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JT-60SA is the superconducting tokamak that will be operated at the Naka Fusion Institute of QST (the National Institutes for Quantum and Radiological Science and Technology) in Japan. The project is being developed under the framework of the Broader Approach Agreement between the EU and Japan (started in 2007) for an early realization of the fusion energy, aimed at conducting supportive and complementary work for the ITER experimental program towards DEMO. The assembly of the tokamak components as well as the related equipment was completed last year and the device is currently undergoing the integrated commissioning phase.Within the European contribution, Spain was one of the stakeholders that committed it, as a Voluntary Contributor, to design and manufacture one of the main components of the device: the cryostat. The cryostat is a large stainless steel vacuum vessel, 14 m diameter, 16 m high, which encloses the tokamak and provides the vacuum boundary (10−3 Pa) necessary to limit the heat loads on the magnets operated at cryogenic temperatures. The component is made up of the Cryostat Base (CB), the Cryostat Vessel Body Cylindrical Section (CVBCS), both designed and fabricated in Spain (through the National Fusion Laboratory at Ciemat), as well as the cryostat top lid (CTL) designed and procured by Japan (through QST).Within the manufacturing phases of the CB and CVBCS an extensive test program was carried out at Ciemat that focussed on the characterization of the welding processes selected for the manufacturing before their final approval. The aim of this paper is to present the results of the mechanical and microstructural tests performed on the welded joints.

This work presents a method to find the optimal configuration of a leg-based stair-climbing wheelchair. This optimization begins with the definition of a high-level control architecture, in which the kinematics restrictions related to the specific obstacles are considered. Then, the reference trajectories for all the actuators are generated as a function of the physical parameters of the mechanism, the dynamic restrictions of the actuators (velocity and acceleration) and the sensor errors. This work illustrates, based on a set of configurations, how the total time to climb up and climb down a defined stair depends on all these parameters, also reporting the best set of parameters that reduces the time and makes the mechanism more stable for a given scenario. The optimization in this work is performed with a brute-force search within a grid of parameters with a resolution of 1 mm. Thus, as the local minima is located, the complexity of the problem is revealed.

We present the design, manufacturing, and dynamical characterization of a mechanical suspension made by a passive magnetic spring and an eddy current damper integrated into a single device. Three configurations with 2, 3, and 4 permanent magnets axially distributed with opposite polarizations are designed, simulated, manufactured, and tested. Stiffness of 2410, 2050, 2090 N/m and damping coefficient of 5.45, 10.52 and 17.25 Ns/m are measured for the 2-, 3-, and 4-magnets configurations, respectively. The magnetic suspension provides good mechanical properties combined with excellent cleanness and high reliability, which is very desirable in mechanical systems for space applications.

An unprecedented global social and economic impact as well as a significant number of fatalities have been brought on by the coronavirus disease 2019 (COVID-19), produced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Acute SARS-CoV-2 infection can, in certain situations, cause immunological abnormalities, leading to an anomalous innate and adaptive immune response. While most patients only experience mild symptoms and recover without the need for mechanical ventilation, a substantial percentage of those who are affected develop severe respiratory illness, which can be fatal. The absence of effective therapies when disease progresses to a very severe condition coupled with the incomplete understanding of COVID-19’s pathogenesis triggers the need to develop innovative therapeutic approaches for patients at high risk of mortality. As a result, we investigate the potential contribution of promising combinatorial cell therapy to prevent death in critical patients.

BackgroundAutopsies can shed light on the pathogenesis of new and emerging diseases.AimTo describe needle core necropsy findings of the lung, heart, and liver in decedents with COVID-19.MaterialCross-sectional study of needle core necropsies in patients who died with virologically confirmed COVID-19. Histopathological analyses were performed, and clinical data and patient course evaluated.ResultsChest core necropsies were performed in 71 decedents with a median age of 81 years (range 52–97); 47 (65.3%) were men. The median interval from symptoms onset to death was 17.5 days (range 1–84). Samples of lung (n = 62, 87.3%), heart (n = 48, 67.6%) and liver (n = 39, 54.9%) were obtained. Fifty-one lung samples (82.3%) were abnormal: 19 (30.6%) showed proliferative diffuse alveolar damage (DAD), 12 (19.4%) presented exudative DAD, and 10 (16.1%) exhibited proliferative plus exudative DAD. Of the 46 lung samples tested for SARS-CoV-19 by RT-PCR, 39 (84.8%) were positive. DAD was associated with premortem values of lactate dehydrogenase of 400 U/L or higher [adjusted odds ratio (AOR) 21.73; 95% confidence interval (CI) 3.22–146] and treatment with tocilizumab (AOR 6.91; 95% CI 1.14–41.7). Proliferative DAD was associated with an onset-to-death interval of over 15 days (AOR 7.85, 95% CI 1.29–47.80). Twenty-three of the 48 (47.9%) heart samples were abnormal: all showed fiber hypertrophy, while 9 (18.8%) presented fibrosis. Of the liver samples, 29/39 (74.4%) were abnormal, due to steatosis (n = 12, 30.8%), cholestasis (n = 6, 15.4%) and lobular central necrosis (n = 5, 12.8%).ConclusionProliferative DAD was the main finding on lung core needle necropsy in people who died from COVID-19; this finding was related to a longer disease course. Changes in the liver and heart were common.

Objectives: Serum levels of potassium (K+) appear to be significantly lower in severe cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the clinical significance of this is unknown. The objective was to investigate whether hypokalemia acts as a biomarker of severity in coronavirus disease 2019 (COVID-19) pneumonia and is associated with major clinical outcomes. Methods: A retrospective cohort study of inpatients with COVID-19 pneumonia (March 3 to May 2, 2020) was performed. Patients were categorized according to nadir levels of K+ in the first 72 h of admission: hypokalemia (K+ ≤3.5 mmol/l) and normokalemia (K+ >3.5 mmol/l). The main outcomes were all-cause mortality and the need for invasive mechanical ventilation (IMV); these were analyzed by multiple logistic regression (odds ratio (OR), 95% confidence interval (CI)). Results: Three hundred and six patients were enrolled. Ninety-four patients (30.7%) had hypokalemia and these patients showed significantly higher comorbidity (Charlson comorbidity index ≥3, 30.0% vs 16.3%; p = 0.02) and CURB65 scores (median (interquartile range): 1.5 (0.0–3.0) vs 1.0 (0.0–2.0); p = 0.04), as well as higher levels of some inflammatory parameters at baseline. After adjustment for confounders, hypokalemia was independently associated with requiring IMV during the admission (OR 8.98, 95% CI 2.54–31.74). Mortality was 15.0% (n = 46) and was not influenced by low K+. Hypokalemia was associated with longer hospital and ICU stays. Conclusions: Hypokalemia is prevalent in patients with COVID-19 pneumonia. Hypokalemia is an independent predictor of IMV requirement and seems to be a sensitive biomarker of severe progression of COVID-19.

During surgical procedures for gliomas, tissue material obtained from cavitational ultrasonic surgical aspirators (CUSAs) is generally discarded but can actually exceed the amount and quality of certain tumour core resections (TCRs). Despite reports indicating the suitability of CUSA-derived material for diagnosis and research, its use is still marginal. We extended these conclusions to formalin-fixed, paraffin-embedded (FFPE) samples, the most common format for archival tumour tissue in anatomical pathology departments, by conducting for the first time RNA-seq analysis in CUSA aspirates. We compared the molecular diagnosis of somatic mutations used in the clinical routine and the gene expression profiles of fixed solid material from CUSA aspirates and TCRs from the same patients in selected gliomas encompassing grades II to IV. Despite the characteristic heterogeneity of gliomas, we found substantial similarities between the corresponding aspirates and TCRs that included transcriptional signatures associated with glioma subtypes. Based on these results, we confirmed that CUSA-fixed biomaterials from glioma surgeries are appropriate for downstream applications and biomarkers screening.

The prediction of microsatellite instability (MSI) using deep learning (DL) techniques could have significant benefits, including reducing cost and increasing MSI testing of colorectal cancer (CRC) patients. Nonetheless, batch effects or systematic biases are not well characterized in digital histology models and lead to overoptimistic estimates of model performance. Methods to not only palliate but to directly abrogate biases are needed. We present a multiple bias rejecting DL system based on adversarial networks for the prediction of MSI in CRC from tissue microarrays (TMAs), trained and validated in 1788 patients from EPICOLON and HGUA. The system consists of an end-to-end image preprocessing module that tile samples at multiple magnifications and a tissue classification module linked to the bias-rejecting MSI predictor. We detected three biases associated with the learned representations of a baseline model: the project of origin of samples, the patient’s spot and the TMA glass where each spot was placed. The system was trained to directly avoid learning the batch effects of those variables. The learned features from the bias-ablated model achieved maximum discriminative power with respect to the task and minimal statistical mean dependence with the biases. The impact of different magnifications, types of tissues and the model performance at tile vs patient level is analyzed. The AUC at tile level, and including all three selected tissues (tumor epithelium, mucin and lymphocytic regions) and 4 magnifications, was 0.87 ± 0.03 and increased to 0.9 ± 0.03 at patient level. To the best of our knowledge, this is the first work that incorporates a multiple bias ablation technique at the DL architecture in digital pathology, and the first using TMAs for the MSI prediction task.

Abstract Gliomas are the most common brain tumors and include a variety of histologic types and grades of malignancy. They arise from glial cells and represent approximately 70% of the primary brain tumors. According to the criteria of the World Health Organization (WHO), the majority of gliomas can be classified into four grades of malignancy (I-IV). Virus infection, especially by DNA viruses and retroviruses, which may cause insertion of viral DNA sequences into the host genome, often triggers the host defense mechanisms. Particularly, the DNA methylation machinery can be activated to cause the methylation of foreign movable viral sequences and, therefore, silence viral gene expression. Several studies have shown the presence of Human Cytomegalovirus (HCMV) in glioblastoma, suggesting that the virus may participate in tumor pathogenesis. But this relationship is controversial because many other studies did not detect HCMV in these tumors. This study aims to detect the presence of HCMV in several samples of human glioma (94 formalin-fixed, paraffin-embedded samples and 28 snap-frozen samples) by different sensitive techniques. We have been unable to detect HCMV DNA and proteins in glioma samples. Therefore, arguments used so far to conclude that HCMV is an oncomodulator virus in gliomas must be, in our view, seriously reconsidered.

Abstract Background Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an essential regulator of glycolysis used as a housekeeping marker for gene/protein normalisation. Given the pivotal role of GAPDH in tumour metabolism, our aim was to correlate its protein expression with tumour staging and prognosis of colorectal cancer. Methods GAPDH expression was immunohistochemically analysed in tumour tissues from 62 colorectal cancer (CRC) patients, and validated at mRNA level in an independent dataset comprising 98 paired stage II CRC and normal samples. Staining quantification was performed by computational image analysis, and correlations between GAPDH expression and tumour progression stage were assessed. Gene expression profiling was performed using Affymetrix microarrays. Probability of patient survival and disease-free survival were analysed by the univariate product-limit method of Kaplan-Meier. Groups were compared using Kruskal-Wallis tests. Results Overexpression of GAPDH is positively associated with early stage tumours without regional lymph node and distant metastases involved. These results were reinforced by those obtained at mRNA level. Conclusion Studying the role of GAPDH in malignant transformation can shed new light on the understanding of tumour onset and lead to the design of more efficient personalised therapies.

Glioblastoma multiforme (GBM) is a poor prognosis type of tumour due to its resistance to chemo and radiotherapy. SOCS1 and SOCS3 have been associated with tumour progression and response to treatments in different kinds of cancers, including GBM. In this study, cell lines of IDH-wildtype GBM from primary cultures were obtained, and the role of SOCS1 and SOCS3 in the radiotherapy response was analysed. Fifty-two brain aspirates from GBM patients were processed, and six new cell lines of IDH-wildtype GBM were established. These new cell lines were characterized according to the WHO classification of CNS tumours. SOCS1 and SOCS3 expression levels were determined, at mRNA level by Q-PCR, at protein level by immunocytochemistry, and Western blot analysis. The results showed that SOCS1 and SOCS3 are overexpressed in GBM, as compared to a non-tumoral brain RNA pool. SOCS1 and SOCS3 expression were reduced by siRNA, and it was found that SOCS3 inhibition increases radioresistance in GBM cell lines, suggesting a key role of SOCS3 in radioresistant acquisition. In addition, radioresistant clonal populations obtained by selective pressure on these cell cultures also showed a significant decrease in SOCS3 expression, while SOCS1 remained unchanged. Furthermore, the induction of SOCS3 expression, under a heterologous promoter, in a radiotherapy resistant GBM cell line increased its radiosensitivity, supporting an important implication of SOCS3 in radiotherapy resistance acquisition. Finally, the treatment with TSA in the most radioresistant established cell line produced an increase in the effect of radiotherapy, that correlated with an increase in the expression of SOCS3. These effects of TSA disappeared if the increase in the expression of SOCS3 prevented with an siRNA against SOCS3. Thus, SOCS3 signal transduction pathway (JAK/STAT) could be useful to unmask new putative targets to improve radiotherapy response in GBM.

[This corrects the article DOI: 10.1371/journal.pone.0212581.].

D-amino acid oxidase (DAAO) catalyzes the oxidation of D-amino acids generating hydrogen peroxide, a potential producer of reactive oxygen species. In this study, we used a CLytA-DAAO chimera, both free and bound to magnetic nanoparticles, against colon carcinoma, pancreatic adenocarcinoma, and glioblastoma cell lines. We found that the enzyme induces cell death in most of the cell lines tested and its efficiency increases significantly when it is immobilized in nanoparticles. We also tested this enzyme therapy in non-tumor cells, and we found that there is not cell death induction, or it is significantly lower than in tumor cells. The mechanism triggering cell death is apparently a classical apoptosis pathway in the glioblastoma cell lines, while in colon and pancreatic carcinoma cell lines, CLytA-DAAO-induced cell death is a necrosis. Our results constitute a proof of concept that an enzymatic therapy, based on magnetic nanoparticles-delivering CLytA-DAAO, could constitute a useful therapy against cancer and besides it could be used as an enhancer of other treatments such as epigenetic therapy, radiotherapy, and treatments based on DNA repair.

OBJECTIVE:The aim of this study was to validate a molecular classification of colorectal cancer (CRC) based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP) status, BRAF, and KRAS and investigate each subtype's response to chemotherapy. DESIGN:This retrospective observational study included a population-based cohort of 878 CRC patients. We classified tumours into five different subtypes based on BRAF and KRAS mutation, CIMP status, and MSI. Patients with advanced stage II (T4N0M0) and stage III tumours received 5-fluoruracil (5-FU)-based chemotherapy or no adjuvant treatment based on clinical criteria. The main outcome was disease-free survival (DFS). RESULTS:Patients with the combination of microsatellite stable (MSS) tumours, BRAF mutation and CIMP positive exhibited the worst prognosis in univariate (log rank P

O aleitamento materno é de suma importância para o binômio mãe-filho, tanto do ponto de vista físico, como psicológico. A maioria das mulheres experenciam o aleitamento materno e necessita do apoio dos profissionais de saúde. Esta pesquisa teve como objetivo conhecer a visão das puérperas em relação ao cuidado prestado pelos profissionais de saúde quanto à prática da amamentação. Trata-se de um estudo descritivo exploratório, realizado com 50 puérperas em uma maternidade no município do Rio de Janeiro, no período de Agosto a Dezembro de 2006. Das entrevistadas, 68% têm idade entre 20 e 29 anos, 40% têm baixa escolaridade, 64% são multíparas. Em relação a gestação atual 72% referiram parto normal, 94% das mulheres realizaram o pré-natal, destes 30% foi acompanhado pela enfermeira. O estudo evidenciou que 58% não foram orientadas quanto à prática da amamentação, 38% referiram falta de orientação prestada por algum profissional e 42% sentiram dificuldade para amamentar. A prática do aleitamento materno deve ser uma das principais ações de profissionais de saúde desde o pré-natal até o puerpério sensibilizando para o manejo e apoio à mulher, recém-nascido e família nos diferentes cenários.

In recent years, the study and design of wearable antennas have been empowered given the success of Wireless Body Area Networks (WBAN) for healthcare and medical purposes. This work analyses a flexible textile antenna whose performance can be optimised by the careful selection of the substrate thickness of the textile material, and by varying the antenna’s geometrical shape. After considering these parameters, several arrangements of antennas were simulated using the Computer Simulation Technology software (CST). The results of the simulations were compared to the experimental prototypes manufactured on a flexible felt material for a range of thicknesses and curvatures of the antenna substrate. Such antenna designs can be utilised in off-body communications and ISM applications.

High-risk features of colonic polyps are based on size, number, and pathologic characteristics. Surveillance colonoscopy is often recommended according to these findings. This study aimed to determine whether the molecular characteristics of polyps might provide information about the risk of metachronous advanced neoplasia.We retrospectively included 308 patients with colonic polyps. A total of 995 polyps were collected and tested for somatic BRAF and KRAS mutations. Patients were classified into 3 subgroups, based on the polyp mutational profile at baseline, as follows: non-mutated polyps (Wild-type), at least one BRAF-mutated polyp, or at least one KRAS-mutated polyp. At surveillance, advanced adenomas were defined as adenomas ≥ 10 mm and/or with high grade dysplasia or a villous component. In contrast, advanced serrated polyps were defined as serrated polyps ≥ 10 mm in any location, located proximal to the splenic flexure with any size or with dysplasia.At baseline, 289 patients could be classified as wild-type (62.3%), BRAF mutated (14.9%), or KRAS mutated (22.8%). In the univariate analysis, KRAS mutations were associated with the development of metachronous advanced polyps (OR: 2.36, 95% CI: 1.22-4.58; P = 0.011), and specifically, advanced adenomas (OR: 2.42, 95% CI: 1.13-5.21; P = 0.023). The multivariate analysis, adjusted for age and sex, also showed associations with the development of metachronous advanced polyps (OR: 2.27, 95% CI: 1.15-4.46) and advanced adenomas (OR: 2.23, 95% CI: 1.02-4.85).Our results suggested that somatic KRAS mutations in polyps represent a potential molecular marker for the risk of developing advanced neoplasia.

O aleitamento materno é de suma importância para o binômio mãe-filho, tanto do ponto de vista físico, como psicológico. A maioria das mulheres experenciam o aleitamento materno e necessita do apoio dos profissionais de saúde. Esta pesquisa teve como objetivo conhecer a visão das puérperas em relação ao cuidado prestado pelos profissionais de saúde quanto à prática da amamentação. Trata-se de um estudo descritivo exploratório, realizado com 50 puérperas em uma maternidade no município do Rio de Janeiro, no período de Agosto a Dezembro de 2006. Das entrevistadas, 68% têm idade entre 20 e 29 anos, 40% têm baixa escolaridade, 64% são multíparas. Em relação a gestação atual 72% referiram parto normal, 94% das mulheres realizaram o pré-natal, destes 30% foi acompanhado pela enfermeira. O estudo evidenciou que 58% não foram orientadas quanto à prática da amamentação, 38% referiram falta de orientação prestada por algum profissional e 42% sentiram dificuldade para amamentar. A prática do aleitamento materno deve ser uma das principais ações de profissionais de saúde desde o pré-natal até o puerpério sensibilizando para o manejo e apoio à mulher, recém-nascido e família nos diferentes cenários.

Lynch syndrome (LS) is a hereditary condition that increases the risk for endometrial and other cancers. The identification of endometrial cancer (EC) patients with LS has the potential to influence life-saving interventions. We aimed to study the prevalence of LS among EC patients in our population.Universal screening for LS was applied for a consecutive series EC. Tumor testing using microsatellite instability (MSI), immunohistochemistry (IHC) for mismatch-repair (MMR) protein expression and MLH1-methylation analysis, when required, was used to select LS-suspicious cases. Sequencing of corresponding MMR genes was performed.One hundred and seventy-three EC (average age, 63 years) were screened. Sixty-one patients (35%) had abnormal IHC or MSI results. After MLH1 methylation analysis, 27 cases were considered suspicious of LS. From these, 22 were contacted and referred for genetic counseling. Nineteen pursued genetic testing and eight were diagnosed of LS. Mutations were more frequent in younger patients (

In colorectal cancer (CRC), an inherited susceptibility risk affects about 35% of patients, whereas high-penetrance germline mutations account for

BackgroundTransketolase-like 1 (TKTL1) induces glucose degradation through anaerobic pathways, even in presence of oxygen, favoring the malignant aerobic glycolytic phenotype characteristic of tumor cells. As TKTL1 appears to be a valid biomarker for cancer prognosis, the aim of the current study was to correlate its expression with tumor stage, probability of tumor recurrence and survival, in a series of colorectal cancer patients. METHODOLODY/PRINCIPAL FINDINGS: Tumor tissues from 63 patients diagnosed with colorectal cancer at different stages of progression were analyzed for TKTL1 by immunohistochemistry. Staining was quantified by computational image analysis, and correlations between enzyme expression, local growth, lymph-node involvement and metastasis were assessed. The highest values for TKTL1 expression were detected in the group of stage III tumors, which showed significant differences from the other groups (Kruskal-Wallis test, P = 0.000008). Deeper analyses of T, N and M classifications revealed a weak correlation between local tumor growth and enzyme expression (Mann-Whitney test, P = 0.029), a significant association of the enzyme expression with lymph-node involvement (Mann-Whitney test, P = 0.0014) and a significant decrease in TKTL1 expression associated with metastasis (Mann-Whitney test, P = 0.0004).Conclusions/significanceTo our knowledge, few studies have explored the association between variations in TKTL1 expression in the primary tumor and metastasis formation. Here we report downregulation of enzyme expression when metastasis appears, and a correlation between enzyme expression and regional lymph-node involvement in colon cancer. This finding may improve our understanding of metastasis and lead to new and more efficient therapies against cancer.