Medication guide for dose adjustment and management of cardiotoxicity and lipid metabolic adverse events of oral antineoplastic therapy.

Objective: The management of cardiotoxicity concerning the use of oral antineoplastic agents (OAAs) is a challenge for healthcare professionals. Our objective was to create a comprehensive medication management guide with dose adjustment recommendations on OAAs concerning cardiotoxic and lipid metabolic adverse events (AEs) to assist healthcare professionals when prescribing OAAs. Materials and methods: A review of the available information on all dose adjustments necessary to safely prescribe and dispense OAAs concerning cardiotoxicity was conducted. In January 2023, we identified all OAAs authorized by the European Medicines Agency (EMA). For each drug, the latest summary of product characteristics (SPC) approved by the EMA and the tertiary data source Lexicomp® were reviewed. Cardiotoxic AEs were recorded, namely, QT interval prolongation, decrease in left ventricular ejection fraction (LVEF), imbalances in blood pressure (hypertension and hypotension), alterations in heart rate (tachycardia and bradycardia), and thrombosis. Any available dose adjustment recommendations in case of an occurrence of these adverse events were collected. Results: In all, 93 different OAAs had been approved by the EMA and were reviewed. Among them, 51.6% have recognized cardiotoxic AEs and 10.8% can cause alterations in lipid metabolism. A total of 27 (29.0%) OAAs had specific recommendations regarding QT prolongation; 88.9% were listed in the SPC and 59.3% in Lexicomp®. Eight OAAs (9.68%) have reported a decrease in LVEF, and four of these drugs, namely, encorafenib, lorlatinib, ripretinib, and sunitinib, have specific management recommendations. Almost half (49.5%) of currently approved OAAs can potentially alter blood pressure; 34 (36.6%) of them have been reported to cause hypertension and 12 (12.9%) are related to hypotension. Tachycardia and/or bradycardia are associated with 22.6% and 8.6% of the evaluated drugs, respectively. Regarding thrombosis, 30 (32.3%) of the drugs analyzed included the appearance of a thrombus as a possible AE. Conclusions: More than half of the OAAs can produce cardiotoxic effects, with the most frequent being blood pressure alteration and QT interval prolongation with a non-depreciable incidence of LV dysfunction or thrombosis. Before starting the treatment, it is necessary to stratify baseline cardiovascular risk, plan a surveillance schedule, and consider referral to cardio-oncology units.

Maternal emulsifier consumption programs offspring metabolic and neuropsychological health in mice.

Modern lifestyle is associated with a major consumption of ultra-processed foods (UPF) due to their practicality and palatability. The ingestion of emulsifiers, a main additive in UPFs, has been related to gut inflammation, microbiota dysbiosis, adiposity, and obesity. Maternal unbalanced nutritional habits during embryonic and perinatal stages perturb offspring's long-term metabolic health, thus increasing obesity and associated comorbidity risk. However, whether maternal emulsifier consumption influences developmental programming in the offspring remains unknown. Here, we show that, in mice, maternal consumption of dietary emulsifiers (1% carboxymethyl cellulose (CMC) and 1% P80 in drinking water), during gestation and lactation, perturbs the development of hypothalamic energy balance regulation centers of the progeny, leads to metabolic impairments, cognition deficits, and induces anxiety-like traits in a sex-specific manner. Our findings support the notion that maternal consumption of emulsifiers, common additives of UPFs, causes mild metabolic and neuropsychological malprogramming in the progeny. Our data call for nutritional advice during gestation.

Fast and easy synthesis of silver, copper, and bimetallic nanoparticles on cellulose paper assisted by ultrasound.

This work focuses on a systematic method to produce Ag, Cu, and Ag/Cu metallic nanoparticles (MNPs) in situ assisted with ultrasound on cellulose paper. By tuning the concentration of AgNO3 and CuSO4 salt precursors and ultrasound time, combined with a fixed concentration of ascorbic acid (AA) as a reducing agent, it was possible to control the size, morphology, and polydispersity of the resulting MNPs on cellulose papers. Notably, high yield and low polydispersity of MNPs and bimetallic nanoparticles are achieved by increasing the sonication time on paper samples pre-treated with salt precursors before reduction with AA. Moreover, mechanical analysis on paper samples presenting well-dispersed and distributed MNPs showed slightly decreasing values of Young's modulus compared to neat papers. The strain at break is substantially improved in papers containing solely Ag or Cu MNPs. The latter suggests that the elastic/plastic transition and deformation of papers are tuned by cellulose and MNPs interfacial interaction, as indicated by mechanical analysis. The proposed method provides insights into each factor affecting the sonochemistry in situ synthesis of MNPs on cellulose papers. In addition, it offers a straightforward alternative to scale up the production of MNPs on paper, ensuring an eco-friendly method.

Citizen science approaches for water quality measurements.

Citizen science has become a widely used approach in water quality studies. Although there are literature reviews about citizen science and water quality assessments, an overview of the most commonly used methods and their strengths and weaknesses is still lacking. Therefore, we reviewed the scientific literature on citizen science for surface water quality assessments and examined the methods and strategies used by the 72 studies that fulfilled our search criteria. Special attention was given to the parameters monitored, the monitoring tools, and the spatial and temporal resolution of the data collected in these studies. In addition, we discuss the advantages and disadvantages of the different approaches used in water quality assessments and their potential to complement traditional hydrological monitoring and research.

Negative energy balance hinders prosocial helping behavior.

The internal state of an animal, including homeostatic requirements, modulates its behavior. Negative energy balance stimulates hunger, thus promoting a range of actions aimed at obtaining food. While these survival actions are well established, the influence of the energy status on prosocial behavior remains unexplored. We developed a paradigm to assess helping behavior in which a free mouse was faced with a conspecific trapped in a restrainer. We measured the willingness of the free mouse to liberate the confined mouse under diverse metabolic conditions. Around 42% of ad libitum-fed mice exhibited a helping behavior, as evidenced by the reduction in the latencies to release the trapped cagemate. This behavior was independent of subsequent social contact reward and was associated with changes in corticosterone indicative of emotional contagion. This decision-making process was coupled with reduced blood glucose excursions and higher Adenosine triphosphate (ATP):Adenosine diphosphate (ADP) ratios in the forebrain of helper mice, suggesting that it was a highly energy-demanding process. Interestingly, chronic (food restriction and type 2 diabetes) and acute (chemogenetic activation of hunger-promoting AgRP neurons) situations mimicking organismal negative energy balance and enhanced appetite attenuated helping behavior toward a distressed conspecific. To investigate similar effects in humans, we estimated the influence of glycated hemoglobin (a surrogate of long-term glycemic control) on prosocial behavior (namely charity donation) using the Understanding Society dataset. Our results evidenced that organismal energy status markedly influences helping behavior and that hypothalamic AgRP neurons are at the interface of metabolism and prosocial behavior.

Architectural anatomy of the human tibialis anterior presents morphological asymmetries between superficial and deep unipennate regions.

The tibialis anterior muscle plays a critical role in human ambulation and contributes to maintaining the upright posture. However, little is known about its muscle architecture in males and females. One hundred and nine physically active males and females were recruited. Tibialis anterior muscle thickness, pennation angle, and fascicle length were measured at rest in both unipennate regions of both legs using real-time ultrasound imaging. A linear mixed model was used with muscle thickness, pennation angle, or fascicle length as the dependent variables. All models were carried out with and without total leg lean mass and shank length as covariates. Causal mediation analysis was computed to explore the effect of muscle thickness on the relationship between fascicle length and pennation angle. There were no significant differences between dominant and nondominant legs regarding muscle architecture. Muscle thickness and pennation angle were greater in the deep than the superficial unipennate region in males (1.9 mm and 1.1°, p < 0.001) and women (3.4 mm and 2.2°, p < 0.001). However, the fascicle length was similar in both regions for both sexes. The differences remained significant after accounting for differences in leg lean mass and shank length. In both regions, muscle thickness was 1-3 mm greater in males and superficial pennation angle 2° smaller in females (both, p < 0.001). After accounting for leg lean mass and shank length, sex differences remained for muscle thickness (1.6 mm, p < 0.05) and pennation angle (3.4°, p < 0.001) but only in the superficial region. In both regions, leg lean mass and shank-adjusted fascicle length were 1.4 mm longer in females than males (p < 0.05). The causal mediation analysis revealed that the estimation of fascicle length was positive, suggesting that a 10% increase in muscle thickness would augment the fascicle length, allowing a 0.38° pennation angle decrease. Moreover, the pennation angle increases in total by 0.54° due to the suppressive effect of the increase in fascicle length. The estimated mediation, direct, and total effects were all significantly different from zero (p < 0.001). Overall, our results indicate that the architectural anatomy of the tibialis anterior shows sexual dimorphism in humans. Tibialis anterior presents morphological asymmetries between superficial and deep unipennate regions in both sexes. Lastly, our causal mediation model identified a suppressive effect of fascicle length on the pennation angle, suggesting that increments in muscle thickness are not always aligned with increments in fascicle length or the pennation angle.

Porcn is essential for growth and invagination of the mammalian optic cup.

Microphthalmia, anophthalmia, and coloboma (MAC) are congenital ocular malformations causing 25% of childhood blindness. The X-linked disorder Focal Dermal Hypoplasia (FDH) is frequently associated with MAC and results from mutations in Porcn, a membrane bound O-acyl transferase required for palmitoylation of Wnts to activate multiple Wnt-dependent pathways. Wnt/ß-catenin signaling is suppressed in the anterior neural plate for initiation of eye formation and is subsequently required during differentiation of the retinal pigment epithelium (RPE). Non-canonical Wnts are critical for early eye formation in frog and zebrafish. However, it is unclear whether this also applies to mammals. We performed ubiquitous conditional inactivation of Porcn in mouse around the eye field stage. In Porcn CKO , optic vesicles (OV) arrest in growth and fail to form an optic cup. Ventral proliferation is significantly decreased in the mutant OV, with a concomitant increase in apoptotic cell death. While pan-ocular transcription factors such as PAX6, SIX3, LHX2, and PAX2 are present, indicative of maintenance of OV identity, regional expression of VSX2, MITF, OTX2, and NR2F2 is downregulated. Failure of RPE differentiation in Porcn CKO is consistent with downregulation of the Wnt/ß-catenin effector LEF1, starting around 2.5 days after inactivation. This suggests that Porcn inactivation affects signaling later than a potential requirement for Wnts to promote eye field formation. Altogether, our data shows a novel requirement for Porcn in regulating growth and morphogenesis of the OV, likely by controlling proliferation and survival. In FDH patients with ocular manifestations, growth deficiency during early ocular morphogenesis may be the underlying cause for microphthalmia.

Food craving-like episodes during pregnancy are mediated by accumbal dopaminergic circuits.

Preparation for motherhood requires a myriad of physiological and behavioural adjustments throughout gestation to provide an adequate environment for proper embryonic development1. Cravings for highly palatable foods are highly prevalent during pregnancy2 and contribute to the maintenance and development of gestational overweight or obesity3. However, the neurobiology underlying the distinct ingestive behaviours that result from craving specific foods remain unknown. Here we show that mice, similarly to humans, experience gestational food craving-like episodes. These episodes are associated with a brain connectivity reorganization that affects key components of the dopaminergic mesolimbic circuitry, which drives motivated appetitive behaviours and facilitates the perception of rewarding stimuli. Pregnancy engages a dynamic modulation of dopaminergic signalling through neurons expressing dopamine D2 receptors in the nucleus accumbens, which directly modulate food craving-like events. Importantly, persistent maternal food craving-like behaviour has long-lasting effects on the offspring, particularly in males, leading to glucose intolerance, increased body weight and increased susceptibility to develop eating disorders and anxiety-like behaviours during adulthood. Our results reveal the cognitively motivated nature of pregnancy food cravings and advocates for moderating emotional eating during gestation to prevent deterioration of the offspring's neuropsychological and metabolic health.

Improving cardiovascular magnetic resonance access in low- and middle-income countries for cardiomyopathy assessment: rapid cardiovascular magnetic resonance.

AIMS: To evaluate the impact of a simplified, rapid cardiovascular magnetic resonance (CMR) protocol embedded in care and supported by a partner education programme on the management of cardiomyopathy (CMP) in low- and middle-income countries (LMICs). METHODS AND RESULTS: Rapid CMR focused particularly on CMP was implemented in 11 centres, 7 cities, 5 countries, and 3 continents linked to training courses for local professionals. Patients were followed up for 24 months to assess impact. The rate of subsequent adoption was tracked. Five CMR conferences were delivered (920 attendees-potential referrers, radiographers, reporting cardiologists, or radiologists) and five new centres starting CMR. Six hundred and one patients were scanned. Cardiovascular magnetic resonance indications were 24% non-contrast T2* scans [myocardial iron overload (MIO)] and 72% suspected/known cardiomyopathies (including ischaemic and viability). Ninety-eighty per cent of studies were of diagnostic quality. The average scan time was 22 ± 6 min (contrast) and 12 ± 4 min (non-contrast), a potential cost/throughput reduction of between 30 and 60%. Cardiovascular magnetic resonance findings impacted management in 62%, including a new diagnosis in 22% and MIO detected in 30% of non-contrast scans. Nine centres continued using rapid CMR 2 years later (typically 1-2 days per week, 30 min slots). CONCLUSIONS: Rapid CMR of diagnostic quality can be delivered using available technology in LMICs. When embedded in care and a training programme, costs are lower, care is improved, and services can be sustained over time.

Hypothalamic pregnenolone mediates recognition memory in the context of metabolic disorders.

Obesity and type 2 diabetes are associated with cognitive dysfunction. Because the hypothalamus is implicated in energy balance control and memory disorders, we hypothesized that specific neurons in this brain region are at the interface of metabolism and cognition. Acute obesogenic diet administration in mice impaired recognition memory due to defective production of the neurosteroid precursor pregnenolone in the hypothalamus. Genetic interference with pregnenolone synthesis by Star deletion in hypothalamic POMC, but not AgRP neurons, deteriorated recognition memory independently of metabolic disturbances. Our data suggest that pregnenolone's effects on cognitive function were mediated via an autocrine mechanism on POMC neurons, influencing hippocampal long-term potentiation. The relevance of central pregnenolone on cognition was also confirmed in metabolically unhealthy patients with obesity. Our data reveal an unsuspected role for POMC neuron-derived neurosteroids in cognition. These results provide the basis for a framework to investigate new facets of POMC neuron biology with implications for cognitive disorders.

Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis.

Appropriate cristae remodeling is a determinant of mitochondrial function and bioenergetics and thus represents a crucial process for cellular metabolic adaptations. Here, we show that mitochondrial cristae architecture and expression of the master cristae-remodeling protein OPA1 in proopiomelanocortin (POMC) neurons, which are key metabolic sensors implicated in energy balance control, is affected by fluctuations in nutrient availability. Genetic inactivation of OPA1 in POMC neurons causes dramatic alterations in cristae topology, mitochondrial Ca2+ handling, reduction in alpha-melanocyte stimulating hormone (α-MSH) in target areas, hyperphagia, and attenuated white adipose tissue (WAT) lipolysis resulting in obesity. Pharmacological blockade of mitochondrial Ca2+ influx restores α-MSH and the lipolytic program, while improving the metabolic defects of mutant mice. Chemogenetic manipulation of POMC neurons confirms a role in lipolysis control. Our results unveil a novel axis that connects OPA1 in POMC neurons with mitochondrial cristae, Ca2+ homeostasis, and WAT lipolysis in the regulation of energy balance.

BACE2 suppression in mice aggravates the adverse metabolic consequences of an obesogenic diet.

OBJECTIVE: Pancreatic ß-cell dysfunction is a central feature in the pathogenesis of type 2 diabetes (T2D). Accumulating evidence indicates that ß-site APP-cleaving enzyme 2 (BACE2) inhibition exerts a beneficial effect on ß-cells in different models of T2D. Thus, targeting BACE2 may represent a potential therapeutic strategy for the treatment of this disease. Here, we aimed to investigate the effects of BACE2 suppression on glucose homeostasis in a model of diet-induced obesity. METHODS: BACE2 knock-out (BKO) and wild-type (WT) mice were fed with a high-fat diet (HFD) for 2 or 16 weeks. Body weight, food intake, respiratory exchange ratio, locomotor activity, and energy expenditure were determined. Glucose homeostasis was evaluated by glucose and insulin tolerance tests. ß-cell proliferation was assessed by Ki67-positive nuclei, and ß-cell function was determined by measuring glucose-stimulated insulin secretion. Leptin sensitivity was evaluated by quantifying food intake and body weight after an intraperitoneal leptin injection. Neuropeptide gene expression and insulin signaling in the mediobasal hypothalamus were determined by qPCR and Akt phosphorylation, respectively. RESULTS: After 16 weeks of HFD feeding, BKO mice exhibited an exacerbated body weight gain and hyperphagia, in comparison to WT littermates. Glucose tolerance was similar in both groups, whereas HFD-induced hyperinsulinemia, insulin resistance, and ß-cell expansion were more pronounced in BKO mice. In turn, leptin-induced food intake inhibition and hypothalamic insulin signaling were impaired in BKO mice, regardless of the diet, in accordance with deregulation of the expression of hypothalamic neuropeptide genes. Importantly, BKO mice already showed increased ß-cell proliferation and glucose-stimulated insulin secretion with respect to WT littermates after two weeks of HFD feeding, before the onset of obesity. CONCLUSIONS: Collectively, these results reveal that BACE2 suppression in an obesogenic setting leads to exacerbated body weight gain, hyperinsulinemia, and insulin resistance. Thus, we conclude that inhibition of BACE2 may aggravate the adverse metabolic effects associated with obesity.

Psychosocial factors associated with frailty in the community-dwelling aged population with depression. A cross-sectional study / Factores psicosociales asociados a fragilidad en ancianos de la comunidad con depresión: estudio observacional transversal

Objective: There is a two-way relationship between frailty and depression, but the mechanisms by which one may influence the other are not well understood. The objective of this study was to evaluate the relationship between psychosocial factors and frailty in community-dwelling aged populations with depression. Design:Observational cross-sectional study. Site: 5 primary care centres. Participants: Community-dwelling subjects with depression aged ≥70 years. Main measurements: Frailty status was established according to Fried criteria, depression and depression severity were evaluated by DSM-IV criteria and the Hamilton Depression Rating Scale, respectively, and psychosocial factors were assessed using the Gijón Social-Familial Evaluation Scale and ad hoc questionnaires. Results: Recruited were 338 subjects (mean age 77.2 years), 82% women and 36.1% rated as frail. A dose–response relationship was observed between depression severity and frailty risk. Widowhood was a risk factor for frailty, while a higher educational level, home internet, stairs in the home, and an active social life had a protective effect. A multivariate analysis showed that age, number of drugs, and depression severity were independent risk factors for frailty, while an active social life was a protective factor. The severity of depressive symptoms showed higher association with frailty than other clinical and socio-demographic characteristics. Conclusions: In depressed elderly subjects, frailty is associated with psychologiocal factors such as the intensity of depressive symptoms and with social factors such as education level, widowhood, loneliness, and limited social life. More research is required to better understand the modifiable psychological risk factors for frailty.(AU)

Objetivo: Existe una relación bidireccional entre la fragilidad y la depresión en la población anciana. El objetivo de este estudio fue evaluar la relación entre los factores psicosociales y la fragilidad en ancianos de la comunidad con depresión. Diseño: Estudio observacional transversal. Sitio: Cinco centros de atención primaria. Participantes: Ancianos ≥70años de la comunidad con depresión. Principales mediciones: La fragilidad se estableció de acuerdo con los criterios de Fried, la depresión y la gravedad de la depresión se evaluaron mediante los criterios DSM-IV y la Escala de Hamilton, respectivamente, y los factores psicosociales se evaluaron utilizando la Escala de Evaluación Social-Familiar de Gijón y cuestionarios ad hoc. Resultados: Se reclutaron 338 sujetos (edad media 77años), 82% mujeres y 36,1% frágiles. Se observó una relación dosis-respuesta entre la gravedad de la depresión y el riesgo de fragilidad. La viudez era un factor de riesgo para la fragilidad, mientras que un nivel educativo más alto, internet en el hogar, escaleras en el hogar y una vida social activa tenían un efecto protector. El análisis multivariado mostró que la edad, el número de medicamentos y la gravedad de la depresión eran factores de riesgo independientes para la fragilidad, mientras que una vida social activa era un factor protector. Conclusiones: En ancianos con depresión la fragilidad se asocia con factores psicológicos como la intensidad de los síntomas depresivos y con factores sociales como el nivel de estudios, la viudez, la soledad o la escasa vida social. Se requiere más investigación para comprender mejor los factores de riesgo psicológicos modificables de fragilidad.(AU)

Psychosocial factors associated with frailty in the community-dwelling aged population with depression. A cross-sectional study.

OBJECTIVE: There is a two-way relationship between frailty and depression, but the mechanisms by which one may influence the other are not well understood. The objective of this study was to evaluate the relationship between psychosocial factors and frailty in community-dwelling aged populations with depression. DESIGN: Observational cross-sectional study. SITE: 5 primary care centres. PARTICIPANTS: Community-dwelling subjects with depression aged ≥70 years. MAIN MEASUREMENTS: Frailty status was established according to Fried criteria, depression and depression severity were evaluated by DSM-IV criteria and the Hamilton Depression Rating Scale, respectively, and psychosocial factors were assessed using the Gijón Social-Familial Evaluation Scale and ad hoc questionnaires. RESULTS: Recruited were 338 subjects (mean age 77.2 years), 82% women and 36.1% rated as frail. A dose-response relationship was observed between depression severity and frailty risk. Widowhood was a risk factor for frailty, while a higher educational level, home internet, stairs in the home, and an active social life had a protective effect. A multivariate analysis showed that age, number of drugs, and depression severity were independent risk factors for frailty, while an active social life was a protective factor. The severity of depressive symptoms showed higher association with frailty than other clinical and socio-demographic characteristics. CONCLUSIONS: In depressed elderly subjects, frailty is associated with psychologiocal factors such as the intensity of depressive symptoms and with social factors such as education level, widowhood, loneliness, and limited social life. More research is required to better understand the modifiable psychological risk factors for frailty.

Potential and real drug interactions in patients treated with abiraterone or enzalutamide in clinical practice.

BACKGROUND: Abiraterone and enzalutamide, androgen receptor pathway inhibitors (ARPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC), are at high risk of potential drug interactions (PDIs). We aimed to describe PDIs and their management, and triggered adverse events (AEs) in clinical practice. METHODS: We conducted a cross-sectional study in mCRPC patients who started treatment with abiraterone or enzalutamide in a university hospital between August 1st, 2016 and July 31st, 2020. Lexicomp® was used to identify and analyze PDIs, and the clinical records to assess their management and the occurrence of AEs. RESULTS: We included 173 patients: 36.8% and 93.0% treated with abiraterone and enzalutamide, respectively, had at least 1 PDI. Globally, 6.3% of PDIs had X-risk (contraindication due to high probability of AE). Treatment was modified in 9.2% of patients and 9.8% suffered AEs due to PDIs. Factors associated with a higher risk of PDIs were polypharmacy (OR= 41.0, p  0.003) and treatment with enzalutamide (OR= 128.26, p < 0.001). CONCLUSIONS: At least two-thirds of patients treated with ARPI suffered a PDI. Overall, abiraterone would have a more favorable PDI profile. Knowing these interaction profiles may be helpful to develop a more efficient therapeutic follow-up and to select the safest treatment.

Nf2 fine-tunes proliferation and tissue alignment during closure of the optic fissure in the embryonic mouse eye.

Uveal coloboma represents one of the most common congenital ocular malformations accounting for up to 10% of childhood blindness (~1 in 5000 live birth). Coloboma originates from defective fusion of the optic fissure (OF), a transient gap that forms during eye morphogenesis by asymmetric, ventral invagination. Genetic heterogeneity combined with the activity of developmentally regulated genes suggests multiple mechanisms regulating OF closure. The tumor suppressor and FERM domain protein Neurofibromin 2 (NF2) controls diverse processes in cancer, development and regeneration, via Hippo pathway and cytoskeleton regulation. In humans, NF2 mutations can cause ocular abnormalities, including coloboma, however, its actual role in OF closure is unknown. Using conditional inactivation in the embryonic mouse eye, our data indicate that loss of Nf2 function results in a novel underlying cause for coloboma. In particular, mutant eyes show substantially increased retinal pigmented epithelium (RPE) proliferation in the fissure region with concomitant acquisition of RPE cell fate. Cells lining the OF margin can maintain RPE fate ectopically and fail to transition from neuroepithelial to cuboidal shape. In the dorsal RPE of the optic cup, Nf2 inactivation leads to a robust increase in cell number, with local disorganization of the cytoskeleton components F-actin and pMLC2. We propose that RPE hyperproliferation is the primary cause for the observed defects causing insufficient alignment of the OF margins in Nf2 mutants and failure to fuse properly, resulting in persistent coloboma. Our findings indicate that limiting proliferation particularly in the RPE layer is a critical mechanism during OF closure.

Pharmacological cancer treatment and venous thromboembolism risk.

Risk factors for cancer-associated thrombosis are commonly divided into three categories: patient-, cancer-, and treatment-related factors. Currently, different types of drugs are used in cancer treatment. Chemotherapy has been identified as an independent risk factor for venous thromboembolism (VTE). However, it should be noted, that the risk of VTE is not consistent among all cytotoxic agents. In addition, different supportive care drugs, such as erythropoiesis stimulating agents or granulocyte colony stimulating factors, and hormonotherapy have been associated to an increased risk of VTE. Immunotherapy and molecular-targeted therapies have significantly changed the treatment of cancer over the past decade. The main subtypes include tyrosine-kinase inhibitors, monoclonal antibodies, small molecules, and immunomodulatory agents. The relationship between VTE and targeted therapies remains largely unknown.

Los factores de riesgo para la trombosis asociada al cáncer se suelen dividir en tres categorías: factores relacionados con el paciente, con el cáncer y con el tratamiento. En la actualidad, existen distintos tipos de fármacos que se emplean en el tratamiento del cáncer. La quimioterapia se ha determinado como un factor de riesgo independiente para el desarrollo de la tromboembolia venosa (TEV). No obstante, cabe destacar que el riesgo de padecer TEV no es coherente entre los agentes citotóxicos. Por otra parte, distintos fármacos de tratamiento paliativo, como los agentes estimulantes de la eritropoyesis o factores estimulantes de colonias de granulocitos, se han asociado a un aumento del riesgo de TEV. La inmunoterapia y los tratamientos dirigidos a dianas moleculares han supuesto un cambio significativo en el tratamiento del cáncer en la última década. En los principales subtipos se incluyen los inhibidores de las tirosina-cinasas, anticuerpos monoclonales, fármacos tradicionales y agentes inmunomoduladores. La relación entre la TEV y los tratamientos dirigidos sigue siendo en gran medida desconocida.

Pro-opiomelanocortin (POMC) neuron translatome signatures underlying obesogenic gestational malprogramming in mice.

OBJECTIVE: Maternal unbalanced nutritional habits during embryonic development and perinatal stages perturb hypothalamic neuronal programming of the offspring, thus increasing obesity-associated diabetes risk. However, the underlying molecular mechanisms remain largely unknown. In this study we sought to determine the translatomic signatures associated with pro-opiomelanocortin (POMC) neuron malprogramming in maternal obesogenic conditions. METHODS: We used the RiboTag mouse model to specifically profile the translatome of POMC neurons during neonatal (P0) and perinatal (P21) life and its neuroanatomical, functional, and physiological consequences. RESULTS: Maternal high-fat diet (HFD) exposure did not interfere with offspring's hypothalamic POMC neuron specification, but significantly impaired their spatial distribution and axonal extension to target areas. Importantly, we established POMC neuron-specific translatome signatures accounting for aberrant neuronal development and axonal growth. These anatomical and molecular alterations caused metabolic dysfunction in early life and adulthood. CONCLUSIONS: Our study provides fundamental insights on the molecular mechanisms underlying POMC neuron malprogramming in obesogenic contexts.

[Utility of Cardiac Magnetic Resonance with Pharmacological Stress to assess Myocardial Ischemia]. / Utilidad de la Resonancia Magnética Cardíaca con Estrés Farmacológico para valorar Isquemia Miocárdica.

Cardiovascular disease (CVD) represents the main cause of death in the world. According to the World Health Organization (WHO), its prevalence is estimated to increase considering the high prevalence of cardiovascular risk factors. In Peru, CVD remains the second cause of death in general population. Ischemia represents a strong predictor of future adverse events such as myocardial infarction and cardiovascular death. Accurate detection of ischemia exerts a pivotal role in the diagnostic strategy of patients with suspected coronary disease. Stress magnetic resonance is a non-invasive diagnostic tool, that offers advantage over other diagnostic techniques, considering that possesses high spatial resolution and no radiation exposure. Its diagnostic precision for detecting coronary artery disease (CAD) is high, in addition of its prognostic value in patients with suspicion of CAD.In this review we will describe how cardiac magnetic resonance with pharmacologic stress is performed in order to detect ischemia. We will also discuss the diagnostic and prognostic values of this tool in patients with suspicion of CAD.