Constitutively Activated PI3K Accelerates Tumor Initiation and Modifies Histopathology of Breast Cancer

The gene encoding phosphatidylinositol 3-kinase catalytic subunit α-isoform (PIK3CA, p110α) is frequently activated by mutation in human cancers. Based on detection in some breast cancer precursors, PIK3CA mutations have been proposed to have a role in tumor initiation. To investigate this hypothesis, we generated a novel mouse model with a Cre-recombinase regulated allele of p110α (myristoylated-p110α, myr-p110α) along with p53fl/fl deletion and KrasG12D also regulated by Cre-recombinase. After instillation of adenovirus-expressing Cre-recombinase into mammary ducts, we found that myr-p110α accelerated breast tumor initiation in a copy number-dependent manner. Breast tumors induced by p53fl/fl;KrasG12D with no or one copy of myr-p110α had predominantly sarcomatoid features, whereas two copies of myr-p110α resulted in tumors with a carcinoma phenotype. This novel model provides experimental support for importance of active p110α in breast tumor initiation, and shows that the amount of PI3K activity can affect the rate of tumor initiation and modify the histological phenotype of breast cancer

Management of hyponatremia associated with acute porphyria-proposal for the use of tolvaptan

Hyponatremia is a common feature during the neurovisceral acute attacks which characterize hepatic porphyrias, as well as a sign of its severity. Therapeutic options for first-line acute attacks are intravenous administration of glucose and/or exogenous heme. The former treatment can aggravate hyponatremia by dilution and cause seizures; thus, the correction of hyponatremia must be carried out with extreme caution. This review summarizes recommendations for the management of hyponatremia during acute episodes of porphyria. Hyponatremia should be corrected slowly and seizures treated with medications in order to not exacerbate motor and sensory axonal neuropathy. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is considered a frequent cause of hyponatremia in acute porphyrias and must be identified as a symptom of an acute porphyria attack. Tolvaptan produces aquaresis and is considered a safe drug in porphyria. However, its use has only been reported in isolated cases during a porphyria attack. The convenience and usefulness of this drug in acute porphyria are discussed

The role of dendritic cell precursors in tumour vasculogenesis

In this review, we discuss the recent identification in vivo of a population of CD11c+ cells exhibiting simultaneous expression of both endothelial and dendritic cell markers, termed vascular leukocytes (VLCs). VLCs are highly represented in human ovarian carcinomas and, depending on the milieu, can assemble into functional blood vessels or act as antigen-presenting cells. The identification of dendritic cell precursors as bipotent cells has important implications for the physiopathology and therapy of tumours. VLCs emerge as a novel therapeutic target against tumour vascularisation

Origin of congenital coronary arterio-ventricular fistulae from anomalous epicardial and myocardial development.

Coronary Artery Fistulae (CAFs) are cardiac congenital anomalies consisting of an abnormal communication of a coronary artery with either a cardiac chamber or another cardiac vessel. In humans, these congenital anomalies can lead to complications such as myocardial hypertrophy, endocarditis, heart dilatation, and failure. Unfortunately, despite their clinical relevance, the aetiology of CAFs remains unknown. In this work, we have used two different species (mouse and avian embryos) to experimentally model CAFs morphogenesis. Both conditional Itga4 (alpha 4 integrin) epicardial deletion in mice and cryocauterisation of chick embryonic hearts disrupted epicardial development and ventricular wall growth, two essential events in coronary embryogenesis. Our results suggest that myocardial discontinuities in the embryonic ventricular wall promote the early contact of the endocardium with epicardial-derived coronary progenitors at the cardiac surface, leading to ventricular endocardial extrusion, precocious differentiation of coronary smooth muscle cells, and the formation of pouch-like aberrant coronary-like structures in direct connection with the ventricular lumen. The structure of these CAF-like anomalies was compared with histopathological data from a human CAF. Our results provide relevant information for the early diagnosis of these congenital anomalies and the molecular mechanisms that regulate their embryogenesis.The authors thank Dr. A. Rojas (CABIMER, Sevilla, Spain) and Prof. Thalia Papayannopoulou (University of Washington, WA, USA) for sharing with us the G2- Gata4-Cre and Itga4-floxed mouse lines, respectively. We also thank Vanessa Benhamo (Institut Imagine) for her expert support with HREM. Finally, we thank all members of “DeCA” laboratory (University of Málaga, Málaga, Spain), and the “Heart Morphogenesis” laboratory (Institut Imagine and Institut Pasteur, Paris, France) for their help and fruitful discussions on this paper. This work was supported by the Spanish Ministry of Science, R+D+i National Programme [grants RTI2018-095410-RBI00 and PID2021-122626-OB-I00], Spanish Ministry of Science-ISCIII [grant number RD16/0011/0030], and University of Málaga [grant number UMA18-FEDERJA-146] to [JMPP]; Consejería de Salud y Familias, Junta de Andalucía [grant number PIER-0084- 2019] to [JAGD]; University of Málaga [grant number I Plan Propio-UMA-A.4] to [ARV]; Spanish Ministry of Science, Innovation, and Universities (MCIU) (CIBER CV) [grant numbers PID2019-104776RB-I00 and CB16/11/00399] to [JLDLP].S

Mediators of outcome in adolescent psychotherapy and their implications for theories and mechanisms of change: a systematic review

Psychotherapeutic treatment of adolescents requires age-specific approaches and thus plausibly also involves different change mechanisms than adult psychotherapy. To guide further research and improve therapeutic outcomes for adolescents, we reviewed all RCTs investigating mechanisms of change in the psychological treatment of adolescents to identify the most promising age-, disorder- or treatment-specific mediators. Following the preferred reporting items for systematic reviews (PRISMA), 106 studies were included that reported 252 statistical mediation tests assessed with 181 different measures. Most often studied and significant mediators were cognitive, followed by family-related, and behavioral variables. Several mediators were identified to be promising for future investigations: changes in negative thoughts, dysfunctional beliefs and metacognitive skills; family functioning and parenting skills; as well as successful engagement in therapy activities and increased impulse control. Symptom change during therapy was least often a mediator for other therapeutic changes. Relational and emotional mediators were largely understudied, whereas peer-influence appeared a promising mediator for intervention outcomes. Adolescence-specific mediators were most commonly investigated. Majority of studied mediators were not disorder-specific. There was a tendency to mainly test change mechanisms of specific theoretical models without considering other possible change theories. Further, virtually no studies fulfilled all criteria for rigorously investigating mediation and only nine were classified with an overall good study quality. While bearing in mind the current limitations in study designs, methodological rigor and reporting, there appears to be substantial evidence for transdiagnostic age-specific change models in the psychological treatment of adolescents. For future research, need for consensus on a core set of transdiagnostic and transtheoretical mediators and measures is highlighted. These should address likely core mechanisms of change, as well as take into account age-relevant developmental challenges and biological markers.38 página

Information consumption patterns from big data

Virtual social networks imply an important opportunity to generate friendlier communication bridges between students, teachers and other actors related to the educational field. In this sense, our study presents an approximation to the connection habits between university students in these networks, which in the future will allow to take advantage of these platforms to achieve a successful communication between actors. Thus, the characterization of uses, habits and consumption of virtual social networks becomes very relevant

Synthesis and Anti-Diabetic Activity of an 8-Purine Derivative as a Novel DPP-4 Inhibitor in Obese Diabetic Zücker Rats

Meriem Chayah,1– 3 Angélica Luque-González,1 Verónica Gómez-Pérez,1 Diego Salagre,4,5 Amjad Al-Shdaifat,6 Joaquín María Campos,1,2 Ana Conejo-García,1,2 Ahmad Agil2,4,5 1Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, University of Granada, Granada, Spain; 2Biosanitary Institute of Granada (Ibs.granada), SAS-University of Granada, Granada, Spain; 3Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government (GENYO), Granada, Spain; 4Department of Pharmacology, Faculty of Medicine, University of Granada, Granada, Spain; 5Federico Oloriz Neuroscience Institute, University of Granada, Granada, Spain; 6Department of Medicine and Family Medicine, Faculty of Medicine, Hashemite University, Zarqa, JordaniaCorrespondence: Ahmad Agil; Ana Conejo-García, Email [email protected]; [email protected]: Type 2 diabetes mellitus (T2DM) is one of the world’s principal metabolic diseases characterized by chronic hyperglycemia. The gut incretin hormones, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), which has been proposed as a new treatment for T2DM, are extensively metabolized by Dipeptidyl peptidase 4 (DPP-4). Inhibitors of DPP-4 block the degradation of GLP-1 and GIP and may increase their natural circulating levels, favoring glycemic control in T2DM. A novel and potent selective inhibitor of DPP-4 with an 8-purine derived structure ( 1) has been developed and tested in vitro and in vivo in Zücker obese diabetic fatty (ZDF) rats, an experimental model of the metabolic syndrome and T2DM to assess the inhibitory activity using vildagliptin as reference standard. ZDF rats were subdivided into three groups (n = 7/group), control (C-ZDF), and those treated with compound 1 (Compound 1-ZDF) and with vildagliptin (V-ZDF), both at 10 mg/kg/d rat body weight, in their drinking water for 12 weeks, and a group of lean littermates (ZL) was used. ZDF rats developed DM (fasting hyperglycemia, 425 ± 14.8 mg/dL; chronic hyperglycemia, HbA1c 8.5 ± 0.4%), compared to ZL rats. Compound 1 and vildagliptin reduced sustained HbAl1c (14% and 10.6%, P < 0.05, respectively) and fasting hyperglycemia values (24% and 19%, P < 0.05, respectively) compared to C-ZDF group (P < 0.001). Compound 1 and vildagliptin have shown a potent activity with an IC50 value of 4.92 and 3.21 μM, respectively. These data demonstrate that oral compound 1 administration improves diabetes in ZDF rats by the inhibitory effect on DPP-4, and the potential to be a novel, efficient and tolerable approach for treating diabetes of obesity-related T2DM, in ZDF rats.Keywords: diabetes mellitus type 2, DPP-4 inhibitors, purine derivatives, ZDF rat