Metabolic and functional reprogramming of myeloid-derived suppressor cells and their therapeutic control in glioblastoma

Glioblastoma, also known as glioblastoma multiforme, is the most common and deadliest form of high-grade malignant brain tumors with limited available treatments. Within the glioblastoma tumor microenvironment (TME), tumor cells, stromal cells, and infiltrating immune cells continuously interact and exchange signals through various secreted factors including cytokines, chemokines, growth factors, and metabolites. Simultaneously, they dynamically reprogram their metabolism according to environmental energy demands such as hypoxia and neo-vascularization. Such metabolic reprogramming can determine fates and functions of tumor cells as well as immune cells. Ultimately, glioma cells in the TME transform immune cells to suppress anti-tumor immune cells such as T, natural killer (NK) cells, and dendritic cells (DC), and evade immune surveillance, and even to promote angiogenesis and tumor metastasis. Glioma-associated microglia/macrophages (GAMM) and myeloid-derived suppressor cells (MDSC) are most abundantly recruited and expanded myeloid lineage cells in glioblastoma TME and mainly lead to immunosuppression. In this review, of myeloid cells we will focus on MDSC as an important driver to induce immunosuppression in glioblastoma. Here, we review current literature on immunosuppressive functions and metabolic reprogramming of MDSCs in glioblastoma and discuss their metabolic pathways as potential therapeutic targets to improve current incurable glioblastoma treatment

Espectroscopia Mössbauer para la caracterización de fases magnéticas en catalizadores del tipo MCM-41 modificados

Se prepararon silicatos mesoporosos del tipo MCM-41 modificados con hierro, mediante el método de impregnación húmeda. Se determinaron las distintas especies metálicas formadas según el contenido de hierro. Para esto se debió utilizar la técnica de espectroscopia Mössbauer, la cual nos dio información acerca de las fases presentes y el comportamiento magnético derivado de las mismas.Mesoporous silica MCM-41 modified with iron, by the method of wet impregnation were prepared. Different metallic species formed by the iron content were determined. This was due to using Mössbauer spectroscopy technique, which gave information about the phases present and the magnetic behavior derivative thereof.Instituto de Física La Plat

Acquisition of Chemoresistance in Gliomas Is Associated with Increased Mitochondrial Coupling and Decreased ROS Production

Temozolomide (TMZ) is an alkylating agent used for treating gliomas. Chemoresistance is a severe limitation to TMZ therapy; there is a critical need to understand the underlying mechanisms that determine tumor response to TMZ. We recently reported that chemoresistance to TMZ is related to a remodeling of the entire electron transport chain, with significant increases in the activity of complexes II/III and cytochrome c oxidase (CcO). Moreover, pharmacologic and genetic manipulation of CcO reverses chemoresistance. Therefore, to test the hypothesis that TMZ-resistance arises from tighter mitochondrial coupling and decreased production of reactive oxygen species (ROS), we have assessed mitochondrial function in TMZ-sensitive and -resistant glioma cells, and in TMZ-resistant glioblastoma multiform (GBM) xenograft lines (xenolines). Maximum ADP-stimulated (state 3) rates of mitochondrial oxygen consumption were greater in TMZ-resistant cells and xenolines, and basal respiration (state 2), proton leak (state 4), and mitochondrial ROS production were significantly lower in TMZ-resistant cells. Furthermore, TMZ-resistant cells consumed less glucose and produced less lactic acid. Chemoresistant cells were insensitive to the oxidative stress induced by TMZ and hydrogen peroxide challenges, but treatment with the oxidant L-buthionine-S,R-sulfoximine increased TMZ-dependent ROS generation and reversed chemoresistance. Importantly, treatment with the antioxidant N-acetyl-cysteine inhibited TMZ-dependent ROS generation in chemosensitive cells, preventing TMZ toxicity. Finally, we found that mitochondrial DNA-depleted cells (ρ°) were resistant to TMZ and had lower intracellular ROS levels after TMZ exposure compared with parental cells. Repopulation of ρ° cells with mitochondria restored ROS production and sensitivity to TMZ. Taken together, our results indicate that chemoresistance to TMZ is linked to tighter mitochondrial coupling and low ROS production, and suggest a novel mitochondrial ROS-dependent mechanism underlying TMZ-chemoresistance in glioma. Thus, perturbation of mitochondrial functions and changes in redox status might constitute a novel strategy for sensitizing glioma cells to therapeutic approaches

CD133 Is a Marker of Bioenergetic Stress in Human Glioma

Mitochondria dysfunction and hypoxic microenvironment are hallmarks of cancer cell biology. Recently, many studies have focused on isolation of brain cancer stem cells using CD133 expression. In this study, we investigated whether CD133 expression is regulated by bioenergetic stresses affecting mitochondrial functions in human glioma cells. First, we determined that hypoxia induced a reversible up-regulation of CD133 expression. Second, mitochondrial dysfunction through pharmacological inhibition of the Electron Transport Chain (ETC) produced an up-regulation of CD133 expression that was inversely correlated with changes in mitochondrial membrane potential. Third, generation of stable glioma cells depleted of mitochondrial DNA showed significant and stable increases in CD133 expression. These glioma cells, termed rho0 or ρ0, are characterized by an exaggerated, uncoupled glycolytic phenotype and by constitutive and stable up-regulation of CD133 through many cell passages. Moreover, these ρ0 cells display the ability to form “tumor spheroids” in serumless medium and are positive for CD133 and the neural progenitor cell marker, nestin. Under differentiating conditions, ρ0 cells expressed multi-lineage properties. Reversibility of CD133 expression was demonstrated by transfering parental mitochondria to ρ0 cells resulting in stable trans-mitochondrial “cybrid” clones. This study provides a novel mechanistic insight about the regulation of CD133 by environmental conditions (hypoxia) and mitochondrial dysfunction (genetic and chemical). Considering these new findings, the concept that CD133 is a marker of brain tumor stem cells may need to be revised

Inflammatory bowel disease nurse specialists for patients on biological therapies: a nationwide Italian survey

Background Management of inflammatory bowel disease (IBD) patients requires a multidisciplinary approach. Among the working team, the role of IBD nurse is expected to be particularly relevant when managing patients receiving biological therapies. We performed a survey to assess the presence of IBD nurse in centers where patients were receiving biologics. Methods For this Italian nationwide survey a specific questionnaire was prepared. IBD nurse was defined as a nurse directly involved in all phases of biological therapy, from pre-therapy screening, administration and monitoring during therapy, to follow up performed by a dedicated helpline, completed a specific training on biological therapy therapy, and observed international guidelines. Results A total of 53 Italian IBD centers participated in the survey, and 91 valid questionnaires were collected. Overall, 34 (37.4%) nurses could be classified as IBD specialists. IBD nurses had a significantly higher educational level than other nurses, they were more frequently operating in Central or Southern than in Northern Italy, they were working in an Academic center rather than in a General hospital, and in IBD centers with >25 patients on biological therapy. On the contrary, mean age, gender distribution, years of nursing, and years working in the IBD unit did not significantly differ between IBD and other nurses. Conclusions Our nationwide survey showed that the presence of an IBD nurse is still lacking in the majority of Italian IBD centers where patients receive biological therapies, suggesting a prompt implementation

Vigilancia epidemiológica de parasitosis zoonóticas en un área centinela desde la perspectiva de Una Salud

El abordaje de las enfermedades zoonóticas debe realizarse desde un enfoque multisectorial. Desde el concepto de Una Salud, las acciones realizadas por un solo sector no resultan eficaces para controlar este tipo de infecciones. En ese sentido, los distintos agentes de enfermedades transmisibles zoonóticas, afectan tanto a animales como a humanos y habitualmente el ecosistema actúa como reservorio o transmisor directo o indirecto, en la interfaz hombre-animal-ambiente. Los caninos pueden diseminar con sus heces enteroparásitos transmisibles a humanos y como animales centinela, pueden utilizarse para realizar vigilancia de la circulación de patógenos. Algunas helmintiasis, varias protozoosis y el alga parásita Blastocystis sp., son comunes en caninos y humanos. Nematodes del género Toxocara spp., enteroparásito de animales, ocasionan en personas toxocarosis, enfermedad de elevada seroprevalencia en la ciudad de La Plata y otras regiones. Sus formas neurológica y ocular tienen generalmente serias consecuencias. Su presencia en humanos se ve influenciada favorablemente por el lugar de residencia y su tejido suburbano. Giardia lamblia, enteroparásito zoonótico, ocasiona síndrome de malabsorción y modificación de moléculas de fármacos, también se correlaciona giardiasis con enfermedad de Whipple y otros disturbios gastroentéricos. El enfoque "Una salud" tiene en su estructura elementos esenciales, ellos son voluntad política (compromiso con las normas internacionales y los Objetivos de Desarrollo Sostenible), planes de financiación sostenibles; comunicación (entre sectores y disciplinas a nivel internacional, regional, nacional y subnacional). Los aprendizajes socialmente productivos y significativos “resignifica el papel social, cultural y económico social del conocimiento” y son aquellos “modifican a los sujetos enseñándoles a transformar su naturaleza y su cultura, enriqueciendo el capital cultural de la sociedad y de las comunidades” (Orozco B, 2009: 88). Los objetivos de este trabajo fueron: Realizar vigilancia y alertas tempranas en cuanto a parasitosis humanas animales y zoonóticas. Ejecutar acciones tendientes a su control. Implementar aprendizajes socialmente significativos.Facultad de Ciencias Veterinaria

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake