PM534, an Optimized Target-Protein Interaction Strategy through the Colchicine Site of Tubulin.

Targeting microtubules is the most effective wide-spectrum pharmacological strategy in antitumoral chemotherapy, and current research focuses on reducing main drawbacks: neurotoxicity and resistance. PM534 is a novel synthetic compound derived from the Structure-Activity-Relationship study on the natural molecule PM742, isolated from the sponge of the order Lithistida, family Theonellidae, genus Discodermia (du Bocage 1869). PM534 targets the entire colchicine binding domain of tubulin, covering four of the five centers of the pharmacophore model. Its nanomolar affinity and high retention time modulate a strikingly high antitumor activity that efficiently overrides two resistance mechanisms in cells (detoxification pumps and tubulin ßIII isotype overexpression). Furthermore, PM534 induces significant inhibition of tumor growth in mouse xenograft models of human non-small cell lung cancer. Our results present PM534, a highly effective new compound in the preclinical evaluation that is currently in its first human Phase I clinical trial.

Validation of an in vivo transit dosimetry algorithm using Monte Carlo simulations and ionization chamber measurements.

PURPOSE: Transit dosimetry is a safety tool based on the transit images acquired during treatment. Forward-projection transit dosimetry software, as PerFRACTION, compares the transit images acquired with an expected image calculated from the DICOM plan, the CT, and the structure set. This work aims to validate PerFRACTION expected transit dose using PRIMO Monte Carlo simulations and ionization chamber measurements, and propose a methodology based on MPPG5a report. METHODS: The validation process was divided into three groups of tests according to MPPG5a: basic dose validation, IMRT dose validation, and heterogeneity correction validation. For the basic dose validation, the fields used were the nine fields needed to calibrate PerFRACTION and three jaws-defined. For the IMRT dose validation, seven sweeping gaps fields, the MLC transmission and 29 IMRT fields from 10 breast treatment plans were measured. For the heterogeneity validation, the transit dose of these fields was studied using three phantoms: 10 , 30 , and a 3 cm cork slab placed between 10 cm of solid water. The PerFRACTION expected doses were compared with PRIMO Monte Carlo simulation results and ionization chamber measurements. RESULTS: Using the 10 cm solid water phantom, for the basic validation fields, the root mean square (RMS) of the difference between PerFRACTION and PRIMO simulations was 0.6%. In the IMRT fields, the RMS of the difference was 1.2%. When comparing respect ionization chamber measurements, the RMS of the difference was 1.0% both for the basic and the IMRT validation. The average passing rate with a γ(2%/2 mm, TH = 20%) criterion between PRIMO dose distribution and PerFRACTION expected dose was 96.0% ± 5.8%. CONCLUSION: We validated PerFRACTION calculated transit dose with PRIMO Monte Carlo and ionization chamber measurements adapting the methodology of the MMPG5a report. The methodology presented can be applied to validate other forward-projection transit dosimetry software.

MYH10 activation rescues contractile defects in arrhythmogenic cardiomyopathy (ACM).

The most prevalent genetic form of inherited arrhythmogenic cardiomyopathy (ACM) is caused by mutations in desmosomal plakophilin-2 (PKP2). By studying pathogenic deletion mutations in the desmosomal protein PKP2, here we identify a general mechanism by which PKP2 delocalization restricts actomyosin network organization and cardiac sarcomeric contraction in this untreatable disease. Computational modeling of PKP2 variants reveals that the carboxy-terminal (CT) domain is required for N-terminal domain stabilization, which determines PKP2 cortical localization and function. In mutant PKP2 cells the expression of the interacting protein MYH10 rescues actomyosin disorganization. Conversely, dominant-negative MYH10 mutant expression mimics the pathogenic CT-deletion PKP2 mutant causing actin network abnormalities and right ventricle systolic dysfunction. A chemical activator of non-muscle myosins, 4-hydroxyacetophenone (4-HAP), also restores normal contractility. Our findings demonstrate that activation of MYH10 corrects the deleterious effect of PKP2 mutant over systolic cardiac contraction, with potential implications for ACM therapy.

Development of a Ready-to-Eat Fish Product Enriched with Fish Oil Entrapped in a κ-Carrageenan Egg White Fish Protein Hydrolysate Dry Powder.

This work describes the development of a ready-to-eat (RTE) product based on an equal mixture of fish mince from three undervalued fish species with different fat contents and protein gelling capacity, which was enriched with fish oil entrapped in a κ-carrageenan egg white fish protein hydrolysate powder, obtained by either spray drying (SD) or heat drying (HD) at 80 °C (HD80). Previously, the spray-dried (SD) powder and heat-dried powders obtained at 45 °C, 60 °C and 80 °C (HD45, HD60 and HD80) were characterised in terms of water solubility, lipid oxidation (TBARS), hygroscopicity and ζ potential. All HD powders showed higher hygroscopicity and lower TBARS than the SD powder. The dry powder was incorporated into a blend composed of salt-ground batter and raw mince to improve binding and textural properties. Changes in water-holding capacity, colour, shear strength and microorganisms were monitored during the processing steps. The RTE product presented a high protein content and a noticeable amount of long-chain ω-3 fatty acids. The use of undervalued fish species together with fish oil and a protein hydrolysate from fish waste contribute to improving the sustainability of fishery resources, being conducive to obtaining a potentially functional RTE product.

Gamma passing rates of daily EPID transit images correlate to PTV coverage for breast cancer IMRT treatment plans.

PURPOSE: The use of the transit image obtained with the electronic portal-imaging device (EPID) is becoming an extended method to perform in-vivo dosimetry. The transit images acquired during each fraction can be compared with a predicted image, if available, or with a baseline image, usually the obtained in the first fraction. This work aims to study the dosimetric impact of the failing fractions and to evaluate the appropriateness of using a baseline image in breast plans. MATERIAL AND METHODS: Twenty breast patients treated in a Halcyon were retrospectively selected. For each patient and fraction, the treatment plan was calculated over the daily CBCT image. For each fraction, the differences respect to the treatment plan values of OARs and PTV dosimetric parameters were analyzed: ΔDmean , ΔD95%, ΔD98%, ΔD2%, ΔV36Gy, ΔV38.5Gy, and ΔV43.5Gy. Daily fractions were ranked according to the differences found in the dosimetric parameters between the treatment plan and the daily CBCT to establish the best fraction. The daily transit images acquired in every fraction were compared to the first fraction using the global gamma index with the Portal Dosimetry tool. The comparison was repeated using the best fraction image as a baseline. We assessed the correlation of the dosimetric differences obtained from the CBCT images-based treatment plans with the gamma index passing rates obtained using first fraction and best fraction as baseline. RESULTS: Average values of -11.6% [-21.4%, -3.3%] and -3.2% [-1.0%, -10.3%] for the ∆PTVD98% and ∆PTVD95% per every 10% decrease in the passing rate were found, respectively. When using the best fraction as baseline patients were detected with failing fractions that were not detected with the first fraction as baseline. CONCLUSION: The gamma passing rates of daily transit images correlate with the coverage loss parameters in breast IMRT plans. Using first fraction image as baseline can lead to the non-detectability of failing fractions.

Neuroimaging uncovers neuronal and metabolic changes in pain modulatory brain areas in a rat model of chemotherapy-induced neuropathy - MEMRI and ex vivo spectroscopy studies.

Chemotherapy-induced neuropathy (CIN) is one of the most common complications of cancer treatment with sensory dysfunctions which frequently include pain. The mechanisms underlying pain during CIN are starting to be uncovered. Neuroimaging allows the identification of brain circuitry involved in pain processing and modulation and has recently been used to unravel the disruptions of that circuitry by neuropathic pain. The present study evaluates the effects of paclitaxel, a cytostatic drug frequently used in cancer treatment, at the neuronal function in the anterior cingulate cortex (ACC), hypothalamus and periaqueductal gray (PAG) using manganese-enhanced magnetic resonance imaging (MEMRI). We also studied the metabolic profile at the prefrontal cortex (PFC) and hypothalamus using ex vivo spectroscopy. Wistar male rats were intraperitoneal injected with paclitaxel or vehicle solution (DMSO). The evaluation of mechanical sensitivity using von Frey test at baseline (BL), 21 (T21), 28 (T28), 49 (T49) and 56 days (T56) after CIN induction showed that paclitaxel-injected rats presented mechanical hypersensitivity from T21 until T56 after CIN induction. The evaluation of the locomotor activity and exploratory behaviors using open-field test at T28 and T56 after the first injection of paclitaxel revealed that paclitaxel-injected rats walked higher distance with higher velocity at late point of CIN accompanied with a sustained exhibition of anxiety-like behaviors. Imaging studies performed using MEMRI at T28 and T56 showed that paclitaxel treatment increased the neuronal activation in the hypothalamus and PAG at T56 in comparison with the control group. The analysis of data from ex vivo spectroscopy demonstrated that at T28 paclitaxel-injected rats presented an increase of N-acetyl aspartate (NAA) levels in the PFC and an increase of NAA and decrease of lactate (Lac) concentration in the hypothalamus compared to the control group. Furthermore, at T56 the paclitaxel-injected rats presented lower NAA and higher taurine (Tau) levels in the PFC. Together, MEMRI and metabolomic data indicate that CIN is associated with neuroplastic changes in brain areas involved in pain modulation and suggests that other events involving glial cells may be happening.

Physical and Oxidative Water-in-Oil Emulsion Stability by the Addition of Liposomes from Shrimp Waste Oil with Antioxidant and Anti-Inflammatory Properties.

Liposomes made of partially purified phospholipids (PL) from Argentine red shrimp waste oil were loaded with two antioxidant lipid co-extracts (hexane-soluble, Hx and acetone-soluble, Ac) to provide a higher content of omega-3 fatty acids. The physical properties of the liposomes were characterized by Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS) and Differential Scanning Calorimetry (DSC). The antioxidant and anti-inflammatory activity of the lipid extracts and liposomal suspensions were evaluated in terms of Superoxide and ABTS radical scavenging capacities and TNF-α inhibition. Uni-lamellar spherical liposomes (z-average ≈ 145 nm) with strong negative ζ potential (≈ -67 mV) were obtained in all cases. The high content of neutral lipids in the Hx extract caused structural changes in the bilayer membrane and decreased entrapment efficiency regarding astaxanthin and EPA + DHA contents. The liposomes loaded with the Hx/Ac extracts showed higher antioxidant and anti-inflammatory activity compared with empty liposomes. The liposomal dispersions improved the physical and oxidative stability of water-in-oil emulsions as compared with the PL extract, inducing pronounced close packing of water droplets. The liposomes decreased hydroperoxide formation in freshly made emulsions and prevented thio-barbituric acid-reactive substances (TBARS) accumulation during chilled storage. Liposomes from shrimp waste could be valuable nanocarriers and stabilizers in functional food emulsions.

Cellular and Molecular Targets of Extracellular Vesicles from Mesenchymal Stem/Stromal Cells in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes progressive joint destruction. Despite the advances in the treatment of this condition there remains a clinical need for safe therapies leading to clinical remission. Mesenchymal stem/stromal cells (MSCs) play immunomodulatory and regenerative roles which can be partly mediated by their secretome. In recent years, the important contribution of extracellular vesicles (EVs) to MSC actions has received an increasing interest as a new therapeutic approach. We provide an extensive overview of the immunomodulatory properties of MSC EVs and their effects on articular cells such as fibroblast-like synoviocytes that play a central role in joint destruction. This review discusses the anti-arthritic effects of MSC EVs in vitro and in animal models of RA as well as their potential mechanisms. Recent preclinical data suggest that transfer of non-coding RNAs by MSC EVs regulates key signaling pathways involved in the pathogenesis of RA. We also examine a number of EV modifications for improving their anti-arthritic efficacy and carrier ability for drug delivery.

Modulation of hypothalamic AMPK phosphorylation by olanzapine controls energy balance and body weight.

BACKGROUND: Second-generation antipsychotics (SGAs) are a mainstay therapy for schizophrenia. SGA-treated patients present higher risk for weight gain, dyslipidemia and hyperglycemia. Herein, we evaluated the effects of olanzapine (OLA), widely prescribed SGA, in mice focusing on changes in body weight and energy balance. We further explored OLA effects in protein tyrosine phosphatase-1B deficient (PTP1B-KO) mice, a preclinical model of leptin hypersensitivity protected against obesity. METHODS: Wild-type (WT) and PTP1B-KO mice were fed an OLA-supplemented diet (5 mg/kg/day, 7 months) or treated with OLA via intraperitoneal (i.p.) injection or by oral gavage (10 mg/kg/day, 8 weeks). Readouts of the crosstalk between hypothalamus and brown or subcutaneous white adipose tissue (BAT and iWAT, respectively) were assessed. The effects of intrahypothalamic administration of OLA with adenoviruses expressing constitutive active AMPKα1 in mice were also analyzed. RESULTS: Both WT and PTP1B-KO mice receiving OLA-supplemented diet presented hyperphagia, but weight gain was enhanced only in WT mice. Unexpectedly, all mice receiving OLA via i.p. lost weight without changes in food intake, but with increased energy expenditure (EE). In these mice, reduced hypothalamic AMPK phosphorylation concurred with elevations in UCP-1 and temperature in BAT. These effects were also found by intrahypothalamic OLA injection and were abolished by constitutive activation of AMPK in the hypothalamus. Additionally, OLA i.p. treatment was associated with enhanced Tyrosine Hydroxylase (TH)-positive innervation and less sympathetic neuron-associated macrophages in iWAT. Both central and i.p. OLA injections increased UCP-1 and TH in iWAT, an effect also prevented by hypothalamic AMPK activation. By contrast, in mice fed an OLA-supplemented diet, BAT thermogenesis was only enhanced in those lacking PTP1B. Our results shed light for the first time that a threshold of OLA levels reaching the hypothalamus is required to activate the hypothalamus BAT/iWAT axis and, therefore, avoid weight gain. CONCLUSION: Our results have unraveled an unexpected metabolic rewiring controlled by hypothalamic AMPK that avoids weight gain in male mice treated i.p. with OLA by activating BAT thermogenesis and iWAT browning and a potential benefit of PTP1B inhibition against OLA-induced weight gain upon oral treatment.

Individual and Joint Effect of Alpha-Tocopherol and Hydroxytyrosol Acetate on the Oxidation of Sunflower Oil Submitted to Oxidative Conditions: A Study by Proton Nuclear Magnetic Resonance.

This study tackles the individual and joint effect of alpha-tocopherol and hydroxytyrosol acetate on the oxidation of sunflower oil submitted to accelerated storage conditions at intermediate temperature, in order to deepen the understanding of antioxidant-prooxidant behaviour. This was accomplished by 1H Nuclear Magnetic Resonance. For this purpose, the evolution of the degradation of both the main components of the oil and the aforementioned added compounds was monitored by this technique throughout the storage time. Furthermore, the formation of a very large number of oxylipins and the evolution of their concentration up to a very advanced stage of oil oxidation, as well as the occurrence of lipolysis, were also simultaneously studied. The results obtained show very clearly and thoroughly that in the oxidation process of the oil enriched in binary mixtures, interactions occur between alpha-tocopherol and hydroxytyrosol acetate that notably reduce the antioxidant effect of the latter compound with the corresponding negative consequences that this entails. The methodology used here has proved to be very efficient to evaluate the antioxidant power of mixtures of compounds.

Connection between Mesenchymal Stem Cells Therapy and Osteoclasts in Osteoarthritis.

The use of mesenchymal stem cells constitutes a promising therapeutic approach, as it has shown beneficial effects in different pathologies. Numerous in vitro, pre-clinical, and, to a lesser extent, clinical trials have been published for osteoarthritis. Osteoarthritis is a type of arthritis that affects diarthritic joints in which the most common and studied effect is cartilage degradation. Nowadays, it is known that osteoarthritis is a disease with a very powerful inflammatory component that affects the subchondral bone and the rest of the tissues that make up the joint. This inflammatory component may induce the differentiation of osteoclasts, the bone-resorbing cells. Subchondral bone degradation has been suggested as a key process in the pathogenesis of osteoarthritis. However, very few published studies directly focus on the activity of mesenchymal stem cells on osteoclasts, contrary to what happens with other cell types of the joint, such as chondrocytes, synoviocytes, and osteoblasts. In this review, we try to gather the published bibliography in relation to the effects of mesenchymal stem cells on osteoclastogenesis. Although we find promising results, we point out the need for further studies that can support mesenchymal stem cells as a therapeutic tool for osteoclasts and their consequences on the osteoarthritic joint.

Alpha-Tocopherol, a Powerful Molecule, Leads to the Formation of Oxylipins in Polyunsaturated Oils Differently to the Temperature Increase: A Detailed Study by Proton Nuclear Magnetic Resonance of Walnut Oil Oxidation.

Lipid oxidation causes food degradation and the formation of toxic compounds. Therefore, the addition to foods of compounds able to avoid, delay or minimize this degradative process is a commonly used strategy. Nevertheless, neither the identity of most of the formed compounds in this complex process nor the way in which their formation is affected by the strategy used are well known. In this context, the effect the temperature increase and the enrichment level in alpha-tocopherol on the evolution of the walnut oil oxidation, as a model of an oil rich in polyunsaturated omega-6 acyl groups, submitted to storage conditions, are tackled by 1H NMR. The study has allowed knowing the degradation kinetic of both the oil acyl groups and alpha-tocopherol, the identification of a very high number of oxylipins and the kinetic of their formation. The temperature increase accelerates the formation of all oxylipins, favouring the formation of hydroperoxy conjugated E,E-dienes and related derivatives versus that of the Z,E-isomers. The enrichment in alpha-tocopherol accelerates the formation of hydroperoxy conjugated Z,E-dienes and related derivatives, and delays in relation to the formation of the former that of the E,E-isomers and related derivatives, hindering, to a certain extent, the formation of the latter in line with the enrichment level.

Influence of Hydroxytyrosol Acetate Enrichment of an Oil Rich in Omega-6 Groups on the Evolution of Its Oxidation and Oxylipin Formation When Subjected to Accelerated Storage. A Global Study by Proton Nuclear Magnetic Resonance.

Sunflower oil samples, both unenriched and enriched with four different concentrations of hydroxytyrosol acetate, were subjected to accelerated storage at 70 °C until a very advanced oxidation stage and the process was monitored by 1H NMR spectroscopy. The aim of the study is to know the effect that the presence of this antioxidant has on the oxidation process of sunflower oil under the aforementioned conditions, as well as on the formation and evolution of the concentration of a significant number of oxylipins. The oxidation process was studied globally by monitoring, during storage time, the degradation of both the linoleic acyl group of sunflower oil, which is the main component of sunflower oil, and the added hydroxytyrosol acetate. Simultaneously, the identification of up to twenty-six different types of oxylipins formed in the oxidation process and the monitoring of the evolution of their concentration over the storage time were carried out. In this way, essential information about the effect that hydroxytyrosol acetate provokes on the oxidation of this oil rich in omega-6 polyunsaturated acyl groups, has been obtained. It has also been shown that the enrichment of sunflower oil with this antioxidant under the conditions tested does not prevent the oxidation process but slows it down, affecting the entire oxidation process.

Anti-Inflammatory Properties, Bioaccessibility and Intestinal Absorption of Sea Fennel (Crithmum maritimum) Extract Encapsulated in Soy Phosphatidylcholine Liposomes.

A sea fennel (Crithmum maritimum) aqueous extract was prepared and loaded into soybean phosphatidylcholine liposomes. Both the free extract (FE), and the empty (L) and loaded (L-FE) liposomes were shown to be non-cytotoxic to THP-1 and Caco-2 cells. The anti-inflammatory effect was tested on THP-1 cells differentiated into macrophages. FE showed anti-inflammatory activity, revealed by the induced secretion of IL-10 cytokines in macrophages that were subsequently stimulated with LPS. Also, a decrease in TNF-α production by L was observed, evidencing that liposomes reduced the pro-inflammatory mediators' secretion. The liposomes (L) showed protective anti-inflammatory activity and also were able to downregulate the inflammation. Furthermore, L-FE were also found to downregulate the inflammation response, as they were able to decrease TNF-α secretion in macrophages previously exposed to LPS. The simulated in vitro gastrointestinal digestion (GID) of FE diminished the chlorogenic acid content (the main polyphenolic compound of the extract) by 40%, while in L-FE, the amount of this phenolic compound increased with respect to the undigested liposomes. The amount of bioaccessible chlorogenic, however, was similar for FE and L-FE. The percentage of chlorogenic acid absorbed through a Caco-2 cell monolayer after 3 h of incubation, was significantly similar for the extract and the liposomes (~1.5%), without finding significant differences once the extract and liposomes were digested.

Family perceptions and experiences of living with patients with fibromyalgia syndrome.

PURPOSE: To explore the perception of the illness and the experience of the illness for relatives of fibromyalgia syndrome (FMS) patients. MATERIALS AND METHODS: This qualitative interpretative study adopted a grounded theory research methodology with a purposive sample. We conducted a focus group with 11 family members of FMS patients. There were six men and five women, five were spouses and six were children (four husbands and one wife, and five daughters and one son). RESULTS: Three categories of family perceptions of FMS emerged: (1) manifestations of FMS; (2) FMS is regarded as a psychological problem; (3) FMS interferes with traditional gender roles. Three categories of family members' experience of living with FMS patients were identified: (1) emotional concerns and exhaustion; (2) overprotective family members; and (3) escape coping. CONCLUSIONS: Family members feel emotionally burdened, can be overprotective and over-involved and find it difficult to set limits ultimately succumbing to a vicious cycle of caregiving and emotional exhaustion from which they find it difficult to escape. As the perceptions and experiences of family members of FMS patients are not commonly studied, the present findings offer new insights for families and elucidate important points of intervention.Implications for rehabilitationBecause family members tend to dismiss fibromyalgia as a psychological problem for which ignoring or distracting the patient is the best approach to coping, rehabilitation programs should give family members education and training to develop the ability to better understand fibromyalgia and reduce stereotypes about the condition.Rehabilitation programs should work to identify and manage marital and family systems dysfunction that may be interfering with fibromyalgia patients' adjustment and quality of life.Family members often engage in maladaptive escape coping to manage the demands of living with patients with fibromyalgia, and rehabilitation professionals should be ready to engage and refer to allied specialists to assist family members in finding alternatives for more effective coping approaches that improve patient and family mental health and social relations.Rehabilitation programs for fibromyalgia patients should use a gender perspective and emphasize patient and spouse equality in activities of daily living as many patients and family members feel uncomfortable about not fulfilling traditional gender roles.

1H NMR Study of the In Vitro Digestion of Highly Oxidized Soybean Oil and the Effect of the Presence of Ovalbumin.

Oxidized lipids containing a wide variety of potentially toxic compounds can be ingested through diet. However, their transformations during digestion are little known, despite this knowledge being essential in understanding their impact on human health. Considering this, the in vitro digestion process of highly oxidized soybean oil, containing compounds bearing hydroperoxy, aldehyde, epoxy, keto- and hydroxy groups, among others, is studied by 1H nuclear magnetic resonance. Lipolysis extent, oxidation occurrence and the fate of oxidation products both present in the undigested oil and formed during digestion are analyzed. Furthermore, the effect during digestion of two different ovalbumin proportions on all the aforementioned issues is also addressed. It is proved that polyunsaturated group bioaccessibility is affected by both a decrease in lipolysis and oxidation occurrence during digestion. While hydroperoxide level declines throughout this process, epoxy-compounds, keto-dienes, hydroxy-compounds, furan-derivatives and n-alkanals persist to a great extent or even increase. Conversely, α,ß-unsaturated aldehydes, especially the very reactive and toxic oxygenated ones, diminish, although part of them remains in the digestates. While a low ovalbumin proportion hardly affects oil evolution during digestion, at a high level it diminishes oxidation and reduces the concentration of potentially bioaccessible toxic oxidation compounds.

SeDREno study - prevalence of hospital malnutrition according to GLIM criteria, ten years after the PREDyCES study.

INTRODUCTION: Background & aims: the last large multicenter study on disease-related malnutrition (DRM) in Spain (the PREDyCES study) showed a 23.7 % prevalence of malnutrition, according to the Nutritional Risk Screening (NRS-2002) tool. The main objective of the SeDREno study was to assess the prevalence of hospital malnutrition upon admission, according to GLIM criteria, ten years later. Methods: a cross-sectional, observational, multicenter study in standard clinical practice, conducted in 17 hospitals during a period of five to seven days. Patients were initially screened using the Malnutrition Universal Screening Tool (MUST), and then assessed using the GLIM criteria for diagnosis and severity grading. Results: a total of 2,185 patients, 54.8 % males, mean age 67.1 (17.0) years (50.2 % aged ≥ 70 years), were evaluated. Malnutrition was observed in 29.7 % of patients according to GLIM criteria (12.5 % severe, 17.2 % moderate). In patients ≥ 70 years malnutrition was observed in 34.8 %. The clinical conditions significantly associated with a higher prevalence of malnutrition were dysphagia (47.6 %), cognitive impairment (43.4 %), cancer (39.1 %), gastrointestinal disease (37.7 %), diabetes (34.8 %), and cardiovascular disease (33.4 %). The multivariate analysis revealed that gender, BMI, diabetes, cancer, gastrointestinal disorders, and polypharmacy were the main independent factors associated with DRM. Malnutrition was associated with an increase in length of hospital stay and death (p < 0.001). Conclusions: DRM in admitted patients has increased in Spain in the last 10 years paralleling ageing of the population. In the SeDREno study almost one in three patients are malnourished. A systematic assessment of nutritional status allows early detection and implementation of nutritional interventions to achieve a better clinical outcome.

INTRODUCCIÓN: Antecedentes y objetivos: el último gran estudio multicéntrico sobre desnutrición relacionada con la enfermedad (DRE) en España (el estudio PREDyCES) mostró una prevalencia de desnutrición del 23,7 % según la herramienta Nutritional Risk Screening (NRS-2002). El principal objetivo del estudio SeDREno fue evaluar la prevalencia de la desnutrición hospitalaria al ingreso según los criterios GLIM diez años después. Métodos: estudio transversal, observacional, multicéntrico, según la práctica clínica estándar, realizado en 17 hospitales durante un período de cinco a siete días. Los pacientes fueron evaluados inicialmente con la herramienta de detección universal de desnutrición (MUST) y luego con los criterios GLIM para el diagnóstico de DRE y la clasificación de la gravedad. Resultados: se evaluaron 2185 pacientes, con un 54,8 % de varones una edad media de 67,1 (17,0) años (50,2 % ≥ 70 años). Se observó desnutrición en el 29,7 % de los pacientes según los criterios GLIM (12,5 % grave, 17,2 % moderada). Entre los pacientes ≥ 70 años se observó desnutrición en el 34,8 %. Las condiciones clínicas asociadas significativamente con una mayor prevalencia de desnutrición fueron la disfagia (47,6 %), el deterioro cognitivo (43,4 %), el cáncer (39,1 %), las enfermedades gastrointestinales (37,7 %), la diabetes (34,8 %) y la patología cardiovascular (33,4 %). El análisis multivariante reveló que el sexo, el IMC, la diabetes, el cáncer, los trastornos gastrointestinales y la polimedicación eran los principales factores independientes asociados a la DRE. La desnutrición se asoció a un aumento de la duración de la estancia hospitalaria y la muerte (p < 0,001). Conclusiones: la DRE en pacientes ingresados ha aumentado en España en los últimos 10 años en paralelo con el aumento del envejecimiento de la población. En el estudio SeDREno, casi uno de cada tres pacientes está desnutrido. La evaluación sistemática del estado nutricional permite la detección e implementación precoces de intervenciones nutricionales para lograr un mejor resultado clínico.

Breast cancer mortality after eight years of an improved screening program using digital breast tomosynthesis.

OBJECTIVES: To assess screening quality metrics and to describe mortality rates eight years after redesign of breast cancer screening and diagnosis pathways, and the introduction of digital breast tomosynthesis. SETTING: Breast Unit of the Toledo Health Area in the region of Castilla-La Mancha (Spain). METHODS: We recorded screening metrics and mortality data following the introduction of digital breast tomosynthesis in 2011 for screening and diagnosis pathways. We then compared the mortality between Toledo Health Area and the rest of Castilla-La Mancha, where digital breast tomosynthesis is not available. RESULTS: All screening quality metrics improved following the introduction of digital breast tomosynthesis. The cancer detection rate significantly increased from 2.3 (95% confidence interval (CI): 1.9-3.6) to 4.5 per 1000 women (95% CI: 3.2-5.2) on average between the periods 2005-2009 and 2015-2018, while the recall rate significantly decreased from 7.0% (95% CI: 6.8%-8.2%) to 2.6% (95% CI: 2.0%-3.6%). Comparing breast cancer mortality rates for 2014-2018 in the Toledo Health Area with the rest of Castilla-La Mancha, which had similar cancer treatment access and management protocols but without digital breast tomosynthesis, the crude mortality rate was 17.79 (95% CI: 15.38 -20.19) vs. 24.76 per 100,000 (95% CI: 26.12-23.39), respectively. The cumulative risk of death was also significantly lower for the Toledo Health Area than for Castilla-La Mancha. CONCLUSION: The introduction of digital breast tomosynthesis improved screening quality indicators. Breast cancer mortality simultaneously decreased with respect to the rest of Castilla-La Mancha. Further research is needed to assess the long-term results, and the role that the redesign may have played in reducing mortality.

Evaluation of Extracellular Vesicles from Adipose Tissue-Derived Mesenchymal Stem Cells in Primary Human Chondrocytes from Patients with Osteoarthritis.

Adipose tissue-derived mesenchymal stem cells (AD-MSCs) offer great therapeutic potential for osteoarthritis (OA) treatment. Recent investigations have revealed the contribution of extracellular vesicles (EVs) to AD-MSC actions. Here, we describe a method to study the in vitro effects of EVs from AD-MSCs in OA chondrocytes. This chapter includes the isolation and analysis of human AD-MSCs and their EVs as well as the isolation and treatment of OA chondrocytes.

Extracellular Vesicles Do Not Mediate the Anti-Inflammatory Actions of Mouse-Derived Adipose Tissue Mesenchymal Stem Cells Secretome.

Adipose tissue represents an abundant source of mesenchymal stem cells (MSC) for therapeutic purposes. Previous studies have demonstrated the anti-inflammatory potential of adipose tissue-derived MSC (ASC). Extracellular vesicles (EV) present in the conditioned medium (CM) have been shown to mediate the cytoprotective effects of human ASC secretome. Nevertheless, the role of EV in the anti-inflammatory effects of mouse-derived ASC is not known. The current study has investigated the influence of mouse-derived ASC CM and its fractions on the response of mouse-derived peritoneal macrophages against lipopolysaccharide (LPS). CM and its soluble fraction reduced the release of pro-inflammatory cytokines, adenosine triphosphate and nitric oxide in stimulated cells. They also enhanced the migration of neutrophils or monocytes, in the absence or presence of LPS, respectively, which is likely related to the presence of chemokines, and reduced the phagocytic response. The anti-inflammatory effect of CM may be dependent on the regulation of toll-like receptor 4 expression and nuclear factor-κB activation. Our results demonstrate the anti-inflammatory effects of mouse-derived ASC secretome in mouse-derived peritoneal macrophages stimulated with LPS and show that they are not mediated by EV.