The Warburg effect in mycobacterial granulomas is dependent on the recruitment and activation of macrophages by interferon-γ

Granulomas are the hallmark of mycobacterial disease. Here, we demonstrate that both the cell recruitment and the increased glucose consumption in granulomatous infiltrates during Mycobacterium avium infection are highly dependent on interferon-y (IFN-y). Mycobacterium avium-infected mice lacking IFN-y signalling failed to developed significant inflammatory infiltrations and lacked the characteristic uptake of the glucose analogue fluorine-18-fluorodeoxyglucose (FDG). To assess the role of macrophages in glucose uptake we infected mice with a selective impairment of IFN-y signalling in the macrophage lineage (MIIG mice). Although only a partial reduction of the granulomatous areas was observed in infected MIIG mice, the insensitivity of macrophages to IFN-y reduced the accumulation of FDG. In vivo, ex vivo and in vitro assays showed that macrophage activated by IFN-y displayed increased rates of glucose uptake and in vitro studies showed also that they had increased lactate production and increased expression of key glycolytic enzymes. Overall, our results show that the activation of macrophages by IFN-y is responsible for the Warburg effect observed in organs infected with M. avium.Funded by project ‘NORTE-07-0124-FEDER-000002-Host-Pathogen Interactions’ co-funded by Programa Operacional Regional do Norte (ON.2—O Novo Norte), under the Quadro de Referência Estratégico Nacional (QREN), through the Fundo Europeu de Desenvolvimento Regional (FEDER) and by Fundação para a Ciência e Tecnologia

Can 11C-PiB-PET relative delivery R1 or 11C-PiB-PET perfusion replace 18F-FDG-PET in the assessment of brain neurodegeneration?

© 2018 – IOS Press and the authors. All rights reserved. This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC 4.0).Background: Pittsburgh Compound B (PiB) positron emission tomography (PET) is used to visualize in vivo amyloid plaques in the brain. Frequently the PiB examinations are complemented with a fluorodeoxyglucose (FDG) PET scan to further assess neurodegeneration. Objective: Our goal is to identify alternative correlates of FDG images by assessing which kinetic methods originate PiB derived relative delivery ratio (R1) images that can be correlated with the FDG images, and to compare them with PiB perfusion (pPiB) images obtained from the early-phase of PiB acquisition. Methods: We selected 52 patients with cognitive impairment who underwent a dynamic PiB and FDG acquisitions. To compute the R1 images, two simplified reference tissue models (SRTM and SRTM2) and two multi-linear reference tissue models (MRTM and MRTM2) were used. The pPiB images were obtained in two different time intervals. Results: All six types of images were of good quality and highly correlated with the FDG images (mean voxelwise withinsubjects r > 0.92). The higher correlation was found for FDG-R1(MRTM). Regarding the voxelwise regional correlation, the higher mean all brain correlations was r = 0.825 for FDG-R1(MRTM) and statistically significant in the whole brain analysis. Conclusion: All R1 and pPiB images here tested have potential to assess the metabolic impact of neurodegeneration almost as reliably as the FDG images. However, this is not enough to validate these images for a single-subject analysis compared with the FDG image, and thus they cannot yet be used clinically to replace the FDG image before such evaluation.This work was supported by the following grants: Strategic project FCT-UID/NEU/04539/ 2013 – COMPETE, POCI-01-0145-FEDER-007440, BIGDATIMAGE, CENTRO-01-0145-FEDER000016, Centro 2020 FEDER, COMPETE, PAC – MEDPERSYST, POCI-01- 0145-FEDER-016428. Authors’ disclosures available online (https:// www.j-alz.com/manuscript-disclosures/18-027 4r2).info:eu-repo/semantics/publishedVersio

Prototype of an affordable pressure-controlled emergency mechanical ventilator for COVID-19

We present a viable prototype of a simple mechanical ventilator intended as a last resort to ventilate COVID-19 patients. The prototype implements the pressure-controlled continuous mandatory ventilation mode (PC-CMV) with settable breathing rates, inspiration/expiration time ratios and FiO2 modulation. Although safe, the design aims to minimize the use of technical components and those used are common in industry, so its construction may be possible in times of logistical shortage or disruption or in areas with reduced access to technical materials and at a moderate cost, affordable to lower income countries. Most of the device can be manufactured by modest technical means and construction plans are provided.Comment: This version differs from version 2 in that it includes toxicological and bio-safety tests and updated electronic

Nucleolin Overexpression Predicts Patient Prognosis While Providing a Framework for Targeted Therapeutic Intervention in Lung Cancer

Notwithstanding the advances in the treatment of lung cancer with immune checkpoint inhibitors, the high percentage of non-responders supports the development of novel anticancer treatments. Herein, the expression of the onco-target nucleolin in patient-derived pulmonary carcinomas was characterized, along with the assessment of its potential as a therapeutic target. The clinical prognostic value of nucleolin for human pulmonary carcinomas was evaluated through data mining from the Cancer Genome Atlas project and immunohistochemical detection in human samples. Cell surface expression of nucleolin was evaluated by flow cytometry and subcellular fraction Western blotting in lung cancer cell lines. Nucleolin mRNA overexpression correlated with poor overall survival of lung adenocarcinoma cancer patients and further predicted the disease progression of both lung adenocarcinoma and squamous carcinoma. Furthermore, a third of the cases presented extra-nuclear expression, contrasting with the nucleolar pattern in non-malignant tissues. A two- to twelve-fold improvement in cytotoxicity, subsequent to internalization into the lung cancer cell lines of doxorubicin-loaded liposomes functionalized by the nucleolin-binding F3 peptide, was correlated with the nucleolin cell surface levels and the corresponding extent of cell binding. Overall, the results suggested nucleolin overexpression as a poor prognosis predictor and thus a target for therapeutic intervention in lung cancer

Data driven diagnostic classification in Alzheimer's disease based on different reference regions for normalization of PiB-PET images and correlation with CSF concentrations of Aβ species

Positron emission tomography (PET) neuroimaging with the Pittsburgh Compound_B (PiB) is widely used to assess amyloid plaque burden. Standard quantification approaches normalize PiB-PET by mean cerebellar gray matter uptake. Previous studies suggested similar pons and white-matter uptake in Alzheimer's disease (AD) and healthy controls (HC), but lack exhaustive comparison of normalization across the three regions, with data-driven diagnostic classification.We aimed to compare the impact of distinct reference regions in normalization, measured by data-driven statistical analysis, and correlation with cerebrospinal fluid (CSF) amyloid β (Aβ) species concentrations.243 individuals with clinical diagnosis of AD, HC, mild cognitive impairment (MCI) and other dementias, from the Biomarkers for Alzheimer's/Parkinson's Disease (BIOMARKAPD) initiative were included. PiB-PET images and CSF concentrations of Aβ38, Aβ40 and Aβ42 were submitted to classification using support vector machines. Voxel-wise group differences and correlations between normalized PiB-PET images and CSF Aβ concentrations were calculated.Normalization by cerebellar gray matter and pons yielded identical classification accuracy of AD (accuracy-96%, sensitivity-96%, specificity-95%), and significantly higher than Aβ concentrations (best accuracy 91%). Normalization by the white-matter showed decreased extent of statistically significant multivoxel patterns and was the only method not outperforming CSF biomarkers, suggesting statistical inferiority. Aβ38 and Aβ40 correlated negatively with PiB-PET images normalized by the white-matter, corroborating previous observations of correlations with non-AD-specific subcortical changes in white-matter. In general, when using the pons as reference region, higher voxel-wise group differences and stronger correlation with Aβ42, the Aβ42/Aβ40 or Aβ42/Aβ38 ratios were found compared to normalization based on cerebellar gray matter.<br /

Therapeutic implications of an enriched cancer stem-like cell population in a human osteosarcoma cell line

<p>Abstract</p> <p>Background</p> <p>Osteosarcoma is a bone-forming tumor of mesenchymal origin that presents a clinical pattern that is consistent with the cancer stem cell model. Cells with stem-like properties (CSCs) have been identified in several tumors and hypothesized as the responsible for the relative resistance to therapy and tumor relapses. In this study, we aimed to identify and characterize CSCs populations in a human osteosarcoma cell line and to explore their role in the responsiveness to conventional therapies.</p> <p>Methods</p> <p>CSCs were isolated from the human MNNG/HOS cell line using the sphere formation assay and characterized in terms of self-renewal, mesenchymal stem cell properties, expression of pluripotency markers and ABC transporters, metabolic activity and tumorigenicity. Cell's sensitivity to conventional chemotherapeutic agents and to irradiation was analyzed and related with cell cycle-induced alterations and apoptosis.</p> <p>Results</p> <p>The isolated CSCs were found to possess self-renewal and multipotential differentiation capabilities, express markers of pluripotent embryonic stem cells Oct4 and Nanog and the ABC transporters P-glycoprotein and BCRP, exhibit low metabolic activity and induce tumors in athymic mice. Compared with parental MNNG/HOS cells, CSCs were relatively more resistant to both chemotherapy and irradiation. None of the treatments have induced significant cell-cycle alterations and apoptosis in CSCs.</p> <p>Conclusions</p> <p>MNNG/HOS osteosarcoma cells contain a stem-like cell population relatively resistant to conventional chemotherapeutic agents and irradiation. This resistant phenotype appears to be related with some stem features, namely the high expression of the drug efflux transporters P-glycoprotein and BCRP and their quiescent nature, which may provide a biological basis for resistance to therapy and recurrence commonly observed in osteosarcoma.</p

COST Action CA19114, Network for Optimized Astatine labelled Radiopharmaceuticals

Cancer is a major health concerns for European citizens. Thus, the main research aim of this Network for Optimized Astatine labeled Radiopharmaceuticals (NOAR) COST Action is to successfully demonstrate that one of the most promising radionuclides for Targeted Alpha Therapy (TAT), namely astatine-211, can become the European standard for treatment of certain cancerous pathologies. To this end, an efficient networking is essential among all European stakeholders interested in promoting astatine-211 for medical applications. NOAR COST Action brings together European and international excellence labs, astatine-211 production centers, hospitals, industry and patient associations from more than 20 countries, thus covering the whole value chain of innovation: production, chemistry, radiochemistry, biology, preclinical and clinical research and delivery of radiopharmaceuticals to patients. A European web portal will be created containing information for patients, practitioners, researchers, Industry and as a contact point for National and European patient associations. The idea is to gather forces at the European level in order to implement actions to leverage hurdles to the development of this powerful radionuclide and to identify pathologies in which it will be particularly relevant. A special emphasis will be given to train a new generation of young researchers and PhD students, promoting interdisciplinary competencies through international and inter-sectoral mobility. The long-term goal of this project is to make Astatine-211 technology available to all European citizen

Métodos computacionais no desenvolvimento de radiofármacos para a tomografia por emissão de positrões.

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