RBM10 loss induces aberrant splicing of cytoskeletal and extracellular matrix mRNAs and promotes metastatic fitness.

RBM10 modulates transcriptome-wide cassette exon splicing. Loss-of-function RBM10 mutations are enriched in thyroid cancers with distant metastases. Analysis of transcriptomes and genes mis-spliced by RBM10 loss showed pro-migratory and RHO/RAC signaling signatures. RBM10 loss increases cell velocity. Cytoskeletal and ECM transcripts subject to exon-inclusion events included vinculin (VCL), tenascin C (TNC) and CD44. Knockdown of the VCL exon inclusion transcript in RBM10-null cells reduced cell velocity, whereas knockdown of TNC and CD44 exon-inclusion isoforms reduced invasiveness. RAC1-GTP levels were increased in RBM10-null cells. Mouse Hras G12V /Rbm1O KO thyrocytes develop metastases that are reversed by RBM10 or by combined knockdown of VCL, CD44 and TNC inclusion isoforms. Thus, RBM10 loss generates exon inclusions in transcripts regulating ECM-cytoskeletal interactions, leading to RAC1 activation and metastatic competency. Moreover, a CRISPR-Cas9 screen for synthetic lethality with RBM10 loss identified NFkB effectors as central to viability, providing a therapeutic target for these lethal thyroid cancers.

ß-Turn Induction by a Diastereopure Azepane-Derived Quaternary Amino Acid.

ß-Turns are one of the most common secondary structures found in proteins. In the interest of developing novel ß-turn inducers, a diastereopure azepane-derived quaternary amino acid has been incorporated into a library of simplified tetrapeptide models in order to assess the effect of the azepane position and peptide sequence on the stabilization of ß-turns. The conformational analysis of these peptides by molecular modeling, NMR spectroscopy, and X-ray crystallography showed that this azepane amino acid is an effective ß-turn inducer when incorporated at the i + 1 position. Moreover, the analysis of the supramolecular self-assembly of one of the ß-turn-containing peptide models in the solid state reveals that it forms a supramolecular helical arrangement while maintaining the ß-turn structure. The results here presented provide the basis for the use of this azepane quaternary amino acid as a strong ß-turn inducer in the search for novel peptide-based bioactive molecules, catalysts, and biomaterials.

Genomic and epigenomic profile of thyroid cancer.

Thyroid cancer is the most common malignancy of the endocrine system, and its incidence has been steadily increasing. Advances in sequencing have allowed analysis of the entire cancer genome, and has provided new information on the genetic lesions and modifications responsible for the onset, progression, dedifferentiation and metastasis of thyroid carcinomas. Moreover, integrated genomics has advanced our understanding of the development of cancer and its behavior, and has facilitated the identification of new genetic mutations and molecular pathways. The functional analysis of epigenetic modifications, such as DNA methylation, histone acetylation and non-coding RNAs, have contributed to define new regulatory mechanisms that control cell malignancy in thyroid cancer, especially aggressive forms. Here we review the most recent advances in genomics and epigenomics of thyroid cancer, which have resulted in a new classification and interpretation of the initiation and progression of thyroid tumors, providing new tools and opportunities for further investigation and for the clinical development of new treatment strategies.

Current therapies for hypertrophic cardiomyopathy: a systematic review and meta-analysis of the literature.

AIMS: The aim of this study was to synthesize the evidence on the effect of the current therapies over the pathophysiological and clinical characteristics of patients with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: A systematic review and meta-analysis of 41 studies identified from 1383 retrieved from PubMed, Web of Science, and Cochrane was conducted. Therapies were grouped in pharmacological, invasive and physical exercise. Pharmacological agents had no effect on functional capacity measured by VO2max (1.11 mL/kg/min; 95% CI: -0.04, 2.25, P < 0.05). Invasive septal reduction therapies increased VO2max (+3.2 mL/kg/min; 95% CI: 1.78, 4.60, P < 0.05). Structured physical exercise programmes did not report contraindications and evidenced the highest increases on functional capacity (VO2max + 4.33 mL/kg/min; 95% CI: 0.20, 8.45, P < 0.05). Patients with left ventricular outflow tract (LVOT) obstruction at rest improved their VO2max to a greater extent compared with those without resting LVOT obstruction (2.82 mL/kg/min; 95% CI: 1.97, 3.67 vs. 1.18; 95% CI: 0.62, 1.74, P < 0.05). Peak LVOT gradient was reduced with the three treatment options with the highest reduction observed for invasive therapies. Left ventricular ejection fraction was reduced in pharmacological and invasive procedures. No effect was observed after physical exercise. Symptomatic status improved with the three options and to a greater extent with invasive procedures. CONCLUSIONS: Invasive septal reduction therapies increase VO2max, improve symptomatic status, and reduce resting and peak LVOT gradient, thus might be considered in obstructive patients. Physical exercise emerges as a coadjuvant therapy, which is safe and associated with benefits on functional capacity. Pharmacological agents improve reported NYHA class, but not functional capacity.

Yap governs a lineage-specific neuregulin1 pathway-driven adaptive resistance to RAF kinase inhibitors.

BACKGROUND: Inactivation of the Hippo pathway promotes Yap nuclear translocation, enabling execution of a transcriptional program that induces tissue growth. Genetic lesions of Hippo intermediates only identify a minority of cancers with illegitimate YAP activation. Yap has been implicated in resistance to targeted therapies, but the mechanisms by which YAP may impact adaptive resistance to MAPK inhibitors are unknown. METHODS: We screened 52 thyroid cancer cell lines for illegitimate nuclear YAP localization by immunofluorescence and fractionation of cell lysates. We engineered a doxycycline (dox)-inducible thyroid-specific mouse model expressing constitutively nuclear YAPS127A, alone or in combination with endogenous expression of either HrasG12V or BrafV600E. We also generated cell lines expressing dox-inducible sh-miR-E-YAP and/or YAPS127A. We used cell viability, invasion assays, immunofluorescence, Western blotting, qRT-PCRs, flow cytometry and cell sorting, high-throughput bulk RNA sequencing and in vivo tumorigenesis to investigate YAP dependency and response of BRAF-mutant cells to vemurafenib. RESULTS: We found that 27/52 thyroid cancer cell lines had constitutively aberrant YAP nuclear localization when cultured at high density (NU-YAP), which rendered them dependent on YAP for viability, invasiveness and sensitivity to the YAP-TEAD complex inhibitor verteporfin, whereas cells with confluency-driven nuclear exclusion of YAP (CYT-YAP) were not. Treatment of BRAF-mutant thyroid cancer cells with RAF kinase inhibitors resulted in YAP nuclear translocation and activation of its transcriptional output. Resistance to vemurafenib in BRAF-mutant thyroid cells was driven by YAP-dependent NRG1, HER2 and HER3 activation across all isogenic human and mouse thyroid cell lines tested, which was abrogated by silencing YAP and relieved by pan-HER kinase inhibitors. YAP activation induced analogous changes in BRAF melanoma, but not colorectal cells. CONCLUSIONS: YAP activation in thyroid cancer generates a dependency on this transcription factor. YAP governs adaptive resistance to RAF kinase inhibitors and induces a gene expression program in BRAFV600E-mutant cells encompassing effectors in the NRG1 signaling pathway, which play a central role in the insensitivity to MAPK inhibitors in a lineage-dependent manner. HIPPO pathway inactivation serves as a lineage-dependent rheostat controlling the magnitude of the adaptive relief of feedback responses to MAPK inhibitors in BRAF-V600E cancers.

Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer.

BACKGROUND: RAS-to-ERK signaling is crucial for the onset and progression of advanced thyroid carcinoma, and blocking ERK dimerization provides a therapeutic benefit in several human carcinomas. Here we analyzed the effects of DEL-22379, a relatively specific ERK dimerization inhibitor, on the activation of the RAS-to-ERK signaling cascade and on tumor-related processes in vitro and in vivo. METHODS: We used a panel of four human anaplastic thyroid carcinoma (ATC) cell lines harboring BRAF or RAS mutations to analyze ERK dynamics and tumor-specific characteristics. We also assessed the impact of DEL-22379 on the transcriptional landscape of ATC cell lines using RNA-sequencing and evaluated its therapeutic efficacy in an orthotopic mouse model of ATC. RESULTS: DEL-22379 impaired upstream ERK activation in BRAF- but not RAS-mutant cells. Cell viability and metastasis-related processes were attenuated by DEL-22379 treatment, but mostly in BRAF-mutant cells, whereas in vivo tumor growth and dissemination were strongly reduced for BRAF-mutant cells and mildly reduced for RAS-mutant cells. Transcriptomics analyses indicated that DEL-22379 modulated the transcriptional landscape of BRAF- and RAS-mutant cells in opposite directions. CONCLUSIONS: Our findings establish that BRAF- and RAS-mutant thyroid cells respond differentially to DEL-22379, which cannot be explained by the previously described mechanism of action of the inhibitor. Nonetheless, DEL-22379 demonstrated significant anti-tumor effects against BRAF-mutant cells in vivo with an apparent lack of toxicity, making it an interesting candidate for the development of combinatorial treatments. Our data underscore the differences elicited by the specific driver mutation for thyroid cancer onset and progression, which should be considered for experimental and clinical approaches.

Identification of an interactome network between lncRNAs and miRNAs in thyroid cancer reveals SPTY2D1-AS1 as a new tumor suppressor.

Thyroid cancer is the most common primary endocrine malignancy in adults and its incidence is rapidly increasing. Long non-coding RNAs (lncRNAs), generally defined as RNA molecules longer than 200 nucleotides with no protein-encoding capacity, are highly tissue-specific molecules that serve important roles in gene regulation through a variety of different mechanisms, including acting as competing endogenous RNAs (ceRNAs) that 'sponge' microRNAs (miRNAs). In the present study, using an integrated approach through RNA-sequencing of paired thyroid tumor and non-tumor samples, we have identified an interactome network between lncRNAs and miRNAs and examined the functional consequences in vitro and in vivo of one of such interactions. We have identified a likely operative post-transcriptional regulatory network in which the downregulated lncRNA, SPTY2D1-AS1, is predicted to target the most abundant and upregulated miRNAs in thyroid cancer, particularly miR-221, a well-known oncomiRNA in cancer. Indeed, SPTY2D1-AS1 functions as a potent tumor suppressor in vitro and in vivo, it is downregulated in the most advanced stages of human thyroid cancer, and it seems to block the processing of the primary form of miR-221. Overall, our results link SPTY2D1-AS1 to thyroid cancer progression and highlight the potential use of this lncRNA as a therapeutic target of thyroid cancer.

Temporal dysregulation of hypothalamic integrative and metabolic nuclei in rats fed during the rest phase.

Temporal coordination of organisms according to the daytime allows a better performance of physiological processes. However, modern lifestyle habits, such as food intake during the rest phase, promote internal desynchronization and compromise homeostasis and health. The hypothalamic suprachiasmatic nucleus (SCN) synchronizes body physiology and behavior with the environmental light-dark cycle by transmitting time information to several integrative hypothalamic nuclei, such as the paraventricular nucleus (PVN), dorsomedial hypothalamic nucleus (DMH) and median preoptic area (MnPO). The SCN receives metabolic information mainly via Neuropeptide Y (NPY) inputs from the intergeniculate nucleus of the thalamus (IGL). Nowadays, there is no evidence of the response of the PVN, DMH and MnPO when the animals are subjected to internal desynchronization by restricting food access to the rest phase of the day. To explore this issue, we compared the circadian activity of the SCN, PVN, DMH and MnPO. In addition, we analyzed the daily activity of the satiety centers of the brainstem, the nucleus of the tractus solitarius (NTS) and area postrema (AP), which send metabolic information to the SCN, directly or via the thalamic intergeniculate leaflet (IGL). For that, male Wistar rats were assigned to three meal protocols: fed during the rest phase (Day Fed); fed during the active phase (Night Fed); free access to food (ad libitum). After 21 d, the daily activity patterns of these nuclei were analyzed by c-Fos immunohistochemistry, as well as NPY immunohistochemistry, in the SCN. The results show that eating during the rest period produces a phase advance in the activity of the SCN, changes the daily activity pattern in the MnPO, NTS and AP and flattens the c-Fos rhythm in the PVN and DMH. Altogether, these results validate previous observations of circadian dysregulation that occurs within the central nervous system when meals are consumed during the rest phase, a behavior that is involved in the metabolic alterations described in the literature.

Factors Associated With Terminally Ill People Who Want to Die.

CONTEXT: The decision to request and proceed with euthanasia or physician-assisted dying is complex, and predictors of such decisions are heterogeneous with regard to physical health, psychological, and social factors. Local research is therefore needed. OBJECTIVES: To examine the interplay of demographic, clinical, and psychosocial factors routinely collected by a standardized clinical instrument, the interRAI Resident Assessment Instrument for Palliative Care (interRAI-PC), in people with a prognosis of less than 12 months who wanted to die. METHODS: All New Zealanders who had an interRAI-PC in 2018 were included. The outcome variable was the single item Wants to die now. Independent variables included biopsychosocial factors and health index scales generated by interRAI-PC. A binary logistic regression was used to determine the predictive factors of Wants to die now (yes vs. no). RESULTS: There were 771 individuals included (mean age 76.0 years; SD 11.6; female 50.1%); 9.3% of whom reported yes to Wants to die now, 59.8% no, and for 30.9%, the assessor was unable to determine. The factors with the largest odds ratios (ORs) were awareness of terminal prognosis (OR 4.8; 95% CI 2.2-10.3), high level of depression (OR 4.6; 95% CI 1.7-12.6), not finding meaning in day-to-day life (OR 3.8; 95% CI 1.8-8.1), and pain (less than severe: OR 3.7; 95% CI 1.3-10.4 and severe to excruciating: OR 3.5; 95% CI 1.1-10.7). CONCLUSION: Addressing the significant factors we identified should form part of a multidisciplinary assessment when terminally ill patients express a wish to die, to ensure their physical, psychological, and existential needs are adequately met.

Intervenciones farmacéuticas: Aporte a la mejora de la calidad asistencial / Pharmaceutical interventions: Contribution to the improvement of healthcare quality

OBJETIVO: Analizar las intervenciones farmacéuticas (IF) realizadas y medir el aporte farmacéutico a la mejora de la calidad asistencial. METODOLOGÍA: Estudio observacional y retrospectivo realizado en un hospital de alta complejidad. Se analizaron las IF registradas entre enero del 2018 y agosto del 2019 en una planilla diseñada para tal fin, teniendo en cuenta las variables: vía de comunicación, receptor de la IF, tipo de intervención, etapa del proceso, clasificación de la IF y aceptación.Se midió mensualmente el indicador "aporte farmacéutico a la mejora de la calidad asistencial"= Nº IF aceptadas/Nº IF realizadas*100. Nivel de aceptación esperado: 80%. RESULTADOS: Se registraron 3683 IF, 0,6 IF/paciente seguido promedio. Los resultados de las variables analizadas fueron: a) 98% activas; 2% pasivas. b) 73% oral; 26% telefónica; 1% escrita. c) 96% médicos; 4% enfermeros. d) 37% prescripción, 58% seguimiento, 4% administración, 1% preparación. e) 86% aceptadas, 11% no aceptadas (4% no aceptadas con justificación, 4% no aceptadas parciales, 3% no aceptadas sin justificación), 3% no evaluables f) 27% se relacionó con posología, 23% suspensión de medicamento, 15% agregado de medicamento, 11% confirmación de la prescripción, 9% forma de administración/preparación, 8% clarificación de la prescripción, 7% otras. Evolución mensual del indicador de octubre/18 a agosto/19: 85%, 85%, 90%, 88%, 77%, 80%, 90 %, 87%, 93%, 86%, 84%. CONCLUSIONES: Se registró un elevado número de intervenciones por paciente seguido, con participación activa del farmacéutico. Se evidenció una relación de mutua confianza y abordaje multidisciplinario con el personal de salud, manifestado por el porcentaje de aceptación. La clasificación de IF nos permitió identificar problemas frecuentes en la utilización de medicamentos y establecer estrategias de prevención. La medición del indicador superó el nivel de aceptación la mayoría de los meses evidenciando el aporte a la mejora de la calidad asistencial.

OBJECTIVE: To analyze the pharmaceutical interventions (PI) carried out and measure the pharmaceutical contribution to the improvement of the quality of care. METHODOLOGY: Observational and retrospective study conducted in a hospital of high complexity. The PI registered between January 20 18 and August 20 19 were analyzed in a form designed for this purpose, taking into account the variables: communication channel, receiver of the PI, type of intervention, stage of the process, classification of the FI and acceptance . The indicator "pharmaceutical contribution to the improvement of the quality of care" was measured monthly = No. PI accepted / No. PI made * 100. Expected level of acceptance: 80%. RESULTS: 3683 PI, 0,6 PI/ patient followed average. The results of the analyzed variables were: a) 98% active; 2% passive b) 73% oral; 26% telephone; 1% written. c) 96% doctors; 4% nurses d) 37% prescription, 58% follow-up, 4% administration, 1% preparation. e) 86% accepted, 11% not accepted (4% not accepted with justification, 4% not partially accepted, 3% not accepted without justification), 3% not evaluable f) 27% related to dosage, 23% suspension of medication, 15% aggregate of medication, 11% confirmation of prescription, 9% form of administration /preparation, 8% clarification of prescription, 7% others. Monthly evolution of the indicator from October / 18 to August / 19: 85%, 85%, 90%, 88%, 77%, 80%, 90%, 87%, 93%, 86%, 84%. CONCLUSIONS: A high number of interventions were recorded per patient followed, with active participation of the pharmacist. A relationship of mutual trust and multidisciplinary approach with health personnel was evidenced, manifested by the percentage of acceptance. The classification of PI allowed us to identify frequent problems in the use of medications and establish prevention strategies. The measurement of the indicator exceeded the level of acceptance most months evidencing the contribution to the improvement of the quality of care.

In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice.

MicroRNAs (miRNAs) are important regulators of gene expression through their ability to destabilize mRNA and inhibit translation of target mRNAs. An ever-increasing number of studies have identified miRNAs as potential biomarkers for cancer diagnosis and prognosis, and also as therapeutic targets, adding an extra dimension to cancer evaluation and treatment. In the context of thyroid cancer, tumorigenesis results not only from mutations in important genes, but also from the overexpression of many miRNAs. Accordingly, the role of miRNAs in the control of thyroid gene expression is evolving as an important mechanism in cancer. Herein, we present a protocol to examine the effects of miRNA-inhibitor delivery as a therapeutic modality in thyroid cancer using human tumor xenograft and orthotopic mouse models. After engineering stable thyroid tumoral cells expressing GFP and luciferase, cells are injected into nude mice to develop tumors, which can be followed by bioluminescence. The in vivo inhibition of a miRNA can reduce tumor growth and upregulate miRNA gene targets. This method can be used to assess the importance of a determined miRNA in vivo, in addition to identifying new therapeutic targets.

Regulators of the RAS-ERK pathway as therapeutic targets in thyroid cancer.

Thyroid cancer is mostly an ERK-driven carcinoma, as up to 70% of thyroid carcinomas are caused by mutations that activate the RAS/ERK mitogenic signaling pathway. The incidence of thyroid cancer has been steadily increasing for the last four decades; yet, there is still no effective treatment for advanced thyroid carcinomas. Current research efforts are focused on impairing ERK signaling with small-molecule inhibitors, mainly at the level of BRAF and MEK. However, despite initial promising results in animal models, the clinical success of these inhibitors has been limited by the emergence of tumor resistance and relapse. The RAS/ERK pathway is an extremely complex signaling cascade with multiple points of control, offering many potential therapeutic targets: from the modulatory proteins regulating the activation state of RAS proteins to the scaffolding proteins of the pathway that provide spatial specificity to the signals, and finally, the negative feedbacks and phosphatases responsible for inactivating the pathway. The aim of this review is to give an overview of the biology of RAS/ERK regulators in human cancer highlighting relevant information on thyroid cancer and future areas of research.

Immune-unreactive urinary albumin as a predictor of cardiovascular events: the Hortega Study.

BACKGROUND: We aimed to determine if immune-unreactive albumin excretion (IURAE) is associated with cardiovascular (CV) events in a representative sample of a general population from Spain. METHODS: We included 1297 subjects (mean age ± standard error 48.0 ± 0.2 years, 48% females), who participated in the Hortega Follow-Up Study. The primary endpoint was incidence of fatal and non-fatal CV events. Urinary albumin excretion (UAE) was measured in spot voided urine, frozen at -80°C, by immunonephelometry [immune-reactive albumin excretion (IRAE)] and by high-performance liquid chromatography (HPLC) [total albumin excretion (AE)]. IURAE was calculated as the difference between HPLC measurements and IRAE. We estimated fully adjusted hazard ratios (HRs) of CV incidence by Cox regression for IRAE, IURAE and total AE. RESULTS: After an average at-risk follow-up of 13 years, we observed 172 CV events. urinary albumin to creatinine ratio (UACR) of ≥30 mg/g assessed by IRAE, IURAE or total AE concentrations was observed in 74, 273 and 417 participants, respectively. Among discordant pairs, there were 49 events in those classified as micro- and macroalbuminuric by IURAE, but normoalbuminuric by IRAE. Only the IRAE was a significant independent factor for the incidence of CV events [HR (95% confidence interval) 1.15 (1.04-1.27)]. The association of UAE with CV events was mainly driven by heart failure (HF) [HR 1.33 (1.15-1.55) for IRAE; HR 1.38 (1.06-1.79) for IURAE; HR 1.62 (1.22-2.13) for total AE]. Those subjects who were micro- and macroalbuminuric by both IRAE and IURAE had a significant increase in risk for any CV event, and especially for HF. CONCLUSIONS: IRAE, IURAE and AE were associated with an increased risk for CV events, but IRAE offered better prognostic assessment.

Centralización en la elaboración y bancos solidarios de drogas oncológicas, una estrategia para mejorar la accesibilidad a los tratamientos / Centralization in the development and solidarity banks of oncological drugs, a strategy to improve accessibility to treatments

El objetivo del estudio es determinar los tratamientos que se generan fruto de la centralización y medir el impacto económico. El proceso de utilización de citostáticos inicia con la confección del protocolo por parte del médico, la validación por el farmacéutico con la confección de la orden de elaboración, y la ejecución por el técnico realizando la preparación en cabina de seguridad biológica. Culmina con la administración por parte de enfermería y seguimiento médico. La centralización disminuye el riesgo de exposición, ofrece protección del producto, paciente, operador, ambiente. Al mismo tiempo disminuye los costos provocando un ahorro significativo si se coordina la programación del protocolo y prescripción médica, la preparación en el servicio de farmacia y la administración en hospital de día agrupando por tratamiento a los pacientes.

The objective of the study is to determine the treatments that are generated by centralization and to measure the economic impact. The process of using cytostatics starts with the preparation of the protocol by the physician, the validation by the pharmacist with the writingof the preparation order, and the execution by the technician carrying out the preparation in the biological safety cabinet. It culminates with nursing administration and medical follow-up. Centralization reduces the risk of exposure, offers protection to the product, the patient, the operator, and the environment. At the same time, it reduces costs, with significant savings if the programming of the protocol and medical prescription, the preparation in the pharmacy service and the administration in the day hospital are coordinated grouping by treatment to the patients.

Clinical interventions in osteosarcopenic obesity: nutrition, physical and psychological activity / Intervenciones clínicas en obesidad osteosarcopénica: alimentación, actividad física y psicológica

Osteosarcopenic obesity (OSO) is a condition associated with adverse outcomes in older adults. Since it is a condition which includes three tissues (obesity, sarcopenia and osteopenia/osteoporosis), it requires simultaneous and multidisciplinary clinical interventions to revert it. Until this moment, there have been published review articles only focused on nutrition or physical activity. However, we believe that assembling the existing evidence on potential treatments (nutritional intervention with micro- and macronutrients), physical activity, farmacological treatment for osteopenia/osteoporosis, possible farmacological treatment for sarcopenia, and, finally, psychological interventions focused on the treatment of psychiatric comorbidities (such as anxiety or depression) will help healthcare providers to improve the body composition of older adults.

La obesidad osteosarcopénica (OOS) es una condición que representa diversos desenlaces adversos en el adulto mayor. Al ser una condición que incluye tres tejidos (obesidad, sarcopenia y osteopenia/osteoporosis), se requiere de intervenciones clínicas simultáneas y multidisciplinarias para lograr revertirla. Hasta el momento, han sido publicados artículos de revisión enfocados solo a la nutrición y a la actividad física. Sin embargo, consideramos que es necesario reunir la evidencia del nivel nutricional (en cuanto a micro- y macronutrientes), de la actividad física habitual o personalizada, de los potenciales tratamientos farmacológicos para la sarcopenia, del actual tratamiento farmacológico para la osteopenia/osteoporosis y, por último, en torno a las posibles intervenciones psicológicas enfocadas a tratar la comorbilidad psiquiátrica (ansiedad o depresión) y directamente hacia la mejora de la composición corporal en adultos mayores.

Paraffin-embedded micrographic surgery for the treatment of dermatofibrosarcoma protuberans: Analysis of 33 patients.

BACKGROUND: Dermatofibrosarcoma protuberans is a rare malignant tumor with a high rate of recurrence after surgery. Moh's micrographic surgery allows examination of all surgical margins to ensure complete removal. OBJECTIVE: To evaluate the use of Moh's micrographic surgery using paraffin-embedded sections for the treatment of dermatofibrosarcoma protuberans. METHODS: We performed a retrospective analysis of 33 patients with dermatofibrosarcoma protuberans treated in our department with paraffin-embedded micrographic surgery between January 2002 and June 2015. Our cases included patients with primary untreated disease and also those with persistent disease previously treated surgically elsewhere, with histologically positive margins. RESULTS: Tumors were most commonly located on the trunk. After the first stage of micrographic surgery, including an initial lateral margin, 20 (60.6%) tumors were completely excised, 11 (33.3%) tumors required two stages and one tumor each (3.0%) required 4 and 6 stages respectively. Patients were monitored for recurrence for a mean duration of 6.5 years. There was no recurrence in any of our 33 patients. CONCLUSIONS: Our results indicate that Moh's micrographic surgery with paraffin-embedded sections may be the method of choice to treat dermatofibrosarcoma protuberans with a low recurrence rate, while preserving surrounding normal healthy tissue.

Food in synchrony with melatonin and corticosterone relieves constant light disturbed metabolism.

Circadian disruption is associated with metabolic disturbances such as hepatic steatosis (HS), obesity and type 2 diabetes. We hypothesized that HS, resulting from constant light (LL) exposure is due to an inconsistency between signals related to food intake and endocrine-driven suprachiasmatic nucleus (SCN) outputs. Indeed, exposing rats to LL induced locomotor, food intake and hormone arrhythmicity together with the development of HS. We investigated whether providing temporal signals such as 12-h food availability or driving a corticosterone plus melatonin rhythm could restore rhythmicity and prevent the metabolic disturbances under LL conditions in male rats. Discrete metabolic improvements under these separate treatments stimulated us to investigate whether the combination of hormone treatment together with mealtime restriction (12-h food during four weeks) could prevent the metabolic alterations. LL exposed arrhythmic rats, received daily administration of corticosterone (2.5 µg/kg) and melatonin (2.5 mg/kg) in synchrony or out of synchrony with their 12-h meal. HS and other metabolic alterations were importantly ameliorated in LL-exposed rats receiving hormonal treatment in synchrony with 12-h restricted mealtime, while treatment out of phase with meal time did not. Interestingly, liver bile acids, a major indication for HS, were only normalized when animals received hormones in synchrony with food indicating that disrupted bile acid metabolism might be an important mechanism for the HS induction under LL conditions. We conclude that food-elicited signals, as well as hormonal signals, are necessary for liver synchronization and that HS arises when there is conflict between food intake and the normal pattern of melatonin and corticosterone.

Genomic reprograming analysis of the Mesothelial to Mesenchymal Transition identifies biomarkers in peritoneal dialysis patients.

Peritoneal dialysis (PD) is an effective renal replacement therapy, but a significant proportion of patients suffer PD-related complications, which limit the treatment duration. Mesothelial-to-mesenchymal transition (MMT) contributes to the PD-related peritoneal dysfunction. We analyzed the genetic reprograming of MMT to identify new biomarkers that may be tested in PD-patients. Microarray analysis revealed a partial overlapping between MMT induced in vitro and ex vivo in effluent-derived mesothelial cells, and that MMT is mainly a repression process being higher the number of genes that are down-regulated than those that are induced. Cellular morphology and number of altered genes showed that MMT ex vivo could be subdivided into two stages: early/epithelioid and advanced/non-epithelioid. RT-PCR array analysis demonstrated that a number of genes differentially expressed in effluent-derived non-epithelioid cells also showed significant differential expression when comparing standard versus low-GDP PD fluids. Thrombospondin-1 (TSP1), collagen-13 (COL13), vascular endothelial growth factor A (VEGFA), and gremlin-1 (GREM1) were measured in PD effluents, and except GREM1, showed significant differences between early and advanced stages of MMT, and their expression was associated with a high peritoneal transport status. The results establish a proof of concept about the feasibility of measuring MMT-associated secreted protein levels as potential biomarkers in PD.

Alternativa con gel de Papaver somniferum (amapola) y Cannabis sativa (marihuana), como tratamiento de artritis reumatoide / Alternative gel Papaver somniferum (poppy) and Cannabis sativa (marihuana), as treatment of rheumatoid arthritis

En la elaboración del presente producto farmacéutico (una formulación galénica entre el gel y la emulsión fluida), se utilizaron dos principios activos naturales considerados psicotrópicos o narcóticos: extracto alcohólico de amapola (Papaver somniferum) y extracto alcohólico de marihuana (Cannabis sativa); éstos tienen actividad biológica conocida dentro del organismo. Son excelentes analgésicos para pacientes con cáncer terminal pero también tienen propiedades antieméticas, estimulantes del apetito, relajantes oculares, bronquíticos, ansiolíticos. Se conoce que para tener una liberación prolongada de un principio activo es muy útil el uso de liposomas; por esta razón se utilizaron liposomas de extracto alcohólico de amapola, considerando que esta planta tiene mejores propiedades analgésicas que la marihuana, por lo cual el extracto de esta última integra un 40% de la formulación.