitoring System Based on Positron Emission Tomography

One of the most challenging areas of sensor development for nuclear medicine is the design of proton therapy monitoring systems. Sensors are operated in a high detection rate regime in beam-on conditions. We realized a prototype of a monitoring system for proton therapy based on the technique of positron emission tomography. We used the Plug and Imaging (P&I) technology in this application. This sensing system includes LYSO/silicon photomultiplier (SiPM) detection elements, fast digital multi voltage threshold (MVT) readout electronics and dedicated image reconstruction algorithms. In this paper, we show that the P&I sensor system has a uniform response and is controllable in the experimental conditions of the proton therapy room. The prototype of PET monitoring device based on the P&I sensor system has an intrinsic experimental spatial resolution of approximately 3 mm (FWHM), obtained operating the prototype both during the beam irradiation and right after it. The count-rate performance of the P&I sensor approaches 5 Mcps and allows the collection of relevant statistics for the nuclide analysis. The measurement of both the half life and the relative abundance of the positron emitters generated in the target volume through irradiation of 1010 protons in approximately 15 s is performed with 0.5% and 5% accuracy, respectively.
Deep Sequencing of H7N9 Influenza A Viruses from 16 Infected Patients from 2013 to 2015 in Shanghai Reveals Genetic Diversity and Antigenic Drift

H7N9 subtype avian influenza viruses caused infections in over 1,400 humans from 2013 to 2017 and resulted in almost 600 deaths. It is important to understand how avian influenza viruses infect and cause disease in humans and to assess their potential for efficient person-to-person transmission. In this study, we used deep sequencing of primary clinical material to assess the evolution and potential for human adaptation of H7N9 influenza viruses. ABSTRACT Influenza A virus (IAV) infections are a major public health concern, including annual epidemics, epizootic outbreaks, and pandemics. A significant IAV epizootic outbreak was the H7N9 avian influenza A outbreak in China, which was first detected in 2013 and which has spread over 5 waves from 2013 to 2017, causing human infections in many different Chinese provinces. Here, RNA from primary clinical throat swab samples from 20 H7N9-infected local patients with different clinical outcomes, who were admitted and treated at one hospital in Shanghai, China, from April 2013 to April 2015, was analyzed. Whole-transcriptome amplification, with positive enrichment of IAV RNA, was performed, all 20 samples were subjected to deep sequencing, and data from 16 samples were analyzed in detail. Many single-nucleotide polymorphisms, including ones not previously reported, and many nonsynonymous changes that could affect hemagglutinin head and stalk antibody binding epitopes were observed. Minor populations representing viral quasispecies, including nonsynonymous hemagglutinin changes shared by antigenically variant H7N9 clades identified in the most recent wave of H7N9 infections in 2016 to 2017, were also identified. IMPORTANCE H7N9 subtype avian influenza viruses caused infections in over 1,400 humans from 2013 to 2017 and resulted in almost 600 deaths. It is important to understand how avian influenza viruses infect and cause disease in humans and to assess their potential for efficient person-to-person transmission. In this study, we used deep sequencing of primary clinical material to assess the evolution and potential for human adaptation of H7N9 influenza viruses.
A systematic revision of the ectomycorrhizal genus Laccaria from Korea

ABSTRACT Species of Laccaria (Hydnangiaceae, Basidiomycota) are important in forest ecosystems as ectomycorrhizal fungi. Nine of the 75 described Laccaria species worldwide been reported from Korea. Most of these have European and North American names, and their identities are based solely on morphological features. To evaluate the taxonomy of Korean Laccaria, we used 443 specimens collected between 1981 and 2016 in a phylogenetic analysis based on sequence data from nuc rDNA internal transcribed spacer ITS1-5.8S-ITS2 rDNA (ITS) region, nuc 28S rDNA (28S), RNA polymerase II subunit 2 (rpb2), and translation elongation factor 1-α (tef1). Ten Laccaria species were identified. Three of these were previously reported from Korea: L. bicolor, L. tortilis, and L. vinaceoavellanea. Laccaria alba, L. japonica, and L. murina are confirmed as new reports from Korea. Lastly, four new Laccaria species are described: L. araneosa, L. parva, L. torosa, and L. versiforma. This study supports the general contention that Asian species of ectomycorrhizal fungi may not be conspecific with morphologically similar species from Europe and North America. Furthermore, identification based on morphology alone is often unreliable in Laccaria due to considerable overlap of characters among species. Thus, use of molecular methods is necessary for effective identification. Illustrations of the four newly described species and a taxonomic key to species of Laccaria in Korea are provided.
Anti-parasitic effect of vitamin C alone and in combination with benznidazole against Trypanosoma cruzi

Background Drugs currently used for the treatment of Chagas’ disease, nifurtimox and benznidazole, have a limited effectiveness and toxic side effects. With the aim of finding new therapeutic approaches, in vitro and in vivo anti-Trypanosoma cruzi activity of vitamin C alone and combined with benznidazole were investigated. Methodology/Principal findings The trypanocidal activity on epimastigote and trypomastigote forms was evaluated by counting parasites in a Neubauer chamber after treatment with the compounds. For the amastigote stage, transgenic parasites expressing β-galactosidase were used and quantified by measuring the β-galactosidase activity. The cytotoxicity of compounds was tested on Vero cells. The redox state of the parasite was evaluated by determining the reduced thiol levels (spectrophotometric assay) and the intracellular oxidative state (by flow cytometry). The in vivo trypanocidal activity was evaluated on a murine model of Chagas’ disease. The trypanocidal activity of vitamin C and benznidazole was similar for the three parasite forms. When combining both drugs, vitamin C did not induce any change in the antiparasitic activity of benznidazole on trypomastigotes; however, on mammal cells, vitamin C diminished the cytotoxicity degree of benznidazole. Two mechanisms of action may be postulated for vitamin C: a lethal pro-oxidant effect on the parasite when used alone, and an antioxidant effect, when combined with benznidazole. A similar behavior was observed on infected mice; i.e., parasite counts in infected mice treated with vitamin C were lower than that of the control group. Animals treated with benznidazole presented lower parasitemia levels, as compared with those treated with vitamin C alone. Again, vitamin C did not cause any effect on the antiparasitic profile of benznidazole. Even though a combined treatment was employed, the antioxidant effect of vitamin C on the host was evidenced; a 100% survival was observed and the weight loss occurring during the acute phase of the infection was reduced. Conclusions/Significance Based on these results, the combination of vitamin C with benznidazole could be considered as an alternative treatment for Chagas’ disease. These preliminary results encourage further research to improve the treatment of Chagas’ disease.
Is It Relevant to Keep Advocating Visual Inspection of the Cervix With Acetic Acid for Primary Cervical Cancer Screening in Limited-Resource Settings?

Although the burden of cervical cancer has significantly declined in high-income settings, this preventable disease has remained a public health priority in most developing countries, where it is still among thecommonest anddeadliestwomen’s cancers. Despite the huge number of resources that havebeen invested over thepast decades, the incidence of cervical cancer has continued to increase in limited-resource settings, and projections for the coming years confirm that this tendency will remain until high-impact interventions (including vaccination against human papilloma virus [HPV], which is the main factor leading to cervical cancer [referred to as primary prevention]) are widely and effectively implemented. While the introduction of vaccines is relatively recent and is still being investigated (ie, number of doses and interval between doses, target age range and population groups, long-term efficacy, and adverse effects), screening and proper management of precancerous lesions (referred to as secondary prevention) have been extensively assessed and promoted around the world to curb this problem.
Sucrosomial® Iron Supplementation in Mice: Effects on Blood Parameters, Hepcidin, and Inflammation

Sucrosomial® Iron is a recently developed formulation to treat iron deficiency based on ferric pyrophosphate covered by a matrix of phospholipids plus sucrose esters of fatty acids. Previous data indicated that Sucrosomial® Iron is efficiently absorbed by iron-deficient subjects, even at low dosage, and without side effects. Its structural properties may suggest that it is absorbed by an intestinal pathway which is different to the one used by ionic iron. Although, studies in vitro showed that Sucrosomial® Iron is readily absorbed, no animal models have been established to study this important aspect. To this aim, we induced iron deficient anemia in mice by feeding them with a low-iron diet, and then we treated them with either Sucrosomial® Iron or sulfate iron by gavage for up to two weeks. Both iron formulations corrected anemia and restored iron stores in a two-week period, but with different kinetics. Ferrous Sulfate was more efficient during the first week and Sucrosomial® Iron in the second week. Of note, when given at the same concentrations, Ferrous Sulfate induced the expression of hepcidin and four different inflammatory markers (Socs3, Saa1, IL6 and CRP), while Sucrosomial® Iron did not. We conclude that anemic mice are interesting models to study the absorption of oral iron, and that Sucrosomial® Iron is to be preferred over Ferrous Sulfate because of similar absorption but without inducing an inflammatory response.
Functional and structural characterization of the chikungunya virus translational recoding signals

Climate change and human globalization have spurred the rapid spread of mosquito-borne diseases to naïve populations. One such emerging virus of public health concern is chikungunya virus (CHIKV), a member of the Togaviridae family, genus Alphavirus. CHIKV pathogenesis is predominately characterized by acute febrile symptoms and severe arthralgia, which can persist in the host long after viral clearance. CHIKV has also been implicated in cases of acute encephalomyelitis, and its vertical transmission has been reported. Currently, no FDA-approved treatments exist for this virus. Recoding elements help expand the coding capacity in many viruses and therefore represent potential therapeutic targets in antiviral treatments. Here, we report the molecular and structural characterization of two CHIKV translational recoding signals: a termination codon read-through (TCR) element located between the nonstructural protein 3 and 4 genes and a programmed −1 ribosomal frameshift (−1 PRF) signal located toward the 3′ end of the CHIKV 6K gene. Using Dual-Luciferase and immunoblot assays in HEK293T and U87MG mammalian cell lines, we validated and genetically characterized efficient TCR and −1 PRF. Analyses of RNA chemical modification data with selective 2′-hydroxyl acylation and primer extension (SHAPE) assays revealed that CHIKV −1 PRF is stimulated by a tightly structured, triple-stem hairpin element, consistent with previous observations in alphaviruses, and that the TCR signal is composed of a single large multibulged hairpin element. These findings illuminate the roles of RNA structure in translational recoding and provide critical information relevant for design of live-attenuated vaccines against CHIKV and related viruses.
Retrieval of reference images of breast masses on mammograms by similarity space modeling

Presentation of reference images that are similar to a query image can be helpful in medical image diagnosis and treatment planning. The purpose of this study is to investigate a method for retrieving relevant images of breast masses on mammograms as a diagnostic reference. In our previous studies, subjective similarities for pairs of masses were obtained from experienced radiologists and used as the gold standard for retrieving visually similar images. By use of multidimensional scaling, a subjective similarity space was spanned so that masses that were placed close to a query image can be retrieved as reference images. This method, however, required manual outlines of masses for image feature determination. In this study, we modelled this similarity space using convolutional neural network. The result was evaluated using the leave-one-out cross validation method in terms of the correlation between the subjective ratings and determined similarity measures. The relevance of retrieved images was also evaluated in terms of the precision, which is the fraction of pathology matched images in the retrieved images. The correlation coefficient between the subjective ratings and the determined similarity measure was moderate with 0.735, which was slightly lower than those of the previous methods. The average precision was high with 0.852 when the most similar image was retrieved, which was higher than those in the previous studies. The results indicate the potential usefulness of the proposed method in similar image retrieval of breast masses on mammograms.
A High-Throughput Immune-Oncology Screen Identifies EGFR Inhibitors as Potent Enhancers of Antigen-Specific Cytotoxic T-lymphocyte Tumor Cell Killing

A screening tool capable of high-throughput identification of compounds and genes affecting antitumor responses is presented. Specific EGFR inhibitors were identified and validated as enhancing T cell–mediated killing of tumor cells, providing a proof-of-principle for this approach. We developed a screening assay in which luciferized ID8 expressing OVA was cocultured with transgenic CD8+ T cells specifically recognizing the model antigen in an H-2b–restricted manner. The assay was screened with a small-molecule library to identify compounds that inhibit or enhance T cell–mediated killing of tumor cells. Erlotinib, an EGFR inhibitor, was the top compound that enhanced T-cell killing of tumor cells. Subsequent experiments with erlotinib and additional EGFR inhibitors validated the screen results. EGFR inhibitors increased both basal and IFNγ-induced MHC class-I presentation, which enhanced recognition and lysis of tumor cell targets by CD8+ cytotoxic T lymphocytes. The ID8 cell line was also transduced to constitutively express Cas9, and a pooled CRISPR screen, utilizing the same target tumor cell/T-cell assay, identified single-guide (sg)RNAs targeting EGFR that sensitized tumor cells to T cell–mediated killing. Combination of PD-1 blockade with EGFR inhibition showed significant synergistic efficacy in a syngeneic model, further validating EGFR inhibitors as immunomodulatory agents that enhance checkpoint blockade. This assay can be screened in high-throughput with small-molecule libraries and genome-wide CRISPR/Cas9 libraries to identify both compounds and target genes, respectively, that enhance or inhibit T-cell recognition and killing of tumor cells. Retrospective analyses of squamous-cell head and neck cancer (SCCHN) patients treated with the combination of afatinib and pembrolizumab demonstrated a rate of clinical activity exceeding that of each single agent. Prospective clinical trials evaluating the combination of an EGFR inhibitor and PD-1 blockade should be conducted.
Hypercalcemia and cancer: Differential diagnosis and treatment

Incidentally detected hypercalcemia usually presents in an indolent manner and is most likely caused by primary hyperparathyroidism. In contrast, hypercalcemia in the patient with a history of cancer presents in a wide range of clinical settings and may be severe enough to warrant hospitalization. This form of hypercalcemia is usually secondary to hypercalcemia of malignancy and can be fatal. Hypercalcemia of malignancy is most commonly mediated by tumoral production of parathyroid hormone–related protein or by cytokines activating osteoclast degradation of bone. The initial workup, differential diagnoses, confirmatory laboratory testing, imaging, and medical and surgical management of hypercalcemia are described in the patient with cancer.
Vitamin D Supplementation and Nordic Walking Training Decreases Serum Homocysteine and Ferritin in Elderly Women

The aim of the study was to verify if coupling 12 weeks of vitamin D supplementation and Nordic walking training favoured lowering the homocysteine (Hcy) level. Ninety-four elderly women were divided into three groups: Nordic walking (NW), supplemented (SG) and control (CG). The NW and SG groups received a weekly dose of 28,000 IU of vitamin D3. A blood analysis was performed at baseline, 1h after the first training session and at the end of the experiment. The amino acid profile (methionine and cysteine) and homocysteine concentration were determined. Additionally, the concentration of myokine was assessed. The first session of NW training reduced serum homocysteine, particularly among women with baseline homocysteine above 10 µmol·L−1: 12.37 ± 2.75 vs. 10.95 ± 3.94 µmol·L−1 (p = 0.05). These changes were accompanied by shifts in the cysteine (p = 0.09) and methionine (p = 0.01) concentration, regardless of the Hcy concentration. Twelve weeks of training significantly decreased the homocysteine (9.91 ± 2.78, vs. 8.90 ± 3.14 µmol·L−1, p = 0.05) and ferritin (94.23 ± 62.49 vs. 73.15 ± 47.04 ng·mL−1, p = 0.05) concentrations in whole NW group. Also, in the NW group, ferritin correlated with the glucose level (r = 0.51, p = 0.00). No changes in the myokine levels were observed after the intervention. Only the brain-derived neurotrophic factor dropped in the NW (42.74 ± 19.92 vs. 31.93 ± 15.91 ng·mL−1, p = 0.01) and SG (37.75 ± 8.08 vs. 16.94 ± 12.78 ng·mL−1, p = 0.00) groups. This study presents a parallel decrease of homocysteine and ferritin in response to regular training supported by vitamin D supplementation.
A 4‐microRNA signature for survival prognosis in pediatric and adolescent acute myeloid leukemia

Acute myeloid leukemia (AML) is a hematologic malignancy with significant molecular heterogeneity. MicroRNAs (miRNAs) play a critical role in AML diagnosis, pathogenesis, and prognosis of AML. Little has been done to identify a miRNA signature in pediatric and adolescent patients for predicting overall survival. This study aims to identify a panel of miRNA signature that could predict the prognosis of all younger AML patients with all subtypes of AML by analyzing data from The Cancer Genome Atlas (TCGA). A total of 229 patients under 23 years with miRNA data and corresponding clinical data from TCGA database were enrolled in this study. Through conducting multivariate analysis in the training test, it was identified that the high expression of hsa‐miR‐509 and hsa‐miR‐542 were independent poor prognostic factors, whereas that of hsa‐miR‐146a and hsa‐miR‐3667 had a trend to be favorable factors. A 4‐miRNA signature was constructed by these miRNAs considering the weight of each. In testing group and all 229 patients’ cohort as well as 59 cytogenetically normal AML (CN‐AML) patients’ cohort, higher risk score was associated with shorter overall survival (OS). All results were confidential by using powerful statistical analysis. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis were carried out to further develop leukemia‐relevant mechanisms supporting the model. The results indicate that the 4‐miRNA‐based signature is a reliable prognostic biomarker for pediatric and adolescent AML patients.
Social Disorganization and Rural/Urban Crime Rates: A County Level Comparison of Contributing Factors

Social disorganization theory (Shaw & McKay, 1929) is a common explanation for crime. However, few studies have examined its significance for the explanation of crime in rural areas. The current study utilizes county level data from the United States Department of Health and Human Services to examine common characteristics of social disorganization for both rural and urban areas and which of these factors greater contribute to crime rates. The findings are consistent with previous research that finds significant differences between urban and rural areas regarding causes of crime. Overall, this study found that common measures of social disorganization such as income, racial heterogeneity, and migration do play a significant role in predicting the crime rate for both urban and rural areas. However, births and international migration play a significant role only in rural areas.