Role of fatty acid amide hydrolase in adult mammary gland development and breast cancer

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, leída el 11-03-2022El cáncer de mama es el cáncer más frecuente en el mundo. Según el Observatorio Global de Cáncer de la Organización Mundial de la Salud, en 2020 se diagnosticaron más de 2.3 millones de nuevos casos, superando por primera vez al cáncer de pulmón en incidencia. Gracias al diagnóstico precoz y a la aparición de terapias dirigidas para los subtipos mayoritarios, el pronóstico de las pacientes con cáncer de mama en etapa temprana ha mejorado notablemente en los últimos años. Sin embargo, la existencia de subtipos tumorales con una biología más agresiva para las cuales no existe terapia dirigida o que presentan resistencia a las terapias convencionales supone un desafío clínico no resuelto. Por otro lado, la enfermedad metastásica afecta a un 30 % de las pacientes y, aunque es potencialmente tratable, a día de hoy se considera incurable. Todo esto hace necesaria la búsqueda de nuevas terapias, así como de nuevas herramientas de cribado que identifiquen a las pacientes con mayor probabilidad de sufrir una enfermedad más agresiva y permitan adaptar su manejo clínico. En este contexto, conocer los mecanismos moleculares que gobiernan el desarrollo de la glándula mamaria adulta y que se ven alterados durante la formación y progresión del cáncer de mama puede resultar de extrema utilidad para entender la biología que subyace a los fenotipos tumorales más agresivos y así poder desarrollar nuevas herramientas para su abordaje en la clínica...Breast cancer is the most common cancer worldwide. According to the Global Cancer Observatory of the World Health Organization, more than 2.3 million new cases were diagnosed in 2020, surpassing lung cancer in incidence for the first time. Thanks to early diagnosis and the development of targeted therapies for the most prevalent subtypes, the prognosis of early-stage breast cancer patients has notably improved in recent years. However, the existence of tumor subtypes with a more aggressive biology for which there is no targeted therapy or that are resistant to conventional therapies represents an unresolved clinical challenge. On the other hand, metastatic disease affects 30 % of patients and, although potentially treatable, is currently considered incurable. All of this makes necessary to seek for new therapies, as well as new screening tools that identify patients with a greater probability of suffering a more aggressive form of the disease and help clinical decisions. In this context, knowing the molecular mechanisms that govern the development of the adult mammary gland and that are altered during the formation and progression of breast cancer can be extremely useful to understand the biology that underlies the most aggressive tumor phenotypes and thus, to be able to develop new tools for its clinical management...Fac. de Ciencias QuímicasTRUEunpu

Identification of fatty acid amide hydrolase as a metastasis suppressor in breast cancer

Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiere, y los autores pertenecientes a la UAMClinical management of breast cancer (BC) metastasis remains an unmet need as it accounts for 90% of BC-associated mortality. Although the luminal subtype, which represents >70% of BC cases, is generally associated with a favorable outcome, it is susceptible to metastatic relapse as late as 15 years after treatment discontinuation. Seeking therapeutic approaches as well as screening tools to properly identify those patients with a higher risk of recurrence is therefore essential. Here, we report that the lipid-degrading enzyme fatty acid amide hydrolase (FAAH) is a predictor of long-term survival in patients with luminal BC, and that it blocks tumor progression and lung metastasis in cell and mouse models of BC. Together, our findings highlight the potential of FAAH as a biomarker with prognostic value in luminal BC and as a therapeutic target in metastatic diseas

Medical versus surgical approach to initial treatment in septic arthritis: A single spanish center’s 8-year experience

Objective The aim of this study was to compare the functional results of 2 different procedure types, medical or surgical used in treating native joint septic arthritis. Methods In this cohort study, we reviewed the clinical registries of patients admitted to a single third-level hospital with the diagnosis of septic arthritis during the period of January 1, 2008, to January 31, 2016. Results A total of 63 cases of septic arthritis were identified in which the initial approach for 49 patients was medical (arthrocentesis), whereas the initial approach for 14 patients was surgical (arthroscopy or arthrotomy). Of the 49 patients who received initial medical treatment (IMT), 15 patients (30%) later required surgical treatment because of poor progress. The median age of the patients was 60 (SD, 18) years. The group who received IMT were older than those who received initial surgical treatment (median, 64 years [interquartile range {IQR}, 54–76 years], vs. 48 years [IQR, 30–60 years]). There was a larger percentage of male patients in the surgical group (78% vs. 42% [p = 0.018]). Thirty percent of the medical group had been receiving corticosteroid treatment (p = 0.018). Results of complete recovery of joint functionality showed no significant differences after 1 year (68% with MT vs. 67% with ST, p = 0.91). Both groups had similar symptom duration until diagnosis, duration of antibiotic therapy (median, 30 days [IQR, 28–49 days], vs. 29.5 days [IQR, 27–49] days), and mortality rate (3 in the medical group). Conclusions The results of the study show that initial surgical treatment in patients with native joint septic arthritis is not superior to IMT. However, half of the patients with shoulder and hip infections treated with IMT eventually required surgical intervention, suggesting that perhaps this should be the preferred initial approach in these cases

Vacuna emocional en la Covid-19: programa de autocuidado para personas mayores

The group of elderly people is one of the most affected by this pandemic. It is considered a risk group and age is a relevant factor in the body’s response to COVID-19. To face this situation and disease, it is important that people take care of themselves at a biopsychosocial level. The aim of this paper is to present a self-care and psychological activation program: “Emotional Vaccine for COVID-19”. It is aimed at elderly people without or with mild cognitive impairment, individually or in groups, in different environments: residential, home, day center, etc., assessing the effect of this program in the improvement of their quality of life, distinguishing between rural and urban contexts. The program consists of 10 sessions of one hour and a half, held twice a week. In each session, a self-care guideline is worked on through a message in the form of a saying that facilitates mnesic activation. From the Acceptance and Commitment Therapy and following the paradigm of the Attention Centered on what is Important for the Person, emotional management, cognitive stimulation and behavioral activation are addressed in order to produce better coping strategies for the current situation. The life project of each participant is emphasized through orientation to values. Using a quasi-experimental pre-post design with a control group, the following instruments are used: behavioral records, scales and questionnaires that measure quality of life, anxiety, depression and experiential avoidance. An improvement in health and well-being through psychological activation is expected in the target sample with respect to the control group. The need for this type of psychological intervention in the gerontological field is highlighted due to its feasibility, efficacy and social demand.El colectivo de personas mayores es uno de los más afectados por esta pandemia. Es considerado grupo de riesgo y la edad es un factor relevante en la respuesta que da el organismo frente a la Covid-19. Para afrontar esta situación y esta enfermedad es importante que las personas se cuiden a nivel biopsicosocial. El presente trabajo tiene como fin exponer un programa de autocuidado y de activación psicológica: “Vacuna Emocional para la COVID-19”. Dirigido a personas mayores sin o con deterioro cognitivo leve, de manera individual o grupal, en diferentes entornos: residencial, domiciliario, centro de día, etc., valorando el efecto de este programa en la mejora de su calidad de vida, distinguiendo entre contextos rurales y urbanos. El programa consta de 10 sesiones de una hora y media de duración aplicándose dos sesiones semanales. En cada sesión se trabaja una pauta de autocuidado a través de un mensaje con forma de refrán que facilita la activación mnésica. Desde la Terapia de Aceptación y Compromiso y siguiendo el paradigma de la Atención Centrada en lo Importante para la Persona, se aborda la gestión emocional, la estimulación cognitiva y la activación conductual de manera que se produzca un mejor afrontamiento de la situación actual. Se enfatiza el proyecto de vida de cada participante a través de la orientación en valores. Utilizando un diseño cuasiexperimental pre-post con grupo control, se emplean los instrumentos: registros conductuales, escalas y cuestionarios que midan calidad de vida, ansiedad, depresión y evitación experiencial. Se espera una mejora en la salud y bienestar a través de la activación psicológica en la muestra diana respecto al grupo control. Se destaca la necesidad de este tipo de intervención psicológica en el ámbito gerontológico por su viabilidad, eficacia y demanda social.

Therapeutic targeting of HER2–CB2R heteromers in HER2-positive breast cancer

There is a subtype of breast cancer characterized by the overexpression of the oncogene HER2. Although most patients with this diagnosis benefit from HER2-targeted treatments, some do not respond to these therapies and others develop resistance with time. New tools are therefore warranted for the treatment of this patient population, and for early identification of those individuals at a higher risk of developing innate or acquired resistance to current treatments. Here, we show that HER2 forms heteromer complexes with the cannabinoid receptor CB2R, the expression of these structures correlates with poor patient prognosis, and their disruption promotes antitumor responses. Collectively, our results support HER2–CB2R heteromers as new therapeutic targets and prognostic tools in HER2+ breast cancer

Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial.

BACKGROUND: Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes. METHODS: In this multicentre, open-label, randomised controlled trial, we recruited women aged 18-40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallel for pregnant participants and for participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin (HbA1c). The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments. Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation. This trial is registered with ClinicalTrials.gov, number NCT01788527. FINDINGS: Between March 25, 2013, and March 22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy). We found a small difference in HbA1c in pregnant women using CGM (mean difference -0·19%; 95% CI -0·34 to -0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM, five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy). INTERPRETATION: Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use. FUNDING: Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research

La producción de la Universidad española en Química reflejada en publicaciones españolas y extranjeras

[ES] Se analiza la producción de la Universidad española en el campo de la Química, en el periodo 1990-91, utilizando Chemical Abstracts como base de datos internacional e ICYT como base de datos nacional; que recoge exhaustivamente todo lo publicado en revistas españolas. La comparación entre ambas series de datos permite deducir tendencias de publicación en el extranjero, así como datos sobre la difusión internacional de la literatura publicada en España.[EN] The scientific production of Spanish Universities in the field of Cbemistry is analyzed for the period 1990-91. Data are obtained from Chemical Abstracts, as international database, and from ICYT as national database, which is compreheusive for articles published in Spanish journals. Comparison between both series of data permits lo draw conclusions on trends to publish abroad, as ivell as on the international diffusion of the literature published in Spain.Peer reviewe

Transglycosylation products generated by Talaromyces amestolkiae GH3 β-glucosidases: effect of hydroxytyrosol, vanillin and its glucosides on breast cancer cells

[Background] Transglycosylation represents one of the most promising approaches for obtaining novel glycosides, and plant phenols and polyphenols are emerging as one of the best targets for creating new molecules with enhanced capacities. These compounds can be found in diet and exhibit a wide range of bioactivities, such as antioxidant, antihypertensive, antitumor, neuroprotective and anti-inflammatory, and the eco-friendly synthesis of glycosides from these molecules can be a suitable alternative for increasing their health benefits.[Results] Transglycosylation experiments were carried out using different GH3 β-glucosidases from the fungus Talaromyces amestolkiae. After a first screening with a wide variety of potential transglycosylation acceptors, mono-glucosylated derivatives of hydroxytyrosol, vanillin alcohol, 4-hydroxybenzyl alcohol, and hydroquinone were detected. The reaction products were analyzed by thin-layer chromatography, high-pressure liquid chromatography, and mass spectrometry. Hydroxytyrosol and vanillyl alcohol were selected as the best options for transglycosylation optimization, with a final conversion yield of 13.8 and 19% of hydroxytyrosol and vanillin glucosides, respectively. NMR analysis confirmed the structures of these compounds. The evaluation of the biological effect of these glucosides using models of breast cancer cells, showed an enhancement in the anti-proliferative capacity of the vanillin derivative, and an improved safety profile of both glucosides.[Conclusions] GH3 β-glucosidases from T. amestolkiae expressed in P. pastoris were able to transglycosylate a wide variety of acceptors. Between them, phenolic molecules like hydroxytyrosol, vanillin alcohol, 4-hydroxybenzyl alcohol, and hydroquinone were the most suitable for its interesting biological properties. The glycosides of hydroxytyrosol and vanillin were tested, and they improved the biological activities of the original aglycons on breast cancer cells.Peer reviewe

Análisis de la producción científica española en ecología y medio ambiente 1989-1993

[ES] Para el estudio de la producción científica española en Ecologia y Medio Ambiente se utilizan cuatro bases de datos: una nacional, ICYT, para lo publicado en revistas españolas, y tres internacionales, Chemical Abstracts, Biosis y ASFA, para lo que se publica en revistas extranjeras. En ambos casos se analiza la distribución temática de los trabajos en cuatro grandes apartados incluidos en el Programa Nacional de Medio Ambiente y Recursos Naturales: Degradación ambiental; Conservación del Medio Ambiente; Tecnologías medioambientales; y Funcionamiento y Dinámica de Ecosistemas. Asimismo, se analiza el origen institucional de los trabajos, su distribución geográfica y las revistas más utilizadas, ianto nacionales como extranjeras. La alta participación de la Universidad, que representa dos tercios del total, justifica un estudio especial de su contribución, tanto por tipos de centros (Facultades y Escuelas Técnicas) como por universidades.[EN] For databases have beeu used to analyze Spanish scientific production in Ecoíog~a. nd Environmeiit: ICYT, a domestic database, for those works published in Spanish joumals, and three intemational databases, Chemical Abstracts, Biosis and ASFA, for articles published in foreign joumals. For both series, a subject distribution is made, accord'ig lo four broad headlies included in the National Programme on Environment and Natural Resources: Environmental destniction; Environmental presemation; Environmental Technologies; and Dynamics of Ecosystems. Corporate sources of the articles are also analyzed, as well as their geogmphic distribution and the most frequently used joumals. The high participation of universities (over iwo thiids of total articles) justifies a more detailed study of this institutional sector.Peer reviewe

Identification of fatty acid amide hydrolase as a metastasis suppressor in breast cancer

Abstract Clinical management of breast cancer (BC) metastasis remains an unmet need as it accounts for 90% of BC-associated mortality. Although the luminal subtype, which represents >70% of BC cases, is generally associated with a favorable outcome, it is susceptible to metastatic relapse as late as 15 years after treatment discontinuation. Seeking therapeutic approaches as well as screening tools to properly identify those patients with a higher risk of recurrence is therefore essential. Here, we report that the lipid-degrading enzyme fatty acid amide hydrolase (FAAH) is a predictor of long-term survival in patients with luminal BC, and that it blocks tumor progression and lung metastasis in cell and mouse models of BC. Together, our findings highlight the potential of FAAH as a biomarker with prognostic value in luminal BC and as a therapeutic target in metastatic disease