Glucose metabolism links astroglial mitochondria to cannabinoid effects.

Astrocytes take up glucose from the bloodstream to provide energy to the brain, thereby allowing neuronal activity and behavioural responses1-5. By contrast, astrocytes are under neuronal control through specific neurotransmitter receptors5-7. However, whether the activation of astroglial receptors can directly regulate cellular glucose metabolism to eventually modulate behavioural responses is unclear. Here we show that activation of mouse astroglial type-1 cannabinoid receptors associated with mitochondrial membranes (mtCB1) hampers the metabolism of glucose and the production of lactate in the brain, resulting in altered neuronal functions and, in turn, impaired behavioural responses in social interaction assays. Specifically, activation of astroglial mtCB1 receptors reduces the phosphorylation of the mitochondrial complex I subunit NDUFS4, which decreases the stability and activity of complex I. This leads to a reduction in the generation of reactive oxygen species by astrocytes and affects the glycolytic production of lactate through the hypoxia-inducible factor 1 pathway, eventually resulting in neuronal redox stress and impairment of behavioural responses in social interaction assays. Genetic and pharmacological correction of each of these effects abolishes the effect of cannabinoid treatment on the observed behaviour. These findings suggest that mtCB1 receptor signalling can directly regulate astroglial glucose metabolism to fine-tune neuronal activity and behaviour in mice.

Comorbidities and use of health services in people with diabetes mellitus according to risk levels by adjusted morbidity groups.

BACKGROUND: People with diabetes mellitus frequently have other comorbidities and involve greater use of primary and hospital care services. The aim of this study was to describe the comorbidities and use of primary and hospital care services of people with diabetes according to their risk level by adjusted morbidity groups (AMG) and to analyse the factors associated with the utilisation of these services. METHODS: Cross-sectional study. People with diabetes were identified within the population of patients with chronic conditions of an urban health care centre by the AMG stratification tool integrated into the primary health care electronic clinical record of the Community of Madrid. Sociodemographic, functional, clinical characteristics and annual health care services utilisation variables were collected. Univariate, bivariate and Poisson regression analyses were performed. RESULTS: A total of 1,063 people with diabetes were identified, representing 10.8% of patients with chronic conditions within the health centre. A total of 51.4% were female, the mean age was 70 years, 94.4% had multimorbidity. According to their risk level, 17.8% were high-risk, 40.6% were medium-risk and 41.6% were low-risk. The most prevalent comorbidities were hypertension (70%), dyslipidaemia (67%) and obesity (32.4%). Almost 50% were polymedicated. Regarding health services utilisation, 94% were users of primary care, and 59.3% were users of hospital care. Among the main factors associated with the utilisation of both primary and hospital care services were AMG risk level and complexity index. In primary care, utilisation was also associated with the need for primary caregivers, palliative care and comorbidities such as chronic heart failure and polymedication, while in hospital care, utilisation was also associated with comorbidities such as cancer, chronic obstructive pulmonary disease or depression. CONCLUSIONS: People with diabetes were older, with important needs for care, many associated comorbidities and polypharmacy that increased in parallel with the patient's risk level and complexity. The utilisation of primary and hospital care services was very high, being more frequent in primary care. Health services utilization were principally associated with functional factors related to the need of care and with clinical factors such as AMG medium and high-risk level, more complexity index, some serious comorbidities and polymedication.

A cannabinoid link between mitochondria and memory.

Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces amnesia in humans and animals, and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB1) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB1 receptors. Genetic exclusion of CB1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB1 receptors signal through intra-mitochondrial Gαi protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects of cannabinoids. Thus, the G protein-coupled mtCB1 receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.

Use of primary and hospital care health services by chronic patients according to risk level by adjusted morbidity groups.

BACKGROUND: Patients with chronic diseases have increased needs for assistance and care. The objective of this study was to describe the characteristics and use of primary care (PC) and hospital care (HC) health services by chronic patients according to risk level based on adjusted morbidity groups (AMG) and to analyze the associated factors. METHODS: Cross-sectional descriptive observational study. Patients from a basic health area classified as chronically ill by the AMG classification system of the Madrid PC electronic medical record were included. Sociodemographic, clinical-care characteristics (classified as predisposing factors or need factors) and service utilization variables were collected. Univariate, bivariate and simple linear regression analyses were performed. RESULTS: The sample consisted of 9866 chronic patients and 8332 (84.4%) used health services. Of these service users, 63% were women, mean age was 55.7 (SD = 20.8), 439 (5.3%) were high risk, 1746 (21.2%) were medium risk, and 6041(73.4%) were low risk. A total of 8226 (98.7%) were PC users, and 4284 (51.4%) were HC users. The average number of annual contacts with PC was 13.9 (SD = 15); the average number of contacts with HC was 4.8 (SD = 6.2). Predisposing factors associated with services utilization at both care levels were: age (B coefficient [BC] = 0.03 and 0.018, 95% CI = 0.017-0.052 and 0.008-0.028, respectively, for PC and HC) and Spanish origin (BC = 0.962 and 3.396, 95% CI = 0.198-1.726 and 2.722-4.070); need factors included: palliative care (BC = 10,492 and 5047; 95% CI = 6457-14,526 and 3098-6995), high risk (BC = 4631 and 2730, 95% CI = 3022-6241 and 1.949-3.512), number of chronic diseases (BC = 1.291 and 0.222, 95% CI = 1.068-1.51 and 0.103-0.341) and neoplasms (BC = 2.989 and 4.309, 95% CI = 1.659-4.319 and 3.629-4.989). CONCLUSIONS: The characteristics and PC and HC service utilization of chronic patients were different and varied according to their AMG risk level. There was greater use of PC services than HC services, although utilization of both levels of care was high. Service use was related to predisposing factors such as age and country of origin and, above all, to need factors such as immobility, high risk, and number and type of chronic diseases that require follow-up and palliative care.

Metabolic and Functional Improvements in a Patient with Charcot-Marie-Tooth Disease Type 2 after EGCG Administration: A Case Report.

Background and objectives: The aim of this study was to report a case of a patient with Charcot-Marie-Tooth disease type 2 (CMT2) treated with epigallocatechin gallate (EGCG) for 4 months in order to assess its therapeutic potential in CMT2. Materials and Methods: The study included a brother and a sister who have CMT2. The sister received 800 mg of EGCG for 4 months, while her brother received placebo for the same period of time. Both participants were assessed before and after daily administration by means of anthropometry; analysis of inflammatory and oxidation markers of interleukin-6 (IL-6) and paraoxonase 1 (PON1) in the blood sample; and motor tests: 2-min walk test (2MWT), 10-m walk test (10MWT), nine-hole peg test (9HPT) and handgrip strength measurement using a handheld Jamar dynamometer. Results: Regarding muscular and motor functions associated with higher inflammation and oxidation, improvements only observed in the woman in all analysed parameters (both biochemical and clinical associated with the metabolism and functionality) after 4 months of treatment with EGCG are noteworthy. Thus, this treatment is proposed as a good candidate to treat the disease.

Blocking Ras inhibition as an antitumor strategy.

Ras proteins are among the most frequently mutated drivers in human cancer and remain an elusive pharmaceutical targeting. Previous studies have improved the understanding of Ras structure, processing, and signaling pathways in cancer cells and have opened new possibilities for inhibiting Ras function. In this review we discuss the most recent advances towards inhibiting Ras activity with small molecules, highlighting the two approaches: (i) compounds that bind directly to Ras protein and (ii) inhibitors of the enzymes involved in the post-translational modifications of Ras. In the former, we analyze the most recent contributions in each of the main classes of Ras direct binders, including the different types of nucleotide exchange inhibitors, allosteric compounds, and molecules that interfere with the interaction between Ras and its effectors. In the latter, we examine the compounds that inhibit Ras activation by blocking any of its post-translational modifications. Also, a special focus is made on those molecules that have progressed the farthest from medicinal chemistry and drug development points of view. Finally, the current scene regarding the clinical trials of Ras inhibitors, together with the future promising avenues for further development of the challenging Ras field are reviewed.

Non-pharmacological interventions to improve constipation amongst older adults in long-term care settings: A systematic review of randomised controlled trials.

Constipation is a highly prevalent condition amongst older adults in long-term care settings and laxatives are not always the solution. We aimed to examine the characteristics and the effects of non-pharmacological interventions to improve constipation amongst older adults in long-term care settings. Eligible studies were identified using PubMed, CINAHL, Scopus, Web of Science, Cochrane and EMBASE (up to April 2019). We included 7 studies with a total of 657 patients. Five interventions improved the number of bowel movements (i.e. laxative tea, fermented oat drink, patient education, probiotics and multi-component intervention). The administration of probiotic capsules and fermented oat drinks also improved stool form. Auricular acupressure improved constipation symptoms and constipation-related quality of life. After appraising the trials' methodological quality and risk of bias, we cannot recommend any non-pharmacological interventions to improve constipation amongst older adults in long-term care settings until more robust studies have been conducted.

Dyadic and Solitary Sexual Desire in Patients With Fibromyalgia: A Controlled Study.

INTRODUCTION: Although fibromyalgia symptoms negatively affect patients' sexual life, sexual desire in women diagnosed with fibromyalgia has been understudied. AIM: To describe and compare sexual desire in women diagnosed with fibromyalgia and healthy control women, and to investigate the influence of fibromyalgia and its pharmacologic treatment on sexual desire among women diagnosed with fibromyalgia. METHODS: 164 women diagnosed with fibromyalgia participated in the study. Participants' sexual desire, fibromyalgia symptoms, symptom interference in daily life activities, and perceived quality of life were measured. Further sociodemographic and health-related data were also recorded. 87 healthy women were selected as a control group, and their sexual desire was compared with those of women diagnosed with fibromyalgia. MAIN OUTCOME MEASURES: Main outcome measures included the Sexual Desire Inventory and the Fibromyalgia Impact Questionnaire. RESULTS: When compared with healthy control subjects, women diagnosed with fibromyalgia exhibited a significantly lower mean score on total desire (47.92 ± 17.48 vs 26.33 ± 21.95; P < .001), solitary desire (10.52 ± 5.96 vs 5.74 ± 7.01; P < .001), and dyadic desire (37.40 ± 13.98 vs 20.59 ± 16.94; P < .001). Women diagnosed with fibromyalgia who were taking antidepressants scored significantly lower on dyadic desire (P < .001), solitary desire (P < .001), and total desire (P < .001) than those who were not. Furthermore, a negative correlation between desire (dyadic and solitary) and Revised Fibromyalgia Impact Questionnaire (total and all subscales) was found. Linear regression showed that taking antidepressants, age, and the total Fibromyalgia Impact Questionnaire score explained 16% of the variance of total desire. CLINICAL IMPLICATIONS: Knowing how fibromyalgia symptoms and their pharmacologic treatment affect women's sexual desire may have implications for designing care strategies according to individual needs. STRENGTHS & LIMITATIONS: To the best of our knowledge, this is the first study that focuses on studying the impact of fibromyalgia on dyadic and solitary sexual desire. Limitations are related to having used an online questionnaire for data collection, having recruited the participants through a convenience sampling technique and not being able to isolate whether certain results are related to fibromyalgia symptoms or are side effects of the pharmacologic treatment used for symptom control. CONCLUSION: Fibromyalgia impact seems to negatively influence dyadic and solitary sexual desire in women. In addition, other factors such as age or taking antidepressant drugs may result in lower sexual desire in these patients. López-Rodríguez MM, Pérez Fernández A, Hernández-Padilla JM, et al. Dyadic and Solitary Sexual Desire in Patients With Fibromyalgia: A Controlled Study. J Sex Med 2019;16:1518-1528.

Barriers to Providing Mother's Own Milk to Extremely Preterm Infants in the NICU.

BACKGROUND: Mothers' own milk (MOM) has more than nutritional benefits for extremely preterm infants (<28 weeks). However, mothers encounter barriers that make it difficult to provide their own milk to their extremely preterm infants. PURPOSE: The aim of this study was to describe and understand the experiences of mothers of extremely preterm infants regarding barriers to providing their own milk during infant hospital stay in the neonatal intensive care unit (NICU). METHODS: This study followed a qualitative, interpretative design using Gadamer's hermeneutic approach and included 15 in-depth semistructured interviews. The data were analyzed using a modified form of the steps described by Fleming. RESULTS: Fifteen mothers of extremely preterm infants participated in the study. The following themes were extracted from the data analysis: (1) "unexpected and unusual lactation," including the subthemes "the extremely preterm birth and the decision to provide MOM," "the battle to produce milk," and "my job was to make milk"; and (2) "providing MOM to a tiny infant in an unknown technological environment," with the subthemes "the limitations of providing MOM in the NICU" and "the difficulties of having an extremely preterm infant." IMPLICATIONS FOR PRACTICE: To provide MOM to an extremely preterm infant, there is a need for informational and practical counseling by neonatal nurses educated in breastfeeding according to mothers' requirements and emotional needs. IMPLICATIONS FOR RESEARCH: Future research may analyze the parents' and neonatal nurses' experience about facilitators to improve MOM provision and the influence of women's sociodemographic characteristics in providing MOM to the extremely preterm infants.

Experiences of Mothers of Extremely Preterm Infants after Hospital Discharge.

PURPOSE: The purpose of this study was to describe and understand the experiences of mothers of extremely preterm infants during the first twelve months at home following discharge from a neonatal intensive care unit. DESIGN AND METHODS: A qualitative, interpretative approach using Gadamer's philosophical hermeneutics was carried out. One focus group and fifteen in-depth, semi-structured interviews were conducted twelve months after hospital discharge. Responses were recorded, transcribed and analyzed using computer-assisted qualitative data analysis. RESULTS: The study´s participants were twenty women. The following themes emerged from the data analysis: 1) 'The journey home: the discharge process', which included the sub-themes 'escaping the hospital environment: between desire and fear' and 'preparing parents for hospital discharge: practice and formal support'; and 2) 'The difficulty of living with an extremely preterm infant', including the sub-themes 'the challenge of an unexpected form of childcare', 'overprotection of and bond with a child with special needs' and 'disturbance in the social/familiar setting: when a mother becomes a nurse'. CONCLUSIONS: The process of hospital discharge and the first months at home are difficult. The birth and care of an extremely preterm infant affect the mothers' quality of life as well as their family and social life. Practice and early discharge programmes can make the discharge process easier. PRACTICE IMPLICATIONS: The knowledge and understanding of the experience of mothers of extremely preterm infants in the first months at home after hospital discharge could help healthcare professionals to develop educational strategies and counselling interventions in accordance with the mothers' needs.

2-Arachidonoylglycerol Reduces Proteoglycans and Enhances Remyelination in a Progressive Model of Demyelination.

The failure to undergo remyelination is a critical impediment to recovery in multiple sclerosis. Chondroitin sulfate proteoglycans (CSPGs) accumulate at demyelinating lesions creating a nonpermissive environment that impairs axon regeneration and remyelination. Here, we reveal a new role for 2-arachidonoylglycerol (2-AG), the major CNS endocannabinoid, in the modulation of CSPGs deposition in a progressive model of multiple sclerosis, the Theiler's murine encephalomyelitis virus-induced demyelinating disease. Treatment with a potent reversible inhibitor of the enzyme monoacylglycerol lipase, which accounts for 85% of the 2-AG degradation in the mouse CNS, modulates neuroinflammation and reduces CSPGs accumulation and astrogliosis around demyelinated lesions in the spinal cord of Theiler's murine encephalomyelitis virus-infected mice. Inhibition of 2-AG hydrolysis augments the number of mature oligodendrocytes and increases MBP, leading to remyelination and functional recovery of mice. Our findings establish a mechanism for 2-AG promotion of remyelination with implications in axonal repair in CNS demyelinating pathologies.SIGNIFICANCE STATEMENT The deposition of chondroitin sulfate proteoglycans contributes to the failure in remyelination associated with multiple sclerosis. Here we unveil a new role for 2-arachidonoylglycerol, the major CNS endocannabinoid, in the modulation of chondroitin sulfate proteoglycan accumulation in Theiler's murine encephalomyelitis virus-induced demyelinating disease. The treatment during the chronic phase with a potent reversible inhibitor of the enzyme monoacylglycerol lipase, which accounts for 85% of the 2-arachidonoylglycerol degradation in the mouse CNS, modulates neuroinflammation and reduces chondroitin sulfate proteoglycan deposition around demyelinated lesions in the spinal cord of Theiler's murine encephalomyelitis virus-infected mice. The increased 2-arachidonoylglycerol tone promotes remyelination in a model of progressive multiple sclerosis ameliorating motor dysfunction.

2-AG limits Theiler's virus induced acute neuroinflammation by modulating microglia and promoting MDSCs.

The innate immune response is mediated by primary immune modulators such as cytokines and chemokines that together with immune cells and resident glia orchestrate CNS immunity and inflammation. Growing evidence supports that the endocannabinoid 2-arachidonoylglycerol (2-AG) exerts protective actions in CNS injury models. Here, we used the acute phase of Theiler's virus induced demyelination disease (TMEV-IDD) as a model of acute neuroinflammation to investigate whether 2-AG modifies the brain innate immune responses to TMEV and CNS leukocyte trafficking. 2-AG or the inhibition of its hydrolysis diminished the reactivity and number of microglia at the TMEV injection site reducing their morphological complexity and modulating them towards an anti-inflammatory state via CB2 receptors. Indeed, 2-AG dampened the infiltration of immune cells into the CNS and inhibited their egress from the spleen, resulting in long-term beneficial effects at the chronic phase of the disease. Intriguingly, it is not a generalized action over leukocytes since 2-AG increased the presence and suppressive potency of myeloid derived suppressor cells (MDSCs) in the brain resulting in higher apoptotic CD4+ T cells at the injection site. Together, these data suggest a robust modulatory effect in the peripheral and central immunity by 2-AG and highlight the interest of modulating endogenous cannabinoids to regulate CNS inflammatory conditions.

A Fluorescent Probe to Unravel Functional Features of Cannabinoid Receptor CB1 in Human Blood and Tonsil Immune System Cells.

The human endogenous cannabinoid system (ECS) regulates key physiological processes and alterations in its signaling pathways, and endocannabinoid levels are associated with diseases such as neurological and neuropsychiatric conditions, cancer, pain and inflammation, obesity, and metabolic and different immune related disorders. Immune system cells express the G-protein coupled cannabinoid receptor 1 (CB1), but its functional role has not been fully understood, likely due to the lack of appropriate tools. The availability of novel tools to investigate the role of CB1 in immune regulation might contribute to identify CB1 as a potential novel therapeutic target or biomarker for many diseases. Herein, we report the development and validation of the first fluorescent small molecule probe to directly visualize and quantify CB1 in blood and tonsil immune cells by flow cytometry and confocal microscopy. We coupled the cannabinoid agonist HU210 to the fluorescent tag Alexa Fluor 488, generating a fluorescent probe with high affinity for CB1 and selectivity over CB2. We validate HU210-Alexa488 for the rapid, simultaneous, and reproducible identification of CB1 in human monocytes, T cells, and B cells by multiplexed flow cytometry. This probe is also suitable for the direct visualization of CB1 in tonsil tissues, allowing the in vivo identification of tonsil CB1-expressing T and B cells. This study provides the first fluorescent chemical tool to investigate CB1 expression and function in human blood and tonsil immune cells, which might well pave the way to unravel essential features of CB1 in different immune and ECS-related diseases.

Development of a Fluorescent Bodipy Probe for Visualization of the Serotonin 5-HT1A Receptor in Native Cells of the Immune System.

Serotonin (5-HT) modulates key aspects of the immune system. However, its precise function and the receptors involved in the observed effects have remained elusive. Among the different serotonin receptors, 5-HT1A plays an important role in the immune system given its presence in cells involved in both the innate and adaptive immune responses, but its actual levels of expression under different conditions have not been comprehensively studied due to the lack of suitable tools. To further clarify the role of 5-HT1A receptor in the immune system, we have developed a fluorescent small molecule probe that enables the direct study of the receptor levels in native cells. This probe allows direct profiling of the receptor expression in immune cells using flow cytometry. Our results show that important subsets of immune cells including human monocytes and dendritic cells express functional 5-HT1A and that its activation is associated with anti-inflammatory signaling. Furthermore, application of the probe to the experimental autoimmune encephalomyelitis model of multiple sclerosis demonstrates its potential to detect the specific overexpression of the 5-HT1A receptor in CD4+ T cells. Accordingly, the probe reported herein represents a useful tool whose use can be extended to study the levels of 5-HT1A receptor in ex vivo samples of different immune system conditions.

Development of a Nucleotide Exchange Inhibitor That Impairs Ras Oncogenic Signaling.

Despite more than three decades of intense effort, no anti-Ras therapies have reached clinical application. Contributing to this failure has been an underestimation of Ras complexity and a dearth of structural information. In this regard, recent studies have revealed the highly dynamic character of the Ras surface and the existence of transient pockets suitable for small-molecule binding, opening up new possibilities for the development of Ras modulators. Herein, a novel Ras inhibitor (compound 12) is described that selectively impairs mutated Ras activity in a reversible manner without significantly affecting wild-type Ras, reduces the Ras-guanosine triphosphate (GTP) levels, inhibits the activation of the mitogen-activated protein kinase (MAPK) pathway, and exhibits remarkable cytotoxic activity in Ras-driven cellular models. The use of molecular dynamics simulations and NMR spectroscopy experiments has enabled the molecular bases responsible for the interactions between compound 12 and Ras protein to be explored. The new Ras inhibitor binds partially to the GTP-binding region and extends into the adjacent hydrophobic pocket delimited by switch II. Hence, Ras inhibitor 12 could represent a new compound for the development of more efficacious drugs to target Ras-driven cancers; a currently unmet clinical need.

Chemoproteomic Approach to Explore the Target Profile of GPCR ligands: Application to 5-HT1A and 5-HT6 Receptors.

Determination of the targets of a compound remains an essential aspect in drug discovery. A complete understanding of all binding interactions is critical to recognize in advance both therapeutic effects and undesired consequences. However, the complete polypharmacology of many drugs currently in clinical development is still unknown, especially in the case of G protein-coupled receptor (GPCR) ligands. In this work we have developed a chemoproteomic platform based on the use of chemical probes to explore the target profile of a compound in biological systems. As proof of concept, this methodology has been applied to selected ligands of the therapeutically relevant serotonin 5-HT1A and 5-HT6 receptors, and we have identified and validated some of their off-targets. This approach could be extended to other drugs of interest to study the targeted proteome in disease-relevant systems.

Fatty acid synthase is a metabolic marker of cell proliferation rather than malignancy in ovarian cancer and its precursor cells.

Ovarian cancer (OC) is caused by genetic aberrations in networks that control growth and survival. Importantly, aberrant cancer metabolism interacts with oncogenic signaling providing additional drug targets. Tumors overexpress the lipogenic enzyme fatty acid synthase (FASN) and are inhibited by FASN blockers, whereas normal cells are FASN-negative and FASN-inhibitor-resistant. Here, we demonstrate that this holds true when ovarian/oviductal cells reside in their autochthonous tissues, whereas in culture they express FASN and are FASN-inhibitor-sensitive. Upon subculture, nonmalignant cells cease growth, express senescence-associated ß-galactosidase, lose FASN and become FASN-inhibitor-resistant. Immortalized ovarian/oviductal epithelial cell lines­although resisting senescence­reveal distinct growth activities, which correlate with FASN levels and FASN drug sensitivities. Accordingly, ectopic FASN stimulates growth in these cells. Moreover, FASN levels and lipogenic activities affect cellular lipid composition as demonstrated by thin-layer chromatography. Correlation between proliferation and FASN levels was finally evaluated in cancer cells such as HOC-7, which contain subclones with variable differentiation/senescence and corresponding FASN expression/FASN drug sensitivity. Interestingly, senescent phenotypes can be induced in parental HOC-7 by differentiating agents. In OC cells, FASN drugs induce cell cycle blockade in S and/or G2/M and stimulate apoptosis, whereas in normal cells they only cause cell cycle deceleration without apoptosis. Thus, normal cells, although growth-inhibited, may survive and recover from FASN blockade, whereas malignant cells get extinguished. FASN expression and FASN drug sensitivity are directly linked to cell growth and correlate with transformation/differentiation/senescence only indirectly. FASN is therefore a metabolic marker of cell proliferation rather than a marker of malignancy and is a useful target for future drug development.

A reversible and selective inhibitor of monoacylglycerol lipase ameliorates multiple sclerosis.

Monoacylglycerol lipase (MAGL) is the enzyme responsible for the inactivation of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibitors show analgesic and tissue-protecting effects in several disease models. However, the few efficient and selective MAGL inhibitors described to date block the enzyme irreversibly, and this can lead to pharmacological tolerance. Hence, additional classes of MAGL inhibitors are needed to validate this enzyme as a therapeutic target. Here we report a potent, selective, and reversible MAGL inhibitor (IC50=0.18 µM) which is active in vivo and ameliorates the clinical progression of a multiple sclerosis (MS) mouse model without inducing undesirable CB1 -mediated side effects. These results support the interest in MAGL as a target for the treatment of MS.

Cancer-Stem-Cell Phenotype-Guided Discovery of a Microbiota-Inspired Synthetic Compound Targeting NPM1 for Leukemia.

The human microbiota plays an important role in human health and disease, through the secretion of metabolites that regulate key biological functions. We propose that microbiota metabolites represent an unexplored chemical space of small drug-like molecules in the search of new hits for drug discovery. Here, we describe the generation of a set of complex chemotypes inspired on selected microbiota metabolites, which have been synthesized using asymmetric organocatalytic reactions. Following a primary screening in CSC models, we identified the novel compound UCM-13369 (4b) whose cytotoxicity was mediated by NPM1. This protein is one of the most frequent mutations of AML, and NPM1-mutated AML is recognized by the WHO as a distinct hematopoietic malignancy. UCM-13369 inhibits NPM1 expression, downregulates the pathway associated with mutant NPM1 C+, and specifically recognizes the C-end DNA-binding domain of NPM1 C+, avoiding the nucleus-cytoplasm translocation involved in the AML tumorological process. The new NPM1 inhibitor triggers apoptosis in AML cell lines and primary cells from AML patients and reduces tumor infiltration in a mouse model of AML with NPM1 C+ mutation. The disclosed phenotype-guided discovery of UCM-13369, a novel small molecule inspired on microbiota metabolites, confirms that CSC death induced by NPM1 inhibition represents a promising therapeutic opportunity for NPM1-mutated AML, a high-mortality disease.

Patient Safety Culture in a Tertiary Hospital: A Cross-Sectional Study.

Patient safety (PS) culture is the set of values and norms common to the individuals of an organization. Assessing the culture is a priority to improve the quality and PS of hospital services. This study was carried out in a tertiary hospital to analyze PS culture among the professionals and to determine the strengths and weaknesses that influence this perception. A cross-sectional descriptive study was carried out. The AHRQ Questionnaire on the Safety of Patients in Hospitals (SOPS) was used. A high perception of PS was found among the participants. In the strengths found, efficient teamwork, mutual help between colleagues and the support of the manager and head of the unit stood out. Among the weaknesses, floating professional templates, a perception of pressure and accelerated pace of work, and loss of relevant information on patient transfer between units and shift changes were observed. Among the areas for improvement detected were favoring feedback to front-line professionals, abandoning punitive measures and developing standardized tools that minimize the loss of information.