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Introduction: High-grade serous ovarian carcinoma is a neoplasm with a bleak prognosis. Despite advancements in therapies, altering the disease trajectory has proven elusive. In this context, immunotherapy emerges as a prospective alternative. Investigation into the tumor immune microenvironment, particularly the characterization and quantification of tumor-infiltrating lymphocytes (TILs), assumes critical significance. Two types of TILs are discerned based on their location within the neoplasm—stromal and intraepithelial. The latter is defined as TILs strongly associated with tumor cords. To precisely quantify TILs, novel methodologies such as digital image analysis are imperative, enabling the derivation of algorithms useful in estimating the prognostic role of TILs, with the potential to identify patients whose tumor microenvironment may be more conducive to immunotherapy. Objectives: Given the aforementioned context, our aim was to quantify the tumor immune microenvironment in a substantial cohort of patients diagnosed with high-grade serous ovarian carcinoma and establish its correlation with the BRCA gene mutation and pertinent oncological parameters. These parameters include the impact of neoadjuvancy, degree of tumor regression, overall survival, and platinum-free interval. To achieve this, original algorithms were devised to discern the prognostic value of TILs based on their location and quantity, with particular emphasis on CD8+ effector T lymphocytes. Materials and Methods: We conducted an analytical observational study involving 76 patients diagnosed with high-grade serous ovarian carcinoma between 2013 and 2022, with updated clinical follow-up. Techniques for quantifying intraepithelial and stromal TILs, encompassing tissue segmentation and cell classification through algorithms based on automatic image application (machine learning), were employed. This comprehensive evaluation was complemented by an immunohistochemical study focusing on CD8+ T lympho

Base de datos de 234 pacientes diagnosticadas de Carcinoma Ductal Infiltrante de mama que recoge un estudio observacional retrospectivo de 5 años donde se estudia en primer lugar la presencia o no de recidiva y/o mortalidad durante el período de estudio (5 años), permitiendo establecer variables independientes como la supervivencia y la mortalidad. En segundo lugar, se realiza un estudio y valoración de la expresión de diversos y distintos marcadores inmunohistoquímicos con el objetivo de correlacionar la expresión de cada una de las moléculas de Inmunohistoquímicas, unas con otras, así como, con la intención de obtener resultados concluyentes que apoyen una relación significativa de la expresión de alguna de éstas moléculas con el riesgo de recidiva (tiempo libre de enfermedad), así como con el riesgo de mortalidad (tiempo de supervivencia). El objetivo principal de esta base de datos es: Definir un perfil de biomarcadores inmunohistoquímicos con valor predictivo en el carcinoma ductal infiltrante de mama. El estudio pretende demostrar el posible valor pronóstico de cada molécula, valorándolo en función de la evolución (que vendrá determinada por la recidiva y la mortalidad), así como con factores pronósticos conocidos como: tamaño, edad, estadio inicial, ganglios y grado de Escala Bloom-Richardson y Escala de Nottingham.

The prevalence of obesity is increasingly widespread, resembling a global epidemic. Lifestyle changes, such as consumption of high-energy-dense diets and physical inactivity, are major contributors to obesity. Common features of this metabolic pathology involve an imbalance in lipid and glucose homeostasis including dyslipidemia, insulin resistance and adipose tissue dysfunction. Moreover, the importance of the gut microbiota in the development and susceptibility to obesity has recently been highlighted. In recent years, new strategies based on the use of functional foods, in particular bioactive peptides, have been proposed to counteract obesity outcomes. In this context, the present study examines the effects of a lupin protein hydrolysate (LPH) on obesity, dyslipidemia and gut dysbiosis in mice fed a high-fat diet (HFD). After 12 weeks of LPH treatment, mice gained less weight and showed decreased adipose dysfunction compared to the HFD-fed group. HFD-induced dyslipidemia (increased triglycerides, cholesterol and LDL concentration) and insulin resistance were both counteracted by LPH consumption. Discriminant analysis differentially distributed LPH-treated mice compared to non-treated mice. HFD reduced gut ecological parameters, promoted the blooming of deleterious taxa and reduced the abundance of commensal members. Some of these changes were corrected in the LPH group. Finally, correlation analysis suggested that changes in this microbial population could be responsible for the improvement in obesity outcomes. In conclusion, this is the first study to show the effect of LPH on improving weight gain, adiposopathy and gut dysbiosis in the context of diet-induced obesity, pointing to the therapeutic potential of bioactive peptides in metabolic diseases.

Cancer is a complex disease that, despite advances in treatment and the greater understanding of the tumor biology until today, continues to be a prevalent and lethal disease. Chemotherapy, radiotherapy, and surgery are the conventional treatments, which have increased the survival for cancer patients. However, the complexity of this disease together with the persistent problems due to tumor progression and recurrence, drug resistance, or side effects of therapy make it necessary to explore new strategies that address the challenges to obtain a positive response. One important point is that tumor cells can interact with the microenvironment, promoting proliferation, dissemination, and immune evasion. Therefore, immunotherapy has emerged as a novel therapy based on the modulation of the immune system for combating cancer, as reflected in the promising results both in preclinical studies and clinical trials obtained. In order to enhance the immune response, the combination of immunotherapy with nanoparticles has been conducted, improving the access of immune cells to the tumor, antigen presentation, as well as the induction of persistent immune responses. Therefore, nanomedicine holds an enormous potential to enhance the efficacy of cancer immunotherapy. Here, we review the most recent advances in specific molecular and cellular immunotherapy and in nano immunotherapy against cancer in the light of the latest published preclinical studies and clinical trials.

Introducción: El melanoma uveal (MU) es la neoplasia maligna primaria más frecuente del ojo, para la que no existen terapias eficaces cuando la enfermedad se disemina y en la que es muy importante conocer su pronóstico. El propósito de este trabajo es caracterizar mediante técnicas de secuenciación masiva (NGS) el perfil mutacional de una serie de MUs para buscar marcadores de utilidad pronóstica y terapéutica. Material y métodos: Hemos realizado un estudio retrospectivo observacional de 69 casos de MU diagnosticados en el Hospital Universitario Virgen Macarena. Para la captura híbrida de las regiones objetivo del estudio, en los primeros 38 casos, se empleó un panel de 519 genes basado en SureSelect HS2 (Agilent Technologies). Para la captura de las zonas dianas en los siguientes 31 casos se utilizó un Kit personalizado con un panel que incluía los 28 genes más frecuentemente mutados en la primera serie. Resultados: Se valoraron un total de 231 variantes genéticas que afectaban a la función de la proteína. Las mutaciones secundarias más frecuentes se produjeron en SF3B1 (en el 26%), seguido de BAP1 (en el 23%), LRP1B (22%) y FGFR4 (20%). La mutación de BAP1 se asoció con una mayor probabilidad de metástasis y con una mayor presencia de células epitelioides. LRP1B también se asoció con la presencia de células epitelioides. La mutación de SF3B1 se asoció significativamente con una morfología fusiforme. Encontramos variantes en RAD51B, TOP2A, PTPRD, TSC2, DHX9, PDK1 y MTOR que no se habían notificado previamente en las bases de datos consultadas. Los MUs que presentaron un subtipo histológico epitelioide, infiltración extraescleral o de cuerpo ciliar, mutación en BAP1, CHEK2, TSC2, DICER o IDO1 tienen más riesgo de producir metástasis en cualquier momento del seguimiento. Conclusiones: BAP1 es el biomarcador más sólido de mal pronóstico en MU y sus mutaciones pueden detectarse mediante NGS. SF3B1 se asocia con el subtipo de células fusiformes, lo que le confiere proba, Introduction: Uveal melanoma (UM) is the most common primary malignancy of the eye and there are no effective therapies for disseminated disease. It is important to try to know the patient’s prognosis. The purpose of this work is to characterize by massive sequencing techniques (NGS), the mutational profile of a series of UMs, to search for markers of prognostic and therapeutic utility. Material and methods: We have performed a retrospective observational study of 69 cases of UM diagnosed in the Hospital Universitario Virgen Macarena. For the hybrid capture of the target regions of the study, a panel of 519 genes based on SureSelect HS2 (Agilent Technologies) was used in the first 38 cases. For the capture of the target regions in the second cohort of cases, a custom kit was used with a panel including the 28 most frequently mutated genes in the first series. Results: A total of 231 genetic variants affecting protein function were assessed. The most frequent secondary mutations occurred in SF3B1 (in 26%), followed by BAP1 (in 23%), LRP1B (22%) and FGFR4 (20%). BAP1 mutation was associated with an increased likelihood of metastasis and with an increased presence of epithelioid cells. LRP1B was also associated with the presence of epithelioid cells. SF3B1 mutation was significantly associated with spindle-shaped morphology. We found variants in RAD51B, TOP2A, PTPRD, TSC2, DHX9, PDK1 and MTOR that were not previously reported in the databases consulted. UMs presenting with a epithelioid histological subtype, extrascleral or ciliary body infiltration, mutation in BAP1, CHEK2, TSC2, DICER or IDO1 are at higher risk of producing metastases at any instant of follow-up. Conclusions: BAP1 is the strongest biomarker of poor prognosis in UM and its mutations can be detected by NGS. SF3B1 is associated with the spindle cell subtype of UM, which probably confers a favorable prognostic value. Our study suggests that mutations in CHEK2, TSC2, DICER or IDO1 may have prognostic valu

Background: Sealing the peri-implant tissue is a determining factor for long-term implant survival. In the transmucosal region, the cervical fraction of the prosthetic crown is in contact with these tissues, so mucointegration will also be influenced by the biomaterial used for the prosthetic restoration. This study aims to compare the tissue response generated by definitive restorative materials and polymeric materials from a histological point of view. Methods: This study performed an observational prospective cohort study in which biopsies of the peri-implant mucosa were taken after placement of implant-supported prosthetic restorations made of different materials (zirconium oxide, lithium disilicate, and PMMA). Results: A statistically significant difference was observed in the increase in the thickness of the non-keratinized epithelium when comparing the definitive materials (zirconium oxide/lithium disilicate) vs. the provisional material (PMMA) and in the number of collagen fibers when comparing zirconium oxide and lithium disilicate. Conclusions: This study found that zirconia is the material that presents the most adequate biological response of peri-implant tissues. It shows a lower intensity of inflammatory cellular content, a total normality in the number of collagen fibers (the arrangement of the fibers is normal in 90% of the cases), and vascular proliferation of connective tissue in 83% of the cases. These parameters make it a material with a predictable response. Similarly, only the following slight statistically significant differences between the definitive and provisional materials are observed, indicating that the biological response generated by the provisional material (PMMA) is not very different from that obtained with the placement of the definitive restoration.

La hiperglucemia es una complicación muy común en el posoperatorio de cirugía cardíaca y, como tal, debe tener unos cuidados de enfermería óptimos y de acuerdo a la evidencia. Para este propósito, se ha desarrollado el algoritmo conocido como enhanced Model Predictive Control, siendo implementado en un dispositivo automatizado controlado por las enfermeras de cuidados intensivos, conocido como Space GlucoseContro®l. Este sistema pretende lograr un manejo de la glucosa en sangre seguro y efectivo, mejorando los protocolos tradicionales en papel de insulina endovenosa. Objetivo El propósito de la tesis doctoral ha sido conocer la efectividad y seguridad del sistema Space GlucoseControl® en el control de la glucemia en el posoperatorio inmediato de pacientes adultos intervenidos de cirugía cardíaca con ingreso en la unidad de cuidados intensivos. Métodos Se ha realizado un estudio intervención “antes y después” de forma prospectiva. Se seleccionaron 160 pacientes adultos de cirugía cardíaca con hiperglucemia: 80 en el grupo control desde mayo a noviembre de 2018 y 80 en el grupo intervención (usando el sistema Space GlucoseControl®) desde enero a diciembre de 2019. La variable de estudio principal fue el porcentaje de tiempo en rango (140-180 mg/dL en el grupo control y 100- 160 mg/dL en el grupo intervención). Resultados El porcentaje de tiempo en rango fue significativamente mayor en el grupo intervención que en el grupo control (70,5% [58,25-80] vs 54,83% [36,08-75], p < 0,001). El rango se alcanzó también de forma más rápida en el grupo intervención (5[3-6,875] horas vs 7 [4- 11] horas, p < 0,05. El primer valor de glucosa en sangre tras alcanzar el rango objetivo fue superior en el grupo control con significación estadística (p < 0,05). No existieron episodios de hipoglucemia en el grupo control. Sin embargo, durante el tratamiento con el Space GlucoseControl®, ocurrieron seis episodios de hipoglucemia, no siendo ninguno de ellos clasificado como grave (valor medi

Background: Mucointegration seems to gain interest when talking about success in the maintenance of dental implants. As we well know, collagen fibres cannot be inserted due to the lack of root structure on the implant surface, so the structural integration of peri-implant tissues that provide a firm seal around implants seems to be of interest when it comes to ensuring the survival of dental implants. To achieve a good epithelial barrier, the physicochemical characteristics of the surfaces of the restorative materials are of vital importance; therefore, the objective of this study is to analyse the histological behaviour of the peri-implant soft tissues in three different restorative materials. Methods: Histological analysis of biopsied peri-implant keratinised mucosa, inflammatory epithelium and connective tissue in contact with a reinforced composite (BRILLIANT Crios), a cross-linked polymethylmethacrylate (TELIO CAD), and a hybrid ceramic (Vita Enamic), restored on a customised Atlantis-type abutment (Dentsply Sirona) between 60 and 180 days after restoration. Results: A greater number of cells per mm2 of keratinised epithelium is observed in the reinforced composite, which could indicate greater surface roughness with greater inflammatory response. In this way, the greater number of lymphocytes and the lateral cellular composition of the inflammatory cells confirm the greater inflammatory activity towards that material. The best material to rehabilitate was hybrid ceramic, as it shows a better cellular response. Conclusions: Knowing the limitations of the proposed study, despite the fact that greater inflammation is observed in the reinforced composite relative to the other materials studied, no statistically significant differences were found.

Systemic lupus erythematosus (SLE) is a chronic immune-inflammatory disease characterized by multiorgan affectation and lowered self-tolerance. Additionally, epigenetic changes have been described as playing a pivotal role in SLE. This work aims to assess the effects of oleacein (OLA), one of the main extra virgin olive oil secoiridoids, when used to supplement the diet of a murine pristane-induced SLE model. In the study, 12-week-old female BALB/c mice were injected with pristane and fed with an OLA-enriched diet (0.01 % (w/w)) for 24 weeks. The presence of immune complexes was evaluated by immunohistochemistry and immunofluorescence. Endothelial dysfunction was studied in thoracic aortas. Signaling pathways and oxidative-inflammatory-related mediators were evaluated by Western blotting. Moreover, we studied epigenetic changes such as DNA methyltransferase (DNMT-1) and micro(mi)RNAs expression in renal tissue. Nutritional treatment with OLA reduced the deposition of immune complexes, ameliorating kidney damage. These protective effects could be related to the modulation of mitogen-activated protein kinases, the Janus kinase/signal transducer and transcription activator of transcription, nuclear factor kappa, nuclear-factor-erythroid-2-related factor 2, inflammasome signaling pathways, and the regulation of miRNAs (miRNA-126, miRNA-146a, miRNA-24-3p, and miRNA-123) and DNMT-1 expression. Moreover, the OLA-enriched diet normalized endothelial nitric oxide synthase and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-1 overexpression. These preliminary results suggest that an OLA-supplemented diet could constitute a new alternative nutraceutical therapy in the management of SLE, supporting this compound as a novel epigenetic modulator of the immunoinflammatory response.

EHMT1 is an epigenetic factor with histone methyltransferase activity that appears mutated in Kleefstra syndrome, a neurodevelopmental genetic disorder characterized by developmental delay, intellectual disability, and autistic-like features. Despite recent progress in the study of the function of this gene and the molecular etiology of the disease, our knowledge of how EHMT1 haploinsufficiency causes Kleefstra syndrome is still very limited. Here, we show that EHMT1 depletion in RPE1 cells leads to alterations in the morphology and distribution of different subcellular structures, such as the Golgi apparatus, the lysosomes and different cell adhesion components. EHMT1 downregulation also increases centriolar satellites detection, which may indicate a role for EHMT1 in centrosome functioning. Furthermore, the migration process is also altered in EHMT1 depleted cells, which show reduced migration capacity. We consider that the described phenotypes could open new possibilities for understanding the functional impact of EHMT1 haploinsufficiency in Kleefstra syndrome, helping to elucidate the link between epigenetic regulation and the underlying cellular mechanisms that result in this neurodevelopmental disorder. This knowledge could be relevant not only for the treatment of this syndrome, but also for other neurodevelopmental conditions that could share similar deregulated cellular pathways.

El cáncer de cabeza y cuello comprende un conjunto de tumores malignos que se originan en diferentes localizaciones anatómicas: cavidad oral, faringe, laringe, senos paranasales, cavidad nasal y glándulas salivales. Estos tumores se caracterizan por presentar una alta heterogeneidad, lo que complica la búsqueda de biomarcadores predictivos y de terapias dirigidas, elevando la tasa de mortalidad y el riesgo de recurrencia de estos tumores. Por estos motivos, en primer lugar, se buscaron genes cuya expresión se encontrara altamente desregulada en el tejido tumoral con respecto al tejido normal en bases de datos de cáncer de cabeza y cuello. Los genes WDR66, SERPINH1 y ZNF622 fueron capaces de estratificar a los pacientes en cuanto a su supervivencia global y, además, se encontró que podrían estar relacionados con el fenotipo de célula madre. Estos resultados nos llevaron a centrar el estudio en el gen WDR66, debido a que fue el que se relacionó con un peor pronóstico de los pacientes de cáncer de cabeza y cuello. WDR66 se expresa a niveles muy altos en cáncer de cabeza y cuello, asociándose esta expresión a una menor probabilidad de supervivencia de los pacientes. Sin embargo, al sobreexpresar este gen en líneas celulares de cáncer de cabeza y cuello procedentes de distintas localizaciones, no se produjeron cambios significativos en las propiedades tumorales ni en las relacionadas con el fenotipo de célula madre in vitro ni in vivo, debido posiblemente a una saturación fenotípica provocada por niveles muy elevados de WDR66 en las líneas celulares estudiadas. No obstante, en general observamos un mayor nivel de expresión de los factores de transcripción relacionados con pluripotencia OCT3/4, SOX2, KLF4 y LIN28. Además, la sobreexpresión de WDR66 ejerció un efecto protector frente a la apoptosis y un aumento de la resistencia a terapias convencionales usadas en cáncer de cabeza y cuello. Por otro lado, al disminuir la expresión de WDR66 mediante la técnica CRISPR-Cas9

Nitric oxide (NO) is a gaseous biomolecule endogenously synthesized with an essential role in embryonic development and several physiological functions, such as regulating mitochondrial respiration and modulation of the immune response. The dual role of NO in embryonic stem cells (ESCs) has been previously reported, preserving pluripotency and cell survival or inducing differentiation with a dose-dependent pattern. In this line, high doses of NO have been used in vitro cultures to induce focused differentiation toward different cell lineages being a key molecule in the regenerative medicine field. Moreover, optimal conditions to promote pluripotency in vitro are essential for their use in advanced therapies. In this sense, the molecular mechanisms underlying stemness regulation by NO have been studied intensively over the current years. Recently, we have reported the role of low NO as a hypoxia-like inducer in pluripotent stem cells (PSCs), which supports using this molecule to maintain pluripotency under normoxic conditions. In this review, we stress the role of NO levels on stem cells (SCs) fate as a new approach for potential cell therapy strategies. Furthermore, we highlight the recent uses of NO in regenerative medicine due to their properties regulating SCs biology.

In this work, the fatigue and cellular performance of novel superficially treated porous titanium dental implants made up using conventional powder metallurgy and space-holder techniques (30 vol.% and 50 vol.%, both with a spacer size range of 100–200 µm) are evaluated. Before the sintering stage, a specific stage of CNC milling of the screw thread of the implant is used. After the consolidation processing, different surface modifications are performed: chemical etching and bioactive coatings (BG 45S5 and BG 1393). The results are discussed in terms of the effect of the porosity, as well as the surface roughness, chemical composition, and adherence of the coatings on the fatigue resistance and the osteoblast cells’ behavior for the proposed implants. Macro-pores are preferential sites of the nucleation of cracks and bone cell adhesion, and they increase the cellular activity of the implants, but decrease the fatigue life. In conclusion, SH 30 vol.% dental implant chemical etching presents the best bio-functional (in vitro osseointegration) and bio-mechanical (stiffness, yield strength and fatigue life) balance, which could ensure the required characteristics of cortical bone tissue.

En la actualidad el hambre y los malos hábitos alimenticios son un problema reconocido por la organización mundial de la salud (OMS). A pesar de todos los esfuerzos propuestos para solventar este problema, la OMS ha admitido que no se alcanzará el objetivo de hambre cero para 2030. Por todo esto y para aportar soluciones imaginativas a este problema, nos propusimos emplear nanopartículas poliméricas cargadas con zinc, junto con la bacteria Pantoea agglomerans, promotora de crecimiento de plantas (PGPR), para mejorar el valor nutricional de plantas como el trigo (Triticum aestivum), mediante bioforitficación. Las plantas de trigo fueron tratadas, tras su previa germinación, y se recogieron medidas de concentración de metales usando técnicas analíticas. Los resultados mostraron que los parámetros físicos y fisiológicos no se vieron afectados y se produjo una acumulación notoria del Zn en la parte aérea.

The chemical composition and surface topography of titanium implants are essential to improve implant osseointegration. The present work studies a non-invasive alternative of electrical impedance spectroscopy for the characterization of the macroporosity inherent to the manufacturing process and the effect of the surface treatment with femtosecond laser of titanium discs. Osteoblasts cell culture growths on the titanium surfaces of the laser-treated discs were also studied with this method. The measurements obtained showed that the femtosecond laser treatment of the samples and cell culture produced a significant increase (around 50%) in the absolute value of the electrical impedance module, which could be characterized in a wide range of frequencies (being more relevant at 500 MHz). Results have revealed the potential of this measurement technique, in terms of advantages, in comparison to tiresome and expensive techniques, allowing semi-quantitatively relating impedance measurements to porosity content, as well as detecting the effect of surface modification, generated by laser treatment and cell culture.

The transcription factor, early growth response-1 (EGR-1), is involved in the regulation of cell differentiation, proliferation, and apoptosis in response to different stimuli. EGR-1 is described to be involved in pancreatic endoderm differentiation, but the regulatory mechanisms controlling its action are not fully elucidated. Our previous investigation reported that exposure of mouse embryonic stem cells (mESCs) to the chemical nitric oxide (NO) donor diethylenetriamine nitric oxide adduct (DETA-NO) induces the expression of early differentiation genes such as pancreatic and duodenal homeobox 1 (Pdx1). We have also evidenced that Pdx1 expression is associated with the release of polycomb repressive complex 2 (PRC2) and P300 from the Pdx1 promoter; these events were accompanied by epigenetic changes to histones and site-specific changes in the DNA methylation. Here, we investigate the role of EGR-1 on Pdx1 regulation in mESCs. This study reveals that EGR-1 plays a negative role in Pdx1 expression and shows that the binding capacity of EGR-1 to the Pdx1 promoter depends on the methylation level of its DNA binding site and its acetylation state. These results suggest that targeting EGR-1 at early differentiation stages might be relevant for directing pluripotent cells into Pdx1-dependent cell lineages.

Introduction: Metanephric adenoma (MA) is an uncommon benign tumor accounting for 0.2–0.7% of adult renal epithelial neoplasms. The clinical course is often indolent, but diagnosis should not be delayed since clinical symptoms (hematuria, fever, palpable abdominal mass, and flank pain) may be non-specific and overlap with those of a malign renal neoplasm. We report on 4 cases of AM, for which morphological and mutational analysis were performed. Material and Methods: Immunohistochemical staining was performed on sections cut from paraffin blocks to assess expression of WT1, vimentin, racemase, CK7, CD10 and RCC. Testing for the BRAF gene mutation V600 was carried out using real-time PCR (Cobas® 4800). Results: In all four cases, tumors were visible as well-circumscribed, non encapsulated masses located in the renal cortex and extending towards the medulla. At immunohistochemical examination, tumor cells stained negative for CK7, CD10 and RCC and positive for both WT1 (nuclear, intense) and vimentin (cytoplasmic, intense, and diffuse). Molecular analysis revealed the BRAF gene mutation V600E in three cases and wild-type BRAF in the fourth. Conclusions: BRAF molecular mutation analysis may aid diagnosis in cases with atypical histological features, especially in small incisional biopsies when reassessment of surgical treatment may be considered.

Background: Merkel cell carcinoma (MCC) is a malignant skin cancer with a 5-year survival rate of approximately 50%. Knowledge of MCC has increased in recent years mostly due to improved diagnosis techniques. In Spain there is lack of information regarding the incidence and tumour characteristics, and the treatment approaches are not standardised. The objective of this study was to provide information of the clinical and epidemiological characteristics of MCC patients in Spain. Methods: Retrospective, observational study involving 192 patients from 25 Spanish hospitals. Evaluated vari ables included overall survival and incidence rate of Merkel cell polyomavirus, in patients diagnosed from 2012 to 2016. Results: The Spanish incidence rate was estimated 0.32/100,000 inhabitants/year, with variations according to geographical regions, being slightly higher in areas with greater sunlight exposure. In total, 61.5% of tumours showed expansive growth (progressive growth of the tumour), 78.6% showed localisation in UV-exposed skin. 97.4% of patients were diagnosed by excisional biopsy. Surgery was the first line treatment in 96.6% of patients, radiotherapy in 24.6%, and chemotherapy in 6.3%. These treatments were not mutually exclusive. Median overall survival was 38.3 months (78.4% at 12 months and 60% at 24 months). MCPyV was present in 33.8% of patients. Conclusion: The incidence of MCC in Spain is one of the highest in Europe, with a slight predominance in men. The sample has shown that a biopsy is available for diagnosis in most cases. Moreover, the treatment is surgical when the tumour is localized and is associated with lymphadenectomy, and/or it is radiotherapy if widespread.

El shock séptico es una enfermedad con una mortalidad que ronda el 50% aproximadamente, según las series, por ello la necesidad continua de la búsqueda de nuevos biomarcadores que nos ayuden en el manejo del volumen, soporte hemodinámico y pronóstico de esta enfermedad. Estudiamos los niveles de MR-proADM y copeptina al inicio del shock séptico o su cambio en las primeras 6 horas para predecir qué pacientes con shock séptico presentarán mayor requerimiento de vasopresores (medido por índice de inotrópicos e índice de dependencia de vasopresores) y aporte de volumen en las primeras 24 h, siendo por tanto tributarios de monitorización hemodinámica invasiva desde el inicio del shock séptico. Realizamos un estudio de cohortes, prospectivo y observacional en el que se incluyeron 103 pacientes ingresados en UCI con edad mayor o igual a 18 años y con diagnóstico de shock séptico según los criterios publicados en 2016. Se midieron valores de lactato, MR-proADM y copeptina basal y a las 6 horas. Se recogieron diferentes variables demográficas, comorbilidades, escalas de gravedad como APACHE II Y SOFA, variables relacionadas con la localización y microorganismo responsable de la infección así como su antibioterapia, tipo y cantidad de fluidos infundidos, dosis de fármacos vasoactivos e inotropos y el tiempo de su empleo. Se realizaron cálculos para el índice de inotropos, índice de dependencia de vasopresores, delta MR-proADM, delta copeptina y delta lactato. Se realizó análisis descriptivo, bivariante y multivariante y tras los resultados obtenidos, podemos concluir: 1.Los pacientes con shock séptico presentan niveles elevados de MR-proADM y copeptina al diagnóstico modificándose a las 6 horas. 2. El valor de MR-proADM plasmático en los pacientes que presentan shock séptico, así como sus cambios a las 6 horas y el delta MR-proADM puede ayudar a predecir aquellos pacientes que van a requerir mayor soporte vasoactivo en las primeras 24 horas. 3. Por cada unidad de incremento d

The Hippo pathway is an evolutionarily conserved modulator of developmental biology with a key role in tissue and organ size regulation under homeostatic conditions. Like other signaling pathways with a significant role in embryonic development, the deregulation of Hippo signaling contributes to oncogenesis. Central to the Hippo pathway is a conserved cascade of adaptor proteins and inhibitory kinases that converge and regulate the activity of the oncoproteins YAP and TAZ, the final transducers of the pathway. Elevated levels and aberrant activation of YAP and TAZ have been described in many cancers. Though most of the studies describe their pervasive activation in epithelial neoplasms, there is increasing evidence pointing out its relevance in mesenchymal malignancies as well. Interestingly, somatic or germline mutations in genes of the Hippo pathway are scarce compared to other signaling pathways that are frequently disrupted in cancer. However, in the case of sarcomas, several examples of genetic alteration of Hippo members, including gene fusions, have been described during the last few years. Here, we review the current knowledge of Hippo pathway implication in sarcoma, describing mechanistic hints recently reported in specific histological entities and how these alterations represent an opportunity for targeted therapy in this heterogeneous group of neoplasm.

Multicenter, prospective, observational study to compare the relative bioavailability of once-daily tacrolimus formulations in de novo kidney transplant recipients. De novo kidney transplant recipients who started a tacrolimus-based regimen were included 14 days post-transplant and followed up for 6 months. Data from 218 participants were evaluated: 129 in the LCPT group (Envarsus) and 89 in the PR-Tac (Advagraf) group. Patients in the LCPT group exhibited higher relative bioavailability (Cmin /total daily dose [TDD]) vs. PR-Tac (61% increase; P < .001) with similar Cmin and 30% lower TDD levels (P < .0001). The incidence of treatment failure was 3.9% in the LCPT group and 9.0% in the PR-Tac group (P = .117). Study discontinuation rates were 6.2% in the LCPT group and 12.4% in the PR-Tac group (P = .113). Adverse events, renal function and other complications were comparable between groups. The median accumulated dose of tacrolimus in the LCPT group from day 14 to month 6 was 889 mg. Compared to PR-Tac, LCPT showed higher relative bioavailability, similar effectiveness at preventing allograft rejection, comparable effect on renal function, safety, adherence, treatment failure and premature discontinuation rates.

Lobar selective internal radiation therapy (SIRT) is widely used to treat liver tumors inducing atrophy of the treated lobe and contralateral hypertrophy. The lack of animal model has precluded further investigations to improve this treatment. We developed an animal model of liver damage and atrophy–hypertrophy complex after SIRT. Three groups of 5–8 rabbits received transportal SIRT with Yttrium 90 resin microspheres of the cranial lobes with different activities (0.3, 0.6 and 1.2 GBq), corresponding to predicted absorbed radiation dose of 200, 400 and 800 Gy, respectively. Another group received non-loaded microspheres (sham group). Cranial and caudal lobes volumes were assessed using CT volumetry before, 15 and 30 days after SIRT. Liver biochemistry, histopathology and gene expression were evaluated. Four untreated rabbits were used as controls for gene expression studies. All animals receiving 1.2 GBq were euthanized due to clinical deterioration. Cranial SIRT with 0.6 GBq induced caudal lobe hypertrophy after 15 days (median increase 34% -ns-) but produced significant toxicity. Cranial SIRT with 0.3 GBq induced caudal lobe hypertrophy after 30 days (median increase 82%, p = 0.04). No volumetric changes were detected in sham group. Transient increase in serum transaminases was detected in all treated groups returning to normal values at 15 days. There was dose-dependent liver dysfunction with bilirubin elevation and albumin decrease. Histologically, 1.2 GBq group developed permanent severe liver damage with massive necrosis, 0.6 and 0.3 GBq groups developed moderate damage with inflammation and portal fibrosis at 15 days, partially recovering at 30 days. There was no difference in the expression of hepatocyte function and differentiation genes between 0.3 GBq and control groups. Cranial SIRT with 0.3 GBq of 90Y resin microspheres in rabbits is a reliable animal model to analyse the atrophy–hypertrophy complex and liver damage without toxicity.

Osteosarcoma is a primary malignant bone tumor usually arising at the metaphysis of long bones, particularly around the knee. The physis has been regarded as a barrier capable of blocking tumor extension, thus allowing it to preserve their epiphysis and therefore improve functional results. With the objective of clarifying how effective the physis is as a barrier to tumor spread, a large series of skeletally immature patients with osteosarcoma were reviewed. From 452 metaphyseal osteosarcomas a selection of 282 cases in which the tumor was close or crossing the physis were carried out. This sub-sample was split into two groups according to the surgical treatment (epiphyseal preservation or not). The specimens obtained by resection were studied, and the physeal and metaphyseal areas were studied by multiple sections. Immunostaining against VEGF of physis was obtained in selected cases. In about half of the patients affected by metaphyseal malignant bone tumors, the growth plate and epiphysis were not compromised by the tumor. Three sequential invasive growth patterns of an osteosarcoma in its relationship with the physis could be distinguished. An intense angiogenesis and osteoclastic reaction could be observed in the growth plate in the free zone between the tumor and the physis. The local recurrence incidence was lower in the epiphyseal preservation treated patients than it was in the conventional treatment (8% vs. 12%). Most local recurrences appeared in the first 2 years. The overall survival of patients treated with epiphyseal preservation was better than that of the patients treated without preserving the epiphysis (73% vs. 59%; p = 0.03) at a mean follow-up of 18 years. We have described an angiogenic and osteoclastic reaction in the base of the growth plate in the proximity of the advance front of the tumor, which could facilitate the osteosarcoma invasion. It is also shown that the preoperative imaging method for examination is a valid approach for the decis

Ewing sarcoma (EWS) is an aggressive bone and soft tissue tumor with high susceptibility to metastasize. The underlying molecular mechanisms leading to EWS metastases remain poorly understood. Epigenetic changes have been implicated in EWS tumor growth and progression. Linking epigenetics and metastases may provide insight into novel molecular targets in EWS and improve its treatment. Here, we evaluated the effects of a selective G9a histone methyltransferase inhibitor (BIX01294) on EWS metastatic process. Our results showed that overexpression of G9a in tumors from EWS patients correlates with poor prognosis. Moreover, we observe a significantly higher expression of G9a in metastatic EWS tumor as compared to either primary or recurrent tumor. Using functional assays, we demonstrate that pharmacological G9a inhibition using BIX01294 disrupts several metastatic steps in vitro, such as migration, invasion, adhesion, colony formation and vasculogenic mimicry. Moreover, BIX01294 reduces tumor growth and metastases in two spontaneous metastases mouse models. We further identified the sialidase NEU1 as a direct target and effector of G9a in the metastatic process in EWS. NEU1 overexpression impairs migration, invasion and clonogenic capacity of EWS cell lines. Overall, G9a inhibition impairs metastases in vitro and in vivo through the overexpression of NEU1. G9a has strong potential as a prognostic marker and may be a promising therapeutic target for EWS patients.

The majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis. This is a paradox, since more than 90% of cancer deaths are attributable to metastatic progression. Integrin alpha9 (ITGA9) has been previously described as playing an essential role in metastasis; however, little is known about the mechanism that links this protein to this process, being one of the less studied integrins. We have now deciphered the importance of ITGA9 in metastasis and provide evidence demonstrating its essentiality for metastatic dissemination in rhabdomyosarcoma and neuroblastoma. However, the most translational advance of this study is to reveal, for the first time, the possibility of reducing metastasis by pharmacological inhibition of ITGA9 with a synthetic peptide simulating a key interaction domain of ADAM proteins, in experimental metastasis models, not only in childhood cancers but also in a breast cancer model.

Pendred syndrome (PDS) is an autosomal recessive disorder caused by mutations in the gene that encodes pendrin. Pendred thyroid tissue is supposedly altered by the absence of functional pendrin, but it is still unknown whether other iodide exchang ers could compensate for the loss of the protein. Moreover, we have recently described that primary cilium, a conserved structure present at the apical surface of normal follicular cells, suffers different alterations in functional thyroid diseases. We aimed (1) to better understand the histopathological changes experienced by PDS thyroids, (2) to analyze the expression of different thyroid-specific genes and alternative iodide transporters and, finally, (3) to determine whether those changes may alter the morphological pattern of primary cilia in follicular cells. Thyroid samples from a series of four PDS patients were analyzed by immunohistochemistry, double immunofluorescence, and morphometry to evaluate changes in primary cilia frequency and length. We found thyroid follicular nodular disease in all PDS thyroids, frequently in association with follicular adenomas. There were only slight changes in the expression of thyroid-specific markers. Although no positivity for pendrin was found, cytoplasmic immunostaining for ANO-1, CLC-5, and CFTR was stronger in diffuse hyperplastic areas when compared to areas with highly cellular follicular nodules (HCFNs). HCFNs and follicular adenomas always showed diminished ciliary frequency and length. Our results suggest a direct relationship between the absence of functional pendrin and the loss of the normal thyroid architecture in PDS patients, which was also accompanied by differences in the expression of specific immunohistochemical markers and altered ciliogenesis. The present data may help the pathologist in screening for PDS.

Ewing Sarcoma (EWS) is an aggressive bone and soft tissue tumor that mainly affects children, adolescents, and young adults. The standard therapy, including chemotherapy, surgery, and radiotherapy, has substantially improved the survival of EWS patients with localized disease. Unfortunately, this multimodal treatment remains elusive in clinics for those patients with recurrent or metastatic disease who have an unfavorable prognosis. Consistently, there is an urgent need to find new strategies for patients that fail to respond to standard therapies. In this regard, in the last decade, treatments targeting epigenetic dependencies in tumor cells and the immune system have emerged into the clinical scenario. Additionally, recent advances in nanomedicine provide novel delivery drug systems, which may address challenges such as side effects and toxicity. Therefore, therapeutic strategies stemming from epigenetics, immunology, and nanomedicine yield promising alternatives for treating these patients. In this review, we highlight the most relevant EWS preclinical and clinical studies in epigenetics, immunotherapy, and nanotherapy conducted in the last five years.

Endoglin (ENG) is a mesenchymal stem cell (MSC) marker typically expressed by active endothelium. This transmembrane glycoprotein is shed by matrix metalloproteinase 14 (MMP14). Our previous work demonstrated potent preclinical activity of first-in-class anti-ENG antibody-drug conjugates as a nascent strategy to eradicate Ewing sarcoma (ES), a devastating rare bone/soft tissue cancer with a putative MSC origin. We also defined a correlation between ENG and MMP14 expression in ES. Herein, we show that ENG expression is significantly associated with a dismal prognosis in a large cohort of ES patients. Moreover, both ENG/MMP14 are frequently expressed in primary ES tumors and metastasis. To deepen in their functional relevance in ES, we conducted transcriptomic and proteomic profiling of in vitro ES models that unveiled a key role of ENG and MMP14 in cell mechano-transduction. Migration and adhesion assays confirmed that loss of ENG disrupts actin filament assembly and filopodia formation, with a concomitant effect on cell spreading. Furthermore, we observed that ENG regulates cell–matrix interaction through activation of focal adhesion signaling and protein kinase C expression. In turn, loss of MMP14 contributed to a more adhesive phenotype of ES cells by modulating the transcriptional extracellular matrix dynamics. Overall, these results suggest that ENG and MMP14 exert a significant role in mediating correct spreading machinery of ES cells, impacting the aggressiveness of the disease.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that arises due to a complex and variable interplay between elements including age, genetic, and environmental risk factors that manifest as the loss of dopaminergic neurons. Contemporary treatments for PD do not prevent or reverse the extent of neurodegeneration that is characteristic of this disorder and accordingly, there is a strong need to develop new approaches which address the underlying disease process and provide benefit to patients with this debilitating disorder. Mitochondrial dysfunction, oxidative damage, and inflammation have been implicated as pathophysiological mechanisms underlying the selective loss of dopaminergic neurons seen in PD. However, results of studies aiming to inhibit these pathways have shown variable success, and outcomes from large-scale clinical trials are not available or report varying success for the interventions studied. Overall, the available data suggest that further development and testing of novel therapies are required to identify new potential therapies for combating PD. Herein, this review reports on the most recent development of antioxidant and anti-inflammatory approaches that have shown positive benefit in cell and animal models of disease with a focus on supplementation with natural product therapies and selected synthetic drugs.

Objectives: Immunostimulatory therapies using immune checkpoint blockers show clinical activity in a subset of glioblastoma (GBM) patients. Several inhibitory mechanisms play a relevant role in the immune response to GBM. With the objective of analyzing the tumor immune microenvi ronment and its clinical significance, we quantified several relevant immune biomarkers. Design: We studied 76 primary (non-recurrent) GBMs with sufficient clinical follow-up, including a subgroup of patients treated with a dendritic cell vaccine. The IDH-mutation, EGFR-amplification, and MGMT methylation statuses were determined. Several relevant immune biomarkers, including CD163, CD8, PD1, and PDL1, were quantified in representative selected areas by digital image analysis and semi quantitative evaluation. The percentage of each immune expression was calculated with respect to the total number of tumor cells. Results: All GBMs were wild-type IDH, with a subgroup of classical GBMs according to the EGFR amplification (44%). Morphologically, CD163 immunostained microglia and intratumor clusters of macrophages were observed. A significant direct correlation was found between the expression of CD8 and the mechanisms of lymphocyte immunosuppression, in such a way that higher values of CD8 were directly associated with higher values of CD163 (p < 0.001), PDL1 (0.026), and PD1 (0.007). In a multivariate analysis, high expressions of CD8+ (HR = 2.05, 95%CI (1.02–4.13), p = 0.034) and CD163+ cells (HR 2.50, 95%CI (1.29–4.85), p = 0.007), were associated with shorter survival durations. The expression of immune biomarkers was higher in the non-classical (non-EGFR amplified tumors) GBMs. Other relevant prognostic factors were age, receipt of the dendritic cell vaccine, and MGMT methylation status. Conclusions: In accordance with the inverse correlation between CD8 and survival and the direct correlation between effector cells and CD163 macrophages and immune-checkpoint expression, we postulate that

Circulating osteogenic precursor (COP) cells are peripheral blood cells with a capacity for osteogenesis. The objective of our study was to ascertain the percentage of COPs as an early biomarker of osteoporosis and the effect of these cells in response to Denosumab (DmAb) (anti-resorptive) or to Teriparatide (TPDP) (anabolic) as very effective drugs in the treatment of the illness. A first study was conducted on healthy volunteers, with three age ranges, to determine the percentage of COPs and relate it to their anthropometric and biochemical characteristics, followed by a second longitudinal study on patients with osteoporosis, whereby one group of patients was treated with TPTD and another with DmAb. All were analyzed by cytometry for COP percentage in blood, bone turnover markers, and bone mass. Our findings show that COPs are influenced by age and become more prolific in the stages of growth and skeletal maturation. A higher percentage of COPs is found in osteoporotic disease, which could constitute a predictive marker thereof. We also show how treatment with TPTD or DmAb mobilizes circulating osteogenic precursors in the blood. Significant increases in % COPs were observed after 12 months of treatment with Dmb (21.9%) and TPTD (17%). These results can be related to an increase in osteogenesis and, consequently, a better and more efficient repair of bone tissue.

Summary REFRA-FLS is a new registry in Spain aimed at identifying individuals over 50 years of age with a fragility fracture. Using this registry, we found hip fracture is the most prevalent fracture. Treatment for osteoporosis was 87.7%, with 65.3% adherence. REFRA-FLS provides fundamental data in the study of fragility fractures. Purpose Fragility fractures are a growing public health concern in modern-aged societies. Fracture Liaison Services (FLS) have been shown to successfully lower rates of secondary fractures. A new registry (REFRA-FLS) has been created to moni tor quality indicators of FLS units in Spain and to explore the occurrence and characteristic of fragility fractures identifed by these centers. Methods We conducted a prospective cohort study based on fragility fractures recorded in the REFRA-FLS registry. Par ticipants were individuals 50 years or above who sufered a low energy fragility fracture identifed by the 10 participating FLS units during the study period. The type of FLS unit, the characteristics of the individuals at baseline, along with patient outcomes as quality indicators among those who completed 1 year of follow-up were analyzed. Results A total of 2965 patients and 3067 fragility fractures were identifed, and the most frequent locations were hip (n=1709, 55.7%) and spine (n=492, 16.0%). A total of 43 refractures (4.5%) and 46 deaths (4.9%) were observed among 948 individuals in the follow-up analyses. Time from fracture to evaluation was less than 3 months in 76.7% of individuals. Osteoporosis treatment was prescribed in 87.7%, and adherence was 65.3% in Morisky–Green test. Conclusion Our results provide a comprehensive picture of fragility fractures identifed in FLS units from Spain. Overall, quality indicators are satisfactory although a much higher use of DXA would be desirable. As the registry grows with the incorporation of new FLS units and longer follow-up, incoming analyses will provide valuable insight.

Background: To assess the cost-effectiveness of using next-generation sequencing (NGS) compared to sequential single-testing (SST) for molecular diagnostic and treatment of patients with advanced non- small cell lung cancer (NSCLC) from a Spanish single-center perspective, the Hospital Universitario Virgen del Rocio (HUVR). Research design and methods: A decision-tree model was developed to assess the alterations detection alterations and diagnostic cost in patients with advanced NSCLC, comparing NGS versus SST. Model inputs such as testing, positivity rates, or treatment allocation were obtained from the literature and the clinical practice of HUVR experts through consultation. Several sensitivity analyses were performed to test the robustness of the model. Results: Using NGS for molecular diagnosis of a 100-patients hypothetical cohort, 30 more alterations could be detected and 3 more patients could be enrolled in clinical-trials than using SST. On the other hand, diagnostic costs were increased up to €20,072 using NGS instead of SST. Using NGS time-to- results would be reduced from 16.7 to 9 days. Conclusions: The implementation of NGS at HUVR for the diagnostic of patients with advanced NSCLC provides significant clinical benefits compared to SST in terms of alterations detected, treatment with targeted-therapies and clinical-trial enrollment, and could be considered a cost-effective strategy.

Background In mammals, the thyroid gland possesses two types of endocrine cells, follicular cells and C cells, which have different functions but share a similar endodermal origin (although from different regions of the primitive pharynx). Specifically, follicular cells derive from the ventral pharyngeal floor, while C cells derive from the fourth pair of pharyngeal pouches through the ultimobranchial bodies (UBBs). Disruptions to human midline thyroid morphogenesis are relatively frequent and known as thyroid dysgenesis, which is the leading cause of congenital hypothyroidism. In contrast, fourth branchial apparatus anomalies are very rare clinical entities. Objectives The aim of this study was to analyze the morphological features and the immunohistochemical pattern of an aberrant ultimobranchial remnant, align with its persistent contribution to the formation of new C cells. Methods The thyroid gland of an old rat was serially sectioned and immunostained for the following markers: calcitonin, thyroglobulin, cytokeratins, PCNA, P63, E-cadherin, beta-tubulin and CD3. Results We detected a spontaneous congenital defect in the organogenesis of the UBB in an old rat, giving rise to an ‘ultimobranchial sinus’, which was accompanied by thymic tissue and an abscess. The epithelium contained basal/stem cells and contributed to the formation of abundant C cells and scarce follicular cells. Conclusions The ultimobranchial sinus is an exceptional finding for representing the first spontaneous abnormality in the development of UBB reported in rats, and the opportunity to observe sustained C-cell differentiation from stem cells in an old rat. These findings are consistent with a common origin of both C cells and follicular cells from UBB.

Rationale: We recently demonstrated that the ‘Metabesity’ factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1-CoREST complex but its expression pattern and function in adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues. Methods: HMG20A expression profile was assessed by quantitative PCR (QT-PCR), Western blotting and/or immunofluorescence in: 1) the hypothalamus of mice exposed or not to either a high-fat diet or a high-fat high-sucrose regimen, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals and 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate. RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A. Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-treated astrocytes. The impact of ORY1001, an inhibitor of the LSD1-CoREST complex, on HMG20A expression, reactive astrogliosis and glucose metabolism was evaluated in vitro and in vivo in high-fat high-sucrose fed mice. Results: We show that Hmg20a is predominantly expressed in hypothalamic astrocytes, the main nutrient-sensing cell type of the brain. HMG20A expression was upregulated in diet-induced obesity and glucose intolerant mice, correlating with increased transcript levels of Gfap and Il1b indicative of inflammation and reactive astrogliosis. Hmg20a transcript levels were also increased in adipose tissue of obese non-diabetic individuals as compared to obese diabetic patients. HMG20A silencing in astrocytes resulted in repression of inflammatory, cholestero

En esta serie de 2 artículos realizamos una revisión de las principales entidades dermatopatológicas que cursan con granulomas. Esta primera parte se ha centrado en la aclaración de los conceptos, la presentación de los tipos de granulomas y de las células gigantes, así como en entidades muy diversas de origen no infeccioso. Algunas de ellas de origen metabólico, como la necrobiosis lipoídica: otras relacionadas con linfomas, como la micosis fungoides granulomatosa, y otras tan extendidas que casi resultan un problema cotidiano en las consultas de dermatología, como la rosácea., This series of 2 articles on dermatopathologic diagnoses reviews conditions in which granulomas form. Part 1 clarifies concepts, discusses the presentation of different types of granulomas and giant cells, and considers a large variety of noninfectious diseases. Some granulomatous diseases have a metabolic origin, as in necrobiosis lipoidica. Others, such as granulomatous mycosis fungoides, are related to lymphomas. Still others, such as rosacea, are so common that dermatologists see them nearly daily in clinical practice.

Introducción: El cáncer de próstata (CaP) constituye un serio problema para la población masculina adulta, siendo la neoplasia sólida no cutánea más frecuente en Europa y la segunda causa de muerte cáncer-específica. Se estima que su incidencia seguirá incrementándose un 3-4% anualmente hasta 2040. Sería interesante conocer nuevos factores que puedan ayudar a clasificar a los pacientes en grupos pronósticos. Por consiguiente, este estudio plantea el análisis de factores histopatológicos que definan mejor la heterogeneidad observada dentro de los grupos estándar actuales, adaptando e indicando mejor la maniobra terapéutica, con el fin de no caer en el sobretratamiento o tratamiento deficiente en algunos de ellos. Objetivo: Analizar si la cantidad tumoral detectada en la biopsia de próstata transrectal, medida en milímetros de cilindros afectos o en porcentaje total de tumor, es un factor predictor de la afectación de márgenes quirúrgicos, así como de progresión bioquímica tras la cirugía. Material y método: Estudio de cohorte retrospectivo que incluye a 142 pacientes del Área de gestión Sanitaria Sur (AGSS) de Sevilla, intervenidos de prostatectomía radical por el servicio de Urología del Hospital de Valme entre junio de 2009 y junio de 2014 tras haber sido diagnosticados de CaP localizado mediante biopsias prostáticas aleatorias guiadas por ecografía transrectal. A través del análisis y la revisión de las muestras de biopsia se definió la proporción de tumor detectada en la biopsia de cada paciente en milímetros de tumor y en porcentaje total de cáncer, comparándola posteriormente con los datos de la pieza quirúrgica y con los de progresión bioquímica. Resultados: La mediana del porcentaje de cáncer en biopsia en pacientes con afectación multifocal de márgenes quirúrgicos difiere en más del 20% de la que presentan los pacientes con márgenes negativos. Existe una diferencia entre medianas mayor de 7,15 mm de tumor en los pacientes con afectación multifocal de márgene

La patología vascular oclusiva es causante de diversas y variadas manifestaciones clínicas, algunas de las cuales son de catastróficas consecuencias para el paciente. Sin embargo, las causas de tal oclusión son muy variadas, extendiéndose desde trombos por acción descontrolada de los mecanismos de coagulación, hasta anomalías de los endotelios de los vasos u oclusión por materiales extrínsecos. En una serie de dos artículos hacemos una revisión de las principales causas de oclusión vascular, resumiendo sus manifestaciones clínicas principales y los hallazgos histopatológicos fundamentales. Esta primera parte corresponde a las oclusiones vasculares que cursan con trombos., Vascular occlusion has multiple, diverse clinical manifestations, some of which can have grave consequences for patients. The causes of vascular occlusion are also highly variable, ranging from thrombi triggered by the uncontrolled activation of coagulation mechanisms, on the one hand, to endothelial dysfunction or occlusion by material extrinsic to the coagulation system on the other. In a 2-part review, we look at the main causes of vascular occlusion and the key clinical and histopathologic findings. In this first part, we focus on vascular occlusion involving thrombi.

One of the major obstacles to the development of effective new cancer treatments and the main factor for the increasing number of clinical trial failures appears to be the paucity of accurate, reproducible and robust drug resistance testing methods. Most research assessing the resistance of cancers to chemotherapy has concentrated on genetic-based molecular mechanisms, while the role of epigenetics in drug resistance has been generally overlooked. This is rather surprising given that an increasing body of evidence pointing to the fact that epigenetic mechanism alterations appear to play a pivotal role in cancer initiation, progression and development of chemoresistance. This resulted in a series of clinical trials involving epi-drug as single treatment or combined with cancer conventional drugs. In this review, we provided the main mechanisms by which the epigenetic regulators control the resistance to cancer drugs.