Tumor and Stromal Cell Targeting with Nintedanib and Alpelisib Overcomes Intrinsic Bladder Cancer Resistance.

Bladder cancer is a highly prevalent tumor, requiring the urgent development of novel therapies, especially for locally advanced and metastatic disease. Nintedanib is a potent antifibrotic angio-kinase inhibitor, which has shown clinical efficacy in combination with chemotherapy in patients with locally advanced muscle-invasive bladder cancer. Nintedanib inhibits fibroblast growth factor receptors (FGFRs), validated targets in patients with bladder cancer harboring FGFR3/2 genetic alterations. Here, we aimed at studying its mechanisms of action to understand therapy resistance, identify markers predictive of response, and improve the design of future clinical trials. We have used a panel of genetically well-characterized human bladder cancer cells to identify the molecular and transcriptomic changes induced upon treatment with nintedanib, in vitro and in vivo, at the tumor and stroma cell levels. We showed that bladder cancer cells display an intrinsic resistance to nintedanib treatment in vitro, independently of their FGFR3 status. However, nintedanib has higher antitumor activity on mouse xenografts. We have identified PI3K activation as a resistance mechanism against nintedanib in bladder cancer and evidenced that the combination of nintedanib with the PI3K inhibitor alpelisib has synergistic antitumor activity. Treatment with this combination is associated with cell-cycle inhibition at the tumoral and stromal levels and potent nontumor cell autonomous effects on α-smooth muscle actin-positive tumor infiltrating cells and tumor vasculature. The combination of nintedanib with PI3K inhibitors not only reversed bladder cancer resistance to nintedanib but also enhanced its antiangiogenic effects.

Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue.

Recent findings have demonstrated that mitochondria can be transferred between cells to control metabolic homeostasis. Although the mitochondria of brown adipocytes comprise a large component of the cell volume and undergo reorganization to sustain thermogenesis, it remains unclear whether an intercellular mitochondrial transfer occurs in brown adipose tissue (BAT) and regulates adaptive thermogenesis. Herein, we demonstrated that thermogenically stressed brown adipocytes release extracellular vesicles (EVs) that contain oxidatively damaged mitochondrial parts to avoid failure of the thermogenic program. When re-uptaken by parental brown adipocytes, mitochondria-derived EVs reduced peroxisome proliferator-activated receptor-γ signaling and the levels of mitochondrial proteins, including UCP1. Their removal via the phagocytic activity of BAT-resident macrophages is instrumental in preserving BAT physiology. Depletion of macrophages in vivo causes the abnormal accumulation of extracellular mitochondrial vesicles in BAT, impairing the thermogenic response to cold exposure. These findings reveal a homeostatic role of tissue-resident macrophages in the mitochondrial quality control of BAT.

Capacidad predictiva para la lactancia y determinación del mejor punto de corte de la escala BSES-SF / Predictive capacity for breastfeeding and determination of the best cut-off point for the breastfeeding self-efficacy scale-short form

Introducción: El instrumento utilizado habitualmente para valorar la autoeficacia de la lactancia materna (LM) es la breastfeeding self-efficacy scale-short form (BSES-SF). Este estudio valora la relación entre la puntuación de la BSES-SF y el riesgo de abandono de la lactancia. También se determina el punto de corte en la puntuación de la escala que optimiza la detección de este riesgo desde la atención primaria. Métodos: Análisis secundario de datos del estudio Lactancia y Desarrollo Infantil (LAyDI). Ensayo de cohorte única realizado a través de la red de investigación de pediatras de atención primaria (PAPenRed). Cada especialista reclutó un recién nacido cada mes durante un año. Se siguió la cohorte durante 24 meses. Las madres respondieron la BSES-SF en la primera visita. Se recogieron datos generales de el embarazo y el parto y se valoró la LM (suplementada o exclusiva) hasta los seis meses. Resultados: n = 1.845. El área bajo la curva ROC para la LM exclusiva fue al primer mes de 0,79 (0,77 a 0,82) y al segundo mes de 0,760 (0,734 a 0,786). Para los cuatro y seis meses, así como para cualquier edad en las madres que dan LM suplementada, el área bajo la curva fue menor de 0,75 y su capacidad predictiva no se consideró adecuada. Para una sensibilidad del 80% en la detección de las mujeres en riesgo de abandono de la lactancia, la puntuación de corte fue 58. Conclusiones: Las madres que en atención primaria presenten una puntuación en la BSES-SF por debajo de 58 tienen riesgo de abandono de la LM exclusiva antes de los dos meses.(AU)

Introduction: The most widely used tool for assessing breastfeeding self-efficacy is the Breastfeeding Self-Efficacy Scale-Short Form (BSES-SF). This study asses the relationship between the BSES-SF score and the risk of breastfeeding (BF) cessation and determine the cut-off point in the scale score that optimizes detection of this risk in primary health care pediatric consultations. Methods: Secondary data analysis of the LAyDI study. It is a cohort study. It was carried out through a research network of primary care pediatricians (PAPenRed). A newborn was recruited every month for one year by 210 pediatricians. The cohort was followed for 24 months. Mothers responded to the BSES-SF at the first visit. General pregnancy and delivery data were collected and assessed to determine whether breastfeeding was exclusive or supplemented during the first six months. Results: n = 1,845. The area under the ROC curve for the exclusive BF was 0.790 (0.765-0.815) the first month and 0.760 (0.734-0.786) the second month. For four and six months, as well as for any age in mothers who give supplemented BF, the Area Under the Curve was less than 0.75 and its predictive capacity was not considered to be good. For a sensitivity of 80% in detecting mothers at risk of BF cessation with the BSES-SF, the cut-off score was 58. Conclusions: Mothers with a BSES-SF score below 58 points in primary health care, are at risk of early withdrawal of exclusive BF within two months.(AU)

Predictive capacity for breastfeeding and determination of the best cut-off point for the breastfeeding self-efficacy scale-short form.

INTRODUCTION: The most widely used tool for assessing breastfeeding self-efficacy is the Breastfeeding Self-Efficacy Scale-Short Form (BSES-SF). This study assesses the relationship between the BSES-SF score and the risk of breastfeeding (BF) cessation and determines the cut-off point in the scale score that optimizes detection of this risk in primary health care pediatric consultations. METHODS: Secondary data analysis of the LAyDI study. Cohort study carried out through a research network of primary care pediatricians (PAPenRed). A newborn was recruited every month for one year by 210 pediatricians. The cohort was followed for 24 months. Mothers responded to the BSES-SF at the first visit. General pregnancy and delivery data were collected and assessed to determine whether breastfeeding was exclusive or supplemented during the first 6 months. RESULTS: N = 1845. The Area Under the ROC Curve for the exclusive BF was 0.790 (0.765-0.815) the first month and 0.760 (0.734-0.786) the second month. For 4 and 6 months, as well as for any age in mothers who give supplemented BF, the Area Under the Curve was less than 0.75 and its predictive capacity was not considered to be good. For a sensitivity of 80% in detecting mothers at risk of BF cessation with the BSES-SF, the cut-off score was 58. CONCLUSIONS: Mothers with a BSES-SF score below 58 points in primary health care, are at risk of early withdrawal of exclusive BF within two months.

Docentes universitarios inclusivos: qué les caracteriza y cómo conciben la discapacidad / Inclusive University Teachers: What Characterizes them and how do they Think about Disability

El incremento de estudiantes con discapacidad en las universidades españo­las conlleva la necesidad de desarrollar prácticas docentes inclusivas que garanticen la par­ticipación y el aprendizaje de todo el alumnado. Con este trabajo se pretende: (1) conocer las concepciones que el profesorado universitario que ejerce prácticas docentes inclusivas tiene sobre la discapacidad; (2) analizar las razones que les motivan para tener en cuenta las necesidades de los estudiantes con discapacidad, y (3) describir las características que les definen. En el estudio participaron 42 docentes que fueron seleccionados como inclusivos por estudiantes con discapacidad de seis universidades públicas de diferentes comunida­des autónomas de España (Andalucía, Valencia y Madrid). Estos docentes pertenecían a diferentes áreas de conocimiento y todos impartían docencia en Facultades de Ciencias de la Educación. Se siguió una metodología biográfico-narrativa, mediante el uso de entrevis­tas semiestructuradas. Los resultados indicaron que la mayoría del profesorado concebía la discapacidad desde el modelo social, abogando por una educación inclusiva. Entre las razones que les llevaban a responder a las necesidades de este alumnado estaban la expe­riencia previa con personas con discapacidad, el principio de igualdad y su responsabilidad como docente. Respecto a las características de estos docentes inclusivos, destacan la em­patía, el compromiso, la flexibilidad y la vocación docente

The increase in the number of students with disabilities in Spanish uni­versities implies the need to develop inclusive teaching practices that guarantee the par­ticipation and learning of all students. This work is intended: (1) to know the concep­tions that the university teaching staff who carry out inclusive teaching practices have about disability; (2) to analyze the reasons that motivate them to attend to the needs of students with disabilities, and (3) to describe the characteristics that define them. The study involved 42 faculty members who were selected as inclusive by students with disabilities from six public universities in different autonomous communities of Spain (Andalusia, Valencia and Madrid). These faculty members belonged to different areas of knowledge and all of them taught in Faculties of Educational Sciences. A biographi­cal-narrative methodology was used by using semi-structured interviews. Results indi­cated that the majority of the faculty conceived disability from the social, advocating for an inclusive education. Among the reasons that led them to approach to these students were previous experience with people with disabilities, the principle of equality and their responsibility as lecturers. Regarding the characteristics of these inclusive faculty members, empathy, commitment, flexibility and teaching vocation stand out

Isolation of exophers from cardiomyocyte-reporter mouse strains by fluorescence-activated cell sorting.

Cardiac exophers are membrane-bound extracellular vesicles released by cardiomyocytes with varied content and an average diameter of 3.5 µm. Here, we provide a detailed protocol to enable the identification and purification of cardiomyocyte-derived exophers by using fluorescence-activated cell sorting for downstream cellular and molecular analysis. This protocol requires the use of mouse strains expressing fluorescent proteins in cardiomyocytes. For complete details on the use and execution of this protocol, please refer to Nicolás-Ávila et al. (2020).

[Predictive capacity for breastfeeding and determination of the best cut-off point for the breastfeeding self-efficacy scale-short form]. / Capacidad predictiva para la lactancia y determinación del mejor punto de corte de la escala BSES-SF.

INTRODUCTION: The most widely used tool for assessing breastfeeding self-efficacy is the Breastfeeding Self-Efficacy Scale-Short Form (BSES-SF). This study asses the relationship between the BSES-SF score and the risk of breastfeeding (BF) cessation and determine the cut-off point in the scale score that optimizes detection of this risk in primary health care pediatric consultations. METHODS: Secondary data analysis of the LAyDI study. It is a cohort study. It was carried out through a research network of primary care pediatricians (PAPenRed). A newborn was recruited every month for one year by 210 pediatricians. The cohort was followed for 24 months. Mothers responded to the BSES-SF at the first visit. General pregnancy and delivery data were collected and assessed to determine whether breastfeeding was exclusive or supplemented during the first six months. RESULTS: n = 1,845. The area under the ROC curve for the exclusive BF was 0.790 (0.765-0.815) the first month and 0.760 (0.734-0.786) the second month. For four and six months, as well as for any age in mothers who give supplemented BF, the Area Under the Curve was less than 0.75 and its predictive capacity was not considered to be good. For a sensitivity of 80% in detecting mothers at risk of BF cessation with the BSES-SF, the cut-off score was 58. CONCLUSIONS: Mothers with a BSES-SF score below 58 points in primary health care, are at risk of early withdrawal of exclusive BF within two months.

A Network of Macrophages Supports Mitochondrial Homeostasis in the Heart.

Cardiomyocytes are subjected to the intense mechanical stress and metabolic demands of the beating heart. It is unclear whether these cells, which are long-lived and rarely renew, manage to preserve homeostasis on their own. While analyzing macrophages lodged within the healthy myocardium, we discovered that they actively took up material, including mitochondria, derived from cardiomyocytes. Cardiomyocytes ejected dysfunctional mitochondria and other cargo in dedicated membranous particles reminiscent of neural exophers, through a process driven by the cardiomyocyte's autophagy machinery that was enhanced during cardiac stress. Depletion of cardiac macrophages or deficiency in the phagocytic receptor Mertk resulted in defective elimination of mitochondria from the myocardial tissue, activation of the inflammasome, impaired autophagy, accumulation of anomalous mitochondria in cardiomyocytes, metabolic alterations, and ventricular dysfunction. Thus, we identify an immune-parenchymal pair in the murine heart that enables transfer of unfit material to preserve metabolic stability and organ function. VIDEO ABSTRACT.

Mitochondrial Adaptations in the Growing Heart.

The heart pumps blood throughout the whole life of an organism, without rest periods during which to replenish energy or detoxify. Hence, cardiomyocytes, the working units of the heart, have mechanisms to ensure constitutive production of energy and detoxification to preserve fitness and function for decades. Even more challenging, the heart must adapt to the varying conditions of the organism from fetal life to adulthood, old age, and pathological stress. Mitochondria are at the nexus of these processes by producing not only energy but also metabolites and oxidative byproducts that can activate alarm signals and be toxic to the cell. We review basic concepts about cardiac mitochondria with a focus on their remarkable adaptations, including elimination, throughout the mammalian lifetime.

MED12 Regulates HSC-Specific Enhancers Independently of Mediator Kinase Activity to Control Hematopoiesis.

Hematopoietic-specific transcription factors require coactivators to communicate with the general transcription machinery and establish transcriptional programs that maintain hematopoietic stem cell (HSC) self-renewal, promote differentiation, and prevent malignant transformation. Mediator is a large coactivator complex that bridges enhancer-localized transcription factors with promoters, but little is known about Mediator function in adult stem cell self-renewal and differentiation. We show that MED12, a member of the Mediator kinase module, is an essential regulator of HSC homeostasis, as in vivo deletion of Med12 causes rapid bone marrow aplasia leading to acute lethality. Deleting other members of the Mediator kinase module does not affect HSC function, suggesting kinase-independent roles of MED12. MED12 deletion destabilizes P300 binding at lineage-specific enhancers, resulting in H3K27Ac depletion, enhancer de-activation, and consequent loss of HSC stemness signatures. As MED12 mutations have been described recently in blood malignancies, alterations in MED12-dependent enhancer regulation may control both physiological and malignant hematopoiesis.