Papel del tejido adiposo en las propiedades de las células madre tumorales del cáncer de páncreas

El adenocarcinoma ductal pancreático (ADP) es uno de los tumores más mortales con peor pronóstico, cuya incidencia se prevé que aumente en la próxima década. La obesidad constituye un factor de riesgo importante que puede influir promoviendo la progresión tumoral. Por otro lado, su agresividad intrínseca, potencial metastásico y quimioresistencia, se debe, en gran medida, a la subpoblación de células madre tumorales (CSCs) que contiene. Las CSCs pancreáticas son altamente dependientes del metabolismo lipídico, lo que favorece el fenotipo de CSC. En particular, los triacilglicéridos (TAGs) almacenados en gotas lipídicas constituyen una fuente principal energética para las células cancerosas. Estudios previos han asociado la captación de lípidos del microambiente tumoral con la progresión tumoral del ADP. Por ello, el objetivo de este trabajo es estudiar la comunicación entre los adipocitos y las CSCs en cáncer de páncreas.En el presente estudio se ha determinado por análisis bioinformático una sobre-expresión de genes del metabolismo lipídico en el tejido de ADP. La incubación de cultivos primarios de ADP con medio condicionado de adipocitos redujo el contenido de CD133+ e incrementó en esta subpoblación el contenido lipídico. Como consecuencia, se optó por un cocultivo indirecto entre esferas de ADP y adipocitos. Por un lado, el contenido de TAGs en el sobrenadante de cocultivos incrementó, mientras que en los adipocitos en cocultivo hubo una menor acumulación de TAGs. Además, en las esferas de ADP hubo un ligero incremento en el contenido lipídico de las CD133+. Por otro lado, no hubo diferencias en el contenido de CD133+ de las esferas provenientes de cocultivo, confirmado por la expresión de los genes de pluripotencia. Por último, los genes de EMT, SLUG y ZEB1 se sobre-expresaron. Además, se determinó que los lípidos derivados de los adipocitos podrían ser captados por el transportador CD36, sobre-expresado en esferas de ADP.En conclusión, los adipocitos desempeñan un papel importante sobre la funcionalidad de las CSCs pancreáticas, así como induciendo cambios metabólicos en las mismas. De hecho, los adipocitos actúan como donadores de lípidos en las células de ADP, pero el destino de los mismos no está claro ya que existen indicios de un comportamiento diferencial entre líneas celulares. Como resultado, esta puesta a punto ha demostrado que existe una comunicación entre los adipocitos y las CSCs de ADP, lo que incita a profundizar más en el papel del metabolismo lipídico y concretamente del tejido adiposo en el ADP.<br /

Pharmacological targeting of the receptor ALK inhibits tumorigenicity and overcomes chemoresistance in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease characterized by its metastatic potential and chemoresistance. These traits are partially attributable to the highly tumorigenic pancreatic cancer stem cells (PaCSCs). Interestingly, these cells show unique features in order to sustain their identity and functionality, some of them amenable for therapeutic intervention. Screening of phospho-receptor tyrosine kinases revealed that PaCSCs harbored increased activation of anaplastic lymphoma kinase (ALK). We subsequently demonstrated that oncogenic ALK signaling contributes to tumorigenicity in PDAC patient-derived xenografts (PDXs) by promoting stemness through ligand-dependent activation. Indeed, the ALK ligands midkine (MDK) or pleiotrophin (PTN) increased self-renewal, clonogenicity and CSC frequency in several in vitro local and metastatic PDX models. Conversely, treatment with the clinically-approved ALK inhibitors Crizotinib and Ensartinib decreased PaCSC content and functionality in vitro and in vivo, by inducing cell death. Strikingly, ALK inhibitors sensitized chemoresistant PaCSCs to Gemcitabine, as the most used chemotherapeutic agent for PDAC treatment. Consequently, ALK inhibition delayed tumor relapse after chemotherapy in vivo by effectively decreasing the content of PaCSCs. In summary, our results demonstrate that targeting the MDK/PTN-ALK axis with clinically-approved inhibitors impairs in vivo tumorigenicity and chemoresistance in PDAC suggesting a new treatment approach to improve the long-term survival of PDAC patients

Does nutritional status influence the effects of a multicomponent exercise programme on body composition and physical fitness in older adults with limited physical function?

Physical exercise effects and ageing on fitness may be influenced by nutritional status. This study investigates the effects of a 6-month multicomponent exercise training (MCT) on nutritional status and evaluates if this type of exercise could affect differently body composition and physical fitness depending on the nutritional status of older adults with decreased functional capacity. Ninety-three participants (80.4 ± 6.0 y) were divided into control (n = 45) and intervention (n = 48) groups. The intervention consisted of a 6-month multicomponent training. Comparisons between changes in body composition and fitness during the 6-months were performed between individuals at risk of malnutrition and those well-nourished, according to the Mini Nutritional Assessment. Model mixed-effect analyses were used to investigate differences after the 6 months of MCT between groups. Well-nourished participants compared with those at risk of malnutrition had higher: arm (13.4 ± 3.5 vs 14.3 ± 33.6 repetitions) and leg strength (9.0 ± 3.0 vs 11.1 ± 3.3 repetitions), maximum walking speed (31.6 ± 13.1 vs 23.7 ± 6.3s), agility (11.9 ± 5.8 vs 8.3 ± 2.1s), and aerobic capacity (31.6 ± 13.1 vs 23.7 ± 6.3 m), at baseline. After the training, those without risk of malnutrition in CON decreased their nutritional status (-1.7 + 0.7 points). Those well-nourished that performed the intervention decreased total fat mass (-1.0 ± 0.3 kg) and body fat percentage (-1.2 ± 0.4%). Both groups of training improved similarly in all tests, except for balance, in which the well-nourished showed improvements of 6.3 ± 1.9s. These results underline the usefulness of MCT in improving physical fitness regardless of nutritional status and preventing nutritional status detriment in well-nourished older adults, who are fitter and benefit more, in terms of body composition. Trial registration:ClinicalTrials.gov identifier: NCT03831841. Highlights Multicomponent exercise programme seems to be effective in delaying detriments in the nutritional status of well-nourished people. Well-nourished older people obtain more benefits in body composition from the multicomponent exercise than those at risk of malnutrition, decreasing adiposity. The positive effect of multicomponent exercise was observed in physical fitness independently of nutritional status

Inhibition of mitochondrial dynamics preferentially targets pancreatic cancer cells with enhanced tumorigenic and invasive potential

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors, partly due to its intrinsic aggressiveness, metastatic potential, and chemoresistance of the contained cancer stem cells (CSCs). Pancreatic CSCs strongly rely on mitochondrial metabolism to maintain their stemness, therefore representing a putative target for their elimination. Since mitochondrial homeostasis de-pends on the tightly controlled balance between fusion and fission processes, namely mitochondrial dynamics, we aim to study this mechanism in the context of stemness. In human PDAC tissues, the mitochondrial fission gene DNM1L (DRP1) was overexpressed and positively correlated with the stemness signature. Moreover, we observe that primary human CSCs display smaller mitochondria and a higher DRP1/MFN2 expression ratio, indicating the activation of the mitochondrial fission. In-terestingly, treatment with the DRP1 inhibitor mDivi-1 induced dose-dependent apoptosis, especially in CD133+ CSCs, due to the accumulation of dysfunctional mitochondria and the subsequent energy crisis in this subpopulation. Mechanistically, mDivi-1 inhibited stemness-related features, such as self-renewal, tumorigenicity, and invasiveness and chemosensitized the cells to the cytotoxic effects of Gemcitabine. In summary, mitochondrial fission is an essential process for pancreatic CSCs and represents an attractive target for designing novel multimodal treatments that will more efficiently eliminate cells with high tumorigenic potentialThis research was funded by the Pancreatic Cancer Research Fund, 2015 Award Round (P.S., C.H.); the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n 602783 (CAM-PaC) (C.H.), theWorldwide Cancer Research Charity together with Fundación Científica Asociación Española contra el Cáncer (FCAECC) (19-0250) (P.S.); A Fero Foundation grant and a Coordinated grant (GC16173694BARB) from the Fundación Asociación Española Contra el Cáncer (AECC) (B.S.J.); and the Instituto de Salud Carlos III through the Miguel Servet Program (CP16/00121) and Fondo de Investigaciones Sanitarias (PI17/00082) (both co-financed by European funds (FSE: “El FSE invierte en tu futuro” and FEDER: “Una manera de hacer Europa,” respectively) (P.S.

Functional Frailty, Dietary Intake, and Risk of Malnutrition. Are Nutrients Involved in Muscle Synthesis the Key for Frailty Prevention?

Frailty is a reversible condition, which is strongly related to physical function and nutri tional status. Different scales are used to screened older adults and their risk of being frail, however, Short Physical Performance Battery (SPPB) may be more adequate than others to measure physical function in exercise interventions and has been less studied. Thus, the main aims of our study were: (1) to describe differences in nutritional intakes by SPPB groups (robust, pre-frail and frail); (2) to study the relationship between being at risk of malnourishment and frailty; and (3) to describe differences in nutrient intake between those at risk of malnourishment and those without risk in the no-frail individuals. One hundred one participants (80.4 ± 6.0 year old) were included in this cross sectional study. A validated semi-quantitative food frequency questionnaire was used to determine food intake and Mini Nutritional Assessment to determine malnutrition. Results revealed differences for the intake of carbohydrates, n-3 fatty acids (n3), and saturated fatty acids for frail, pre-frail, and robust individuals and differences in vitamin D intake between frail and robust (all p < 0.05). Those at risk of malnutrition were approximately 8 times more likely to be frail than those with no risk. Significant differences in nutrient intake were found between those at risk of malnourishment and those without risk, specifically in: protein, PUFA n-3, retinol, ascorbic acid, niacin equivalents, folic acid, magnesium, and potassium, respectively. Moreover, differences in alcohol were also observed showing higher intake for those at risk of malnourishment (all p < 0.05). In conclusion, nutrients related to muscle metabolism showed to have different intakes across SPPB physical function groups. The intake of these specific nutrients related with risk of malnourishment need to be promoted in order to prevent frailty

Application of Quality by Design to the robust preparation of a liposomal GLA formulation by DELOS-susp method

Fabry disease is a lysosomal storage disease arising from a deficiency of the enzyme α-galactosidase A (GLA). The enzyme deficiency results in an accumulation of glycolipids, which over time, leads to cardiovascular, cerebrovascular, and renal disease, ultimately leading to death in the fourth or fifth decade of life. Currently, lysosomal storage disorders are treated by enzyme replacement therapy (ERT) through the direct administration of the missing enzyme to the patients. In view of their advantages as drug delivery systems, liposomes are increasingly being researched and utilized in the pharmaceutical, food and cosmetic industries, but one of the main barriers to market is their scalability. Depressurization of an Expanded Liquid Organic Solution into aqueous solution (DELOS-susp) is a compressed fluid-based method that allows the reproducible and scalable production of nanovesicular systems with remarkable physicochemical characteristics, in terms of homogeneity, morphology, and particle size. The objective of this work was to optimize and reach a suitable formulation for in vivo preclinical studies by implementing a Quality by Design (QbD) approach, a methodology recommended by the FDA and the EMA to develop robust drug manufacturing and control methods, to the preparation of α-galactosidase-loaded nanoliposomes (nanoGLA) for the treatment of Fabry disease. Through a risk analysis and a Design of Experiments (DoE), we obtained the Design Space in which GLA concentration and lipid concentration were found as critical parameters for achieving a stable nanoformulation. This Design Space allowed the optimization of the process to produce a nanoformulation suitable for in vivo preclinical testing

Treatment variability and its relationships to outcomes among patients with Wernicke's encephalopathy: A multicenter retrospective study

Background: Despite guidelines and recommendations, Wernicke's encephalopathy (WE) treatment lacks evidence, leading to clinical practice variability.Aims: Given the overall lack of information on thiamine use for WE treatment, we analyzed data from a large, well-characterized multicenter sample of patients with WE, examining thiamine dosages; factors associated with the use of different doses, frequencies, and routes; and the influence of differences in thiamine treatment on the outcome.Methods: This retrospective study was conducted with data from 443 patients from 21 centers obtained from a nationwide registry of the Spanish Society of Internal Medicine (from 2000 to 2012). Discharge codes and Caine criteria were applied for WE diagnosis, and treatment-related (thiamine dosage, frequency, and route of administration) demographic, clinical, and outcome variables were analyzed.Results: We found marked variability in WE treatment and a low rate of high-dose intravenous thiamine administration. Seventy-eight patients out of 373 (20.9%) received > 300 mg/day of thiamine as initial dose. Patients fulfilling the Caine criteria or presenting with the classic WE triad more frequently received parenteral treatment. Delayed diagnosis (after 24 h hospitalization), the fulfillment of more than two Caine criteria at diagnosis, mental status alterations, and folic acid deficiency were associated significantly with the lack of complete recovery. Malnutrition, reduced consciousness, folic acid deficiency, and the lack of timely thiamine treatment were risk factors for mortality.Conclusions: Our results clearly show extreme variability in thiamine dosages and routes used in the management of WE. Measures should be implemented to ensure adherence to current guidelines and to correct potential nutritional deficits in patients with alcohol use disorders or other risk factors for WE

Long runs of homozygosity are associated with Alzheimer's disease

Altres ajuts: The Genome Research at Fundació ACE project (GR@ACE) is supported by Fundación bancaria "La Caixa," Grifols SA and Fundació ACE. L.M.R. is supported by Consejería de Salud de la Junta de Andalucía (Grant PI-0001/2017).Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [ β (CI 95%) = 0.070 (0.037-0.104); P = 3.91 × 10 −5 ; β (CI95%) = 0.043 (0.009-0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10 −16). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10 −4), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability

Safety and preliminary efficacy on cognitive performance and adaptive functionality of epigallocatechin gallate (EGCG) in children with Down syndrome. A randomized phase Ib clinical trial (PERSEUS study)

Purpose: Although some caregivers are using epigallocatechin gallate (EGCG) off label in hopes of improving cognition in young adults with Down syndrome (DS), nothing is known about its safety, tolerability, and efficacy in the DS pediatric population. We aimed to evaluate safety and tolerability of a dietary supplement containing EGCG and if EGCG improves cognitive and functional performance. Methods: A total of 73 children with DS (aged 6-12 years) were randomized. Participants received 0.5% EGCG (10 mg/kg daily dose) or placebo for 6 months with 3 months follow up after treatment discontinuation. Results: In total, 72 children were treated and 66 completed the study. A total of 38 participants were included in the EGCG group and 35 in the placebo group. Of 72 treated participants, 62 (86%) had 229 treatment-emergent adverse events (AEs). Of 37 participants in the EGCG group, 13 (35%) had 18 drug-related treatment-emergent AEs and 12 of 35 (34%) from the placebo group had 22 events. In the EGCG group, neither severe AEs nor increase in the incidence of AEs related to safety biomarkers were observed. Cognition and functionality were not improved compared with placebo. Secondary efficacy outcomes in girls point to a need for future work. Conclusion: The use of EGCG is safe and well-tolerated in children with DS, but efficacy results do not support its use in this population. (C) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks : The GR@ACE project

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series