An Integrative Decision-Making Mechanism for Consumers’ Brand Selection using 2-Tuple Fuzzy Linguistic Perceptions and Decision Heuristics

Consumers perform decision-making (DM) processes to select their preferred brands during their entire consumer journeys. These DM processes are based on the multiple perceptions they have about the products available in the market they are aware of. These consumers usually perform different DM strategies and employ diverse heuristics depending on the nature of the purchase, ranging from more pure optimal choices to faster decisions. Therefore, the design of realistic DM approaches for modeling these consumer behaviors requires a good representation of consumer perceptions and a reliable process for integrating their corresponding heuristics. In this work, we use fuzzy linguistic information to represent consumer perceptions and propose four consumer DM heuristics to model the qualitative linguistic information for the consumer buying decision. In particular, we use 2-tuple fuzzy linguistic variables, which is a substantially more natural and realistic representation without falling in a loss of information. The set of selected heuristics differ in the degree of involvement the consumers give to their decisions. Additionally, we propose a heuristic selection mechanism to integrate the four heuristics in a single DM procedure by using a regulation parameter. Our experimental analysis shows that the combination of these heuristics in a portfolio manner improves the performance of our model with a realistic representation of consumer perceptions. The model’s outcome matches the expected behavior of the consumers in several real market scenarios

Genomics improves risk stratification of adults with T-cell acute lymphoblastic leukemia enrolled in measurable residual disease-oriented trials

Genomics; T-cell acute lymphoblastic leukemiaGenòmica; leucèmia limfoblàstica aguda de cèl·lules TGenómica; Leucemia linfoblástica aguda de células TGenetic information has been crucial to understand the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) at diagnosis and at relapse, but still nowadays has a limited value in a clinical context. Few genetic markers are associated with the outcome of T-ALL patients, independently of measurable residual disease (MRD) status after therapy. In addition, the prognostic relevance of genetic features may be modulated by the specific treatment used. We analyzed the genetic profile of 145 T-ALL patients by targeted deep sequencing. Genomic information was integrated with the clinicalbiological and survival data of a subset of 116 adult patients enrolled in two consecutive MRD-oriented trials of the Spanish PETHEMA (Programa Español de Tratamientos en Hematología) group. Genetic analysis revealed a mutational profile defined by DNMT3A/ N/KRAS/ MSH2/ U2AF1 gene mutations that identified refractory/resistant patients. Mutations in the DMNT3A gene were also found in the non-leukemic cell fraction of patients with T-ALL, revealing a possible mutational-driven clonal hematopoiesis event to prime T-ALL in elderly. The prognostic impact of this adverse genetic profile was independent of MRD status on day +35 of induction therapy. The combined worse-outcome genetic signature and MRD on day +35 allowed risk stratification of T-ALL into standard or high-risk groups with significantly different 5- year overall survival (OS) of 52% (95% confidence interval: 37-67) and 17% (95% confidence interval: 1-33), respectively. These results confirm the relevance of the tumor genetic profile in predicting patient outcome in adult T-ALL and highlight the need for novel gene-targeted chemotherapeutic schedules to improve the OS of poor-prognosis T-ALL patients.This project was supported by the AECC (GC16173697BIGA); ISCIII (PI19/01828 and PI19/01183), co-funded by ERDF/ESF, "A way to make Europe"/"Investing in your future", CERCA/Generalitat de Catalunya SGR 2017 288 (GRC)/ “La Caixa”. C Gon-zález-Gil was supported by AGAUR grant (ref: 2020 FI_B2 00210)

A new nanomedicine platform to deliver a carnitine palmitoyl-transferase 1 (CPT1) inhibitor into glioma cells and neurons

Obesity and glioblastoma multiforme (GB) are two unmet medical needs where effective therapies are lacking. Carnitine palmitoyl transferase 1 (CPT1), an enzyme catalyzing the rate-lim- iting step in fatty acid oxidation (FAO), is a viable target for both diseases. C75, a fatty acid synthase (FAS) inhibitor, forms an adduct with coenzyme A (CoA) to form C75-CoA, which is a strong com- petitive inhibitor to CPT1 that is selective in its target. However, it is polar and charged, having low cell membrane permeability, and therefore needing a delivery system for intracellular transport. (±)-C75-CoA and its enantio-separated forms (+)- and (−)-C75-CoA were used to form poly-ion com- plex (PIC) micelles with the cationic block co-polymer PEG-PAsp(DET). The drug and polymer were mixed in a 1:1 anion/cation ratio to give 50-70 nm micelles with a unimodal size profile and narrow polydispersity. Size was maintained upon introduction of physiological saline. Micellar (±)-, (+)-, and (−)-C75-CoA were all significantly more cytotoxic compared to the respective free drugs in U87MG. We examined whether C75-CoA inhibits FAO by measuring ATP concentrations in U87MG and GT1-7. ATP generation was found to be hampered after adding C75-CoA in both cell types, with micelle-treated cells producing significantly lower ATP than those treated with free drug, suggesting that the effective intracellular delivery of C75-CoA leads to a more pronounced FAO inhibition. A fluorescent CoA derivative, Fluor-CoA, also yielded monodisperse micelles sim- ilar to C75-CoA. Micellar internalization was significantly greater than that of the free dye. Uptake of both increased with time, with this effect is more pronounced in U87MG than GT1-7. The %Fluor- CoA+ cells were also expressively higher for the micelle across cell lines. From this data, it can be convincingly concluded that neuronal and glioma cellular uptake of micelles is superior to that of the free dye, validating the need for cellular delivery systems for anionic, CoA-type molecules. The micellar form neutralized the negative charge of the cargo, promoting transport into the cell. These outcomes strongly support the effectiveness of using a PIC micelle-type system to deliver anionic small molecules into glioma cells and neurons meant to inhibit enzymes such as CPT1, for future applications in diseases like obesity and cancer

Comportamiento agronómico de seis genotipos de Cannabis sp. no psicoactivo bajo invernadero, en el intertrópico andino alto de Colombia: Agronomic behavior of six non-psychoactive Cannabis sp. genotypes under greenhouse in the high Andean tropics of Colombia

Within the framework of Decree 613 of 2017, which regulates Law 1787 of 2017, the legal production of cannabis for medical and scientific use begins in Colombia. As it is a crop with no legal history in the country, it is necessary to carry out an agronomic evaluation test (AET), through which its stability in a determined subregion is demonstrated, during a complete cycle. This study presents the results of a AET carried out in the Andean zone of moderate cold (from 1800 to 2200 m asl) in the eastern department of Antioquia, Colombia, under plastic cover, with six genotypes of non-psychoactive cannabis (THC < 1%) pre-existing in the seed source registered with the ICA. The evaluation was carried out between September 30, 2019 and January 15, 2020. The genotypes were spatially distributed based on a randomized complete block design, with three replicates per genotype and 20 plants per experimental unit, planted at a density of four plants per square meter. The total fresh biomass (stem, leaves and inflorescences) per square meter presented a general average of 3525.62 g, of which 775.42 g (22 %) corresponded to the flowers. The flowers had an average content of 10.70% CBD and 0.47% THC. These materials are classified as non-psychoactive, in accordance with Colombian regulations, and can therefore be used for any of the purposes established in Section 5 of Decree 613 of 2017.En el marco del Decreto 613 de 2017, que reglamenta la Ley 1787 de 2017, se da inicio en Colombia a la producción legal del cannabis para uso médico y científico. Al tratarse de un cultivo sin historial legal en el país, es necesario realizar una prueba de evaluación agronómica (pea), mediante la cual se demuestre su estabilidad en una subregión determinada, durante un ciclo completo. Este estudio presenta los resultados de una pea realizada en la zona andina de frío moderado (de 1800 a 2200 m s.n.m.) del oriente del departamento de Antioquia, Colombia, bajo cubierta plástica, con seis genotipos de cannabis no psicoactivo (thc < 1 %) preexistentes en la fuente semillera registrada ante el ica. La evaluación se desarrolló entre el 30 de septiembre del 2019 y el 15 de enero del 2020. Los genotipos se distribuyeron espacialmente con base en un esquema de aleatorización de bloques completos al azar, con tres réplicas por genotipo y 20 plantas por unidad experimental, sembradas a una densidad de cuatro plantas por metro cuadrado. La biomasa total fresca (tallo, hojas e inflorescencias) por metro cuadrado presentó una media general de 3525,62 g, de los cuales 775,42 g (22 %) correspondieron a las flores. Las flores presentaron un contenido promedio de 10,70 % de cbd y 0,47 % de thc. Estos materiales clasifican como no psicoactivos, acorde con la normatividad colombiana, pudiendo destinarse, por tanto, a cualquiera de las finalidades que establece la sección 5 del Decreto 613 de 2017.

An overview of nanomedicines for neuron targeting

Medical treatments of neuron-related disorders are limited due to the difficulty of targeting brain cells. Major drawbacks are the presence of the blood-brain barrier and the lack of specificity of the drugs for the diseased cells. Nanomedicine-based approaches provide promising opportunities for overcoming these limitations. Although many previous reviews are focused on brain targeting with nanomedicines in general, none of those are concerned explicitly on the neurons, while targeting neuronal cells in central nervous diseases is now one of the biggest challenges in nanomedicine and neuroscience. We review the most relevant advances in nanomedicine design and strategies for neuronal drug delivery that might successfully bridge the gap between laboratory and bedside treatment in neurology

Evolution of the Use of Corticosteroids for the Treatment of Hospitalised COVID-19 Patients in Spain between March and November 2020: SEMI-COVID National Registry

Objectives: Since the results of the RECOVERY trial, WHO recommendations about the use of corticosteroids (CTs) in COVID-19 have changed. The aim of the study is to analyse the evolutive use of CTs in Spain during the pandemic to assess the potential influence of new recommendations. Material and methods: A retrospective, descriptive, and observational study was conducted on adults hospitalised due to COVID-19 in Spain who were included in the SEMI-COVID-19 Registry from March to November 2020. Results: CTs were used in 6053 (36.21%) of the included patients. The patients were older (mean (SD)) (69.6 (14.6) vs. 66.0 (16.8) years; p < 0.001), with hypertension (57.0% vs. 47.7%; p < 0.001), obesity (26.4% vs. 19.3%; p < 0.0001), and multimorbidity prevalence (20.6% vs. 16.1%; p < 0.001). These patients had higher values (mean (95% CI)) of C-reactive protein (CRP) (86 (32.7-160) vs. 49.3 (16-109) mg/dL; p < 0.001), ferritin (791 (393-1534) vs. 470 (236-996) mu g/dL; p < 0.001), D dimer (750 (430-1400) vs. 617 (345-1180) mu g/dL; p < 0.001), and lower Sp0(2)/Fi0(2) (266 (91.1) vs. 301 (101); p < 0.001). Since June 2020, there was an increment in the use of CTs (March vs. September; p < 0.001). Overall, 20% did not receive steroids, and 40% received less than 200 mg accumulated prednisone equivalent dose (APED). Severe patients are treated with higher doses. The mortality benefit was observed in patients with oxygen saturation </=90%. Conclusions: Patients with greater comorbidity, severity, and inflammatory markers were those treated with CTs. In severe patients, there is a trend towards the use of higher doses. The mortality benefit was observed in patients with oxygen saturation </=90%

Genomics improves risk stratifi cation of adults with T-cell acute lymphoblastic leukemia enrolled in measurable residual disease-oriented trials

Genetic information has been crucial to understand the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) at diagnosis and at relapse, but still nowadays has a limited value in a clinical context. Few genetic markers are associated with the outcome of T-ALL patients, independently of measurable residual disease (MRD) status after therapy. In addition, the prognostic relevance of genetic features may be modulated by the specific treatment used. We analyzed the genetic profile of 145 T-ALL patients by targeted deep sequencing. Genomic information was integrated with the clinical -biological and survival data of a subset of 116 adult patients enrolled in two consecutive MRD-oriented trials of the Spanish PETHEMA (Programa Espanol de Tratamientos en Hematologia) group. Genetic analysis revealed a mutational profile defined by DNMT3A/ N/KRAS/ MSH2/ U2AF1 gene mutations that identified refractory/resistant patients. Mutations in the DMNT3A gene were also found in the non-leukemic cell fraction of patients with T-ALL, revealing a possible mutational-driven clonal hematopoiesis event to prime T-ALL in elderly. The prognostic impact of this adverse genetic profile was independent of MRD status on day +35 of induction therapy. The combined worse-outcome genetic signature and MRD on day +35 allowed risk stratification of T-ALL into standard or high-risk groups with significantly different 5 -year overall survival (OS) of 52% (95% confidence interval: 37-67) and 17% (95% confidence interval: 1-33), respectively. These results confirm the relevance of the tumor genetic profile in predicting patient outcome in adult T-ALL and highlight the need for novel gene-targeted chemotherapeutic schedules to improve the OS of poor-prognosis T-ALL patients

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions

Development of C75-CoA loaded polymeric micelles targeting brain CPT1A: A novel nanomedicine-based approach to fight obesity and cancer

Brain lipid metabolism has a key role in many physiological processes, and its malfunction is associated with a plethora of diseases, such as obesity and glioblastoma multiforme (GBM). Carnitine palmitoyl transferase 1A (CPT1A), an important protein in the fatty acid oxidation (FAO) pathway, has a prominent role in this association. In the brain, activation of CPT1A in hypothalamic neurons increases food intake and body weight in mice, while its inhibition causes the opposite effect, indicating its antiobesity potential. In GBM cells, overexpression of CPT1A and other lipid metabolism proteins has been described as a crucial pathway for GBM cell survival. Then, pharmacological inhibition of CPT1A and therefore fatty acid oxidation, could constitute a promising treatment for these diseases. However, targeting CPT1A in brain cells is difficult to reach with the current formulations in vivo. The racemic drug Compound 75 (C75) is a well-known CPT1A inhibitor when conjugated with Coenzyme A, but with important constraints such as polarity and low cell-permeability that limit the cellular uptake

Parallel G-quadruplex Structures Increase Cellular Uptake and Cytotoxicity of 5-Fluoro-2¿-deoxyuridine Oligomers in 5-Fluorouracil Resistant Cells

Introduction: Cancer is currently one of the world¿s leading causes of death and 5-Fluorouracil is one of the most successful drugs used in chemotherapy. It is internalized and metabolized producing different active compounds which interfere in multiple critical cellular processes. Although, cells can become immune to this drug mainly by increasing 5-FU catabolism or by scaling the rate of dTMP biosynthesis. Aptamers have proved to be very attractive as therapeutic agents. G-rich oligonucleotides adapt the structure of a G-quadruplex motif, which is further stabilized by monovalent cations. G-quadruplexes recognized selectively different protein targets in cancer cells what make aptamers very helpful for targeting and drug delivery. Objective: Synthesis of G-rich oligonucleotides attatched with FdU, stability studies and cellular activity in different cancer cells lines. Results: The presence of (FdU)5 at the 5¿-termini didn¿t disrupt the formation of the parallel G-quadruplex. The G-quadruplex facilitated the internalization of the FdU oligomers increasing the cytotoxic properties of its. More FdU attach to the same nanocarrier is advantageous in more FdU resistance colorectal cancer lines Conclusions: The G-quadruplex formation has a clear benefit for the antitumoral activity of these antimetabolite nucleosides that most probably comes from the cellular uptake throw cancer protein receptors