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La terapia con aspirina a dosis bajas al principio del embarazo puede prevenir: "preeclampsia y la restricción del crecimiento intrauterino (RCIU)", estas complicaciones están asociadas con la disfunción placentaria y podrían prevenirse, lo que sugiere que exista un mecanismo fisiopatológico que las asocien. Objetivo: Determinar el rol del ácido acetilsalicílico en preeclampsia y restricción del crecimiento intrauterino durante el embarazo. Material y métodos es un estudio de revisión bibliográfica sistémica para lo cual se usaron los "descriptores en ciencias de la salud" (DeCS) usando la siguiente terminología: " ácido acetilsalicílico ", "tratamiento", "preeclampsia" y "restricción del crecimiento intrauterino", así como su combinación y expansión. Además, se utilizaron base de datos de revistas, guías clínicas protocolos, artículos publicados en revistas indexadas. Resultados: la literatura basada en la evidencia indica que la disfunción placentaria es prevenible al principio del embarazo, para lo cual se debe prescribir dosis bajas de ácido acetilsalicílico en menores de 16 semanas de gestación, mientras tanto no existe evidencia contundente que indica los beneficios en la RCIU. Conclusiones: la prevención a nivel primario es primordial para disminuir la morbi -mortalidad materna neonatal implementando tempranamente este tratamiento.

(1) Background: Focal and segmental glomerulosclerosis (FSGS) is a pattern of injury that results from podocyte loss in the setting of a wide variety of injurious mechanisms. These include both acquired and genetic as well as primary and secondary causes, or a combination thereof, without optimal therapy, and a high rate of patients develop end-stage renal disease (ESRD). Genetic studies have helped improve the global understanding of FSGS syndrome; thus, we hypothesize that patients with primary FSGS may have underlying alterations in adhesion molecules or extracellular matrix glycoproteins related to previously unreported mutations that may be studied through next-generation sequencing (NGS). (2) Methods: We developed an NGS panel with 29 genes related to adhesion and extracellular matrix glycoproteins. DNA was extracted from twenty-three FSGS patients diagnosed by renal biopsy; (3) Results: The average number of accumulated variants in FSGS patients was high. We describe the missense variant ITGB3c.1199G>A, which is considered pathogenic; in addition, we discovered the nonsense variant CDH1c.499G>T, which lacks a Reference SNP (rs) Report and is considered likely pathogenic. (4) Conclusions: To the best of our knowledge, this is the first account of a high rate of change in extracellular matrix glycoproteins and adhesion molecules in individuals with adult-onset FSGS. The combined effect of all these variations may result in a genotype that is vulnerable to the pathogenesis of glomerulopathy.

El avance imparable de las pandemias a lo largo de la historia, ha significado estragos y repercusiones multifocales para la humanidad. Ello se acompaña con los aspectos vinculados a las condiciones en que los trabajos son realizados. El impacto que puede conllevar a nivel ergonómico, bajo un enfoque biopsicosocial, puede hacer de una labor en concreto, un auténtico desafío que puede desembocar en el colapso de las personas, y del sistema del que forman parte. Un crudo panorama que, en los últimos tres años, ha puesto a prueba el temple y la salud de profesionales de la salud, hasta llevarlos al límite de sus capacidades. En la presente revisión bibliográfica, se propuso evidenciar con bibliografía actualizada consistente, el impacto en términos ergonómicos de la pandemia por SARS-CoV-II, sobre la salud integral del personal sanitario, en los últimos años. El análisis evidencia que el avance del Covid-19, supone un gran impacto en el personal de salud, afectando su integridad a nivel físico, mental, y social. Se identificaron datos estadísticos nacionales e internacionales, que dan consistencia a los hallazgos clínicos, abordando aspectos demográficos y económicos. Estos datos, ofrecen una perspectiva importante para mejorar las condiciones laborales del personal de salud, a fin de que su integridad no se deteriore, por cumplir sus deberes con las personas que atienden en los diversos niveles de atención sanitarios. Los datos en conjunto, aportan una visión que pone en evidencia la importancia de velar por la salud integral del personal de salud.

Introduction Mammary analogue secretory carcinoma (MASC) is a recent discovered entity of salivary glands tumors, reported for first time in 2010. The presence of a translocation encodes the ETS variant transcription factor 6-neurotrophic tyrosine receptor kinase (ETV6-NTRK3) gene fusion differences MASC from other tumors. Case presentation A 68-year-old male showed a non-painful right parotid enlargement, came from dermatology service, and followed by some facial squamous cell carcinomas. A computed tomography (CT) scan showed a 1.7×1.6 cm right parotid enlargement in superficial lobe. The patient underwent a right superficial parotidectomy. The final pathology confirmed the presence of ETV6-NTRK3-positive MASC. Complete right deep parotidectomy and functional cervical emptying were performed. Discussions and conclusions It is necessary to establish an appropriated differential diagnosis between salivary gland tumors. MASC is a low-grade malignancy cancer that sometimes can evolve to a high-grade tumor that might produce local and distance dissemination. Most times, these tumors are only treated by surgical resection and evaluating by a multidisciplinary team the need of more treatments. In our case, the patient showed a primary parotid tumor, removed surgically with free edges, and being identified as MASC. We decided to underwent neck dissection and discovered a second MASC focus on cervical salivary gland; however, there was no nodal dissemination. The patient remains disease-free after 14 months from last surgery. It is important to keep studying genetic therapy targets to ETV6-NTRK3 to obtain a new therapy line to treat those cases that require.

Resumen Introduccion y objetivos La recaida peritoneal como forma aislada de recurrencia en el cancer de colon suele suceder en el 25% de casos durante los dos anos siguientes a una colectomia curativa. Actualmente, las limitaciones diagnosticas de los estudios de imagen y la ausencia de escalas predictivas para la recurrencia peritoneal excusa la realizacion de una cirugia de «second look» en pacientes de alto riesgo. El objetivo de este estudio es evaluar la capacidad de algunos biomarcadores de transicion epitelio-mesenquima (c-Met, IGF-1R y plexina β1) para predecir la colonizacion peritoneal posquirurgica y desarrollar un modelo matematico capaz de predecir dicha recidiva carcinomatosa. Metodos Estudio retrospectivo mediante tecnicas inmunohistoquimicas para c-Met, IGF-1R y plexina β1 en 87 pacientes intervenidos por cancer de colon con intencion curativa. Fueron divididos en dos grupos segun hubieran presentado recurrencia peritoneal o solo factores de riesgo para dicha recaida. La positividad de las muestras fue valorada por la tasa de celulas tenidas y la intensidad de la inmunotincion. Se evaluo una posible asociacion entre los hallazgos inmunohistoquimicos y la recaida peritoneal. El analisis estadistico de los biomarcadores con mayor valor pronostico permitio desarrollar una formula matematica de riesgo a partir de coeficientes que aportan un valor especifico a cada biomarcador y paciente. Resultados La expresion en el tumor primario de c-Met mostro una tendencia estadistica elevada (p: 0,074) mientras que IGF-1 (p: 0,022) y plexina β1 (p: 0,021) manifestaron una fuerte asociacion con la recaida peritoneal. Sin embargo, el analisis multivariante selecciono c-Met y plexina β1 como factores utiles para el modelo matematico predictivo de recurrencia peritoneal con una sensibilidad del 75,8% y una especificidad del 80,5% en pacientes con una tincion superior al 50% para ambos biomarcadores. Conclusion La sobrexpresion de c-Met y plexina β1 se relaciona con un mayor riesgo de recaida peritoneal cuando es factible una reseccion radical en cancer de colon. La alta probabilidad de exito en el modelo matematico propuesto anima a su aplicacion clinica en busca de candidatos a carcinoprofilaxis.

The survival rate in lung cancer remains stubbornly low and there is an urgent need for the identification of new therapeutic targets. In the last decade, several members of the SWI/SNF chromatin remodeling complexes have been described altered in different tumor types. Nevertheless, the precise mechanisms of their impact on cancer progression, as well as the application of this knowledge to cancer patient management are largely unknown. In this study, we performed targeted sequencing of a cohort of lung cancer patients on genes involved in chromatin structure. In addition, we studied at the protein level the expression of these genes in cancer samples and performed functional experiments to identify the molecular mechanisms linking alterations of chromatin remodeling genes and tumor development. Remarkably, we found that 20% of lung cancer patients show ARID2 protein loss, partially explained by the presence of ARID2 mutations. In addition, we showed that ARID2 deficiency provokes profound chromatin structural changes altering cell transcriptional programs, which bolsters the proliferative and metastatic potential of the cells both in vitro and in vivo. Moreover, we demonstrated that ARID2 deficiency impairs DNA repair, enhancing the sensitivity of the cells to DNA-damaging agents. Our findings support that ARID2 is a bona fide tumor suppressor gene in lung cancer that may be exploited therapeutically., IV is supported by SAF2012-31627 and SAF2016-76758-R grants from the Spanish Ministerio de Economía y Competitividad (MINECO), by a Fundación Ramón Areces grant and by ERC2014-StG637904 grant from the European Research Council. IV has been awardee of the Programa Ramón y Cajal (MINECO, Spain). TM has been awardee of the Ayudas para la contratación de investigadores predoctorales (MINECO, Spain). BM is awardee of the Ayudas para la formación de profesorado universitario (FPU, Ministerio de Educación y Formación Profesional, Spain). PC laboratory is supported by grant SAF-2015-63638R (MINECO/FEDER, UE); by Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) and by Asociación Española Contra el Cáncer (AECC), grant GCB141423113. BC has been supported by a Retos Jóvenes Investigadores grant SAF-2015-73364-JIN (AEI/FEDER, UE) and a grant from Fundación Francisco Cobos. PS is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001152) and the UK Medical Research Council (FC001152). HUCA/IUOPA is jointly financed by Servicio de Salud del Principado de Asturias, Instituto de Salud Carlos III, and Fundación Bancaria Cajastur. This research was funded in part by the Wellcome Trust [FC001152].

AimNext generation sequencing (NGS) represents a key diagnostic tool to identify clinically relevant gene alterations for treatment-decision making in cancer care. However, the complex manual workflow required for NGS has limited its implementation in routine clinical practice. In this worldwide study, we validated the clinical performance of the TargetPlex FFPE-Direct DNA Library Preparation Kit for NGS analysis. Impressively, this new assay obviates the need for separate, labour intensive and time-consuming pre-analytical steps of DNA extraction, purification and isolation from formalin-fixed paraffin embedded (FFPE) specimens in the NGS workflow.MethodsThe TargetPlex FFPE-Direct DNA Library Preparation Kit, which enables NGS analysis directly from FFPE, was specifically developed for this study by TargetPlex Genomics Pleasanton, California. Eleven institutions agreed to take part in the study coordinated by the Molecular Cytopathology Meeting Group (University of Naples Federico II, Naples, Italy). All participating institutions received a specific Library Preparation Kit to test eight FFPE samples previously assessed with standard protocols. The analytical parameters and mutations detected in each sample were then compared with those previously obtained with standard protocols.ResultsOverall, 92.8% of the samples were successfully analysed with the TargetPlex FFPE-Direct DNA Library Preparation Kit on Thermo Fisher Scientific and Illumina platforms. Altogether, in comparison with the standard workflow, the TargetPlex FFPE-Direct DNA Library Preparation Kit was able to detect 90.5% of the variants.ConclusionThe TargetPlex FFPE-Direct DNA Library Preparation Kit combined with the SiRe panel constitutes a convenient, practical and robust cost-saving solution for FFPE NGS analysis in routine practice.

The internal cushioning systems of hydraulic linear actuators avoid mechanical shocks at the end of their stroke. The design where the piston with perimeter grooves regulates the flow by standing in front of the outlet port has been investigated. First, a bond graph dynamic model has been developed, including the flow throughout the internal cushion design, characterized in detail by computational fluid-dynamic simulation. Following this, the radial movement of the piston and the fluid-dynamic coefficients, experimentally validated, are integrated into the dynamic model. The registered radial movement is in coherence with the significant drag force estimated in the CFD simulation, generated by the flow through the grooves, where the laminar flow regime predominates. Ultimately, the model aims to predict the behavior of the cushioning during the movement of the arm of an excavator. The analytical model developed predicts the performance of the cushioning system, in coherence with empirical results. There is an optimal behavior, highly influenced by the mechanical stress conditions of the system, subject to a compromise between an increasing section of the grooves and an optimization of the radial gap.

ContextIt has been more than 10 years since the human papillomavirus (HPV) vaccination program was initiated in most advanced countries. Thus, it seems necessary to change the uterine cervical cancer screening strategy. Molecular-based tests are considered essential in this scenario.ObjectiveWe aimed to review the distribution of the HPV genotypes after the introduction of the vaccination program with Cervarix® and Gardasil 4® in two autonomous communities in Spain, looking for possible changes in distribution and the occurrence of a herd effect.DesignA cross-sectional study was performed in 45,362 samples that were processed in the Cantabria and Aragon communities during the period from 2002 to 2016. We compared the genotype distribution before and after the vaccination program was initiated.ResultsGenotypes HPV6 and HPV11 have decreased significantly after the introduction of the vaccine. HPV16 has had a decrease, but not a significant one in the statistical analysis. However, HPV31, HPV52, and HPV45 have increased in percentage. A replacement phenomenon with other genotypes not included in the vaccine has been observed in our population.ConclusionsContinued surveillance is needed to provide further indication of any changes over time in the genotypes in circulation. This will be facilitated by monitoring the genotyping results from the new model of cervical screening using primary HPV DNA testing.

The survival rate in lung cancer remains stubbornly low and there is an urgent need for the identification of new therapeutic targets. Last decade’s research has evidenced a clear role of chromatin structure in cancer development and several members of the SWI/SNF chromatin remodeling complexes have been described altered in different tumor types. Nevertheless, the precise mechanisms of their impact on cancer progression, as well as the application of this knowledge to cancer patient management are largely unknown.In this study, we have performed targeted sequencing of a cohort of lung cancer patients on genes involved in chromatin structure, as well as functional experiments to identify the molecular mechanisms linking alterations of chromatin remodeling genes and tumor development.We have identified ARID2 production loss in 20% of lung cancer patients. Additionally, we have shown that ARID2-deficiency provokes profound chromatin structural changes, alters the transcriptional programme and impairs DNA repair which bolster the proliferative and metastatic potential of the cells both in vitro and in vivo. Moreover, we have demonstrated that ARID2 deficiency significantly affects the sensitivity of the cells to PARP inhibition.All these results support that ARID2 is a bona-fide tumor suppressor gene in lung cancer that might be exploited therapeutically.

Peritoneal relapse as an isolated form of recurrence in colon cancer occurs in 25% of cases during the first two years subsequent to a curative colectomy. Currently, the diagnostic limitations of imaging studies and the absence of predictive scales for peritoneal recurrence warrant "second look" surgery in high-risk patients. The aim of this study is to assess features of some epithelial-mesenchymal transition biomarkers (c-Met, IGF-1R and plexin β1) in order to predict post-surgical peritoneal colonization and develop a mathematical model to predict carcinomatous relapse.A retrospective study of the histopathological samples of 87 patients diagnosed with colon cancer who underwent radical resection was carried out, using immunohistochemical techniques for c-Met, IGF-1R and plexin β1. The patients were divided into two groups; those who had presented peritoneal recurrence and those who only had risk factors for this kind of relapse. Every stained sample was assessed by the rate of stained cells and immunostaining intensity. A possible association between immunohistochemical findings and peritoneal relapse was evaluated. Statistical analysis of the biomarkers with higher prognostic value allowed a risk mathematical formula to be developed based on coefficients, providing a specific value to each biomarker and patient.c-Met expression in the primary tumour showed a high statistical trend (p: .074) while IGF-1 (p: .022) and plexin β1 (p: .021) revealed a significative association with peritoneal relapse. However, the multivariate analysis selected c-Met y plexin β1 as useful factors for a predictive mathematical model on peritoneal recurrence with a 75.8% sensitivity and 80.5% specificity in patients with a staining more than 50% for both biomarkers.c-Met and plexin B1 overexpression is related to an increased risk of peritoneal relapse in cases of colon cancer where a radical resection is feasible. The encouraging outcomes of the proposed mathematical model may prove useful clinically in the identification of candidates for carcinoprophylaxis.

A major complication of colorectal cancer (CRC), one of the most frequent and deadly types of cancer, is disease progression via liver metastases. At this stage, very few treatment options are available for patients, and the disease remains incurable. Herein, we used a well-established mouse model of CRC liver metastasis (CLM) to identify new regulators of this process. Using serial transplantation of murine MC38 adenocarcinoma cells, we obtained liver metastatic variants that displayed extremely strong colonization abilities. Using these newly established cell lines, we performed gene expression arrays and microRNA (miR) profiling. Comparative and predictive analyses between the two arrays showed higher expression of c-met and concomitant reduction of miR-146a in the mestastatic variants. In CRC patients, expression levels of both c-met and miR-146a were similar between primary tumors and liver metastases. Interestingly, we identified c-met as a new target for miR-146a, as miR-146a was able to impede c-met translation. Of relevance, overexpression of miR-146a in metastatic clones showed reduced in vitro malignancy and abolished the development of primary tumor and liver metastases. Our results document a new mechanism for c-met regulation in CLM and highlight the crucial role of miR-146a in suppressing tumorigenesis.

A pulmonary Langerhans cell histiocytosis is presented in a 40 year-old woman two years after bilateral lung transplantation for emphysema without any signs of Langerhans cells proliferation in the explanted lungs. A microsatellite molecular analysis showed the proliferating cells were generated in a recipient cellular clone. The patient did not quit smoking after transplantation. No signs of disease were detected in the implanted lungs before surgery. Strict control of immunosupressive drug levels stabilized the disease. A "de novo" monoclonal origin of stem cells, probably from the bone marrow is suggested. The reason she did not develop disease in the native lungs is unknown, although we suggest an interaction between tobacco or some other antigens and local cellular receptors.

Clinical cases of neonatal listeriosis are associated with brain disease and fetal loss due to complications in early or late pregnancy, which suggests that microglial function is altered. This is believed to be the first study to link microglial apoptosis with neonatal listeriosis and listeriosis-associated brain disease, and to propose a new nanovaccine formulation that reverses all effects of listeriosis and confers Listeria monocytogenes (LM)-specific immunity. We examined clinical cases of neonatal listeriosis in 2013–2015 and defined two useful prognostic immune biomarkers to design listeriosis vaccines: high anti-GAPDH1-22 titres and tumor necrosis factor (TNF)/ interleukin (IL)-6 ratios. Therefore, we developed a nanovaccine with gold glyconanoparticles conjugated to LM peptide 1-22 of GAPDH (Lmo2459), GNP-GAPDH1-22 nanovaccines formulated with a pro-inflammatory Toll-like receptor 2/4-targeted adjuvant. Neonates born to non-vaccinated pregnant mice with listeriosis, showed brain and vascular diseases and significant microglial dysfunction by induction of TNF-α-mediated apoptosis. This programmed TNF-mediated suicide explains LM dissemination in brains and livers and blocks production of early pro-inflammatory cytokines such as IL-1β and interferon-α/β. In contrast, neonates born to GNPGAPDH 1–22-vaccinated mothers before LM infection, did not develop listeriosis or brain diseases and had functional microglia. In nanovaccinated mothers, immune responses shifted towards Th1/IL-12 pro-inflammatory cytokine profiles and high production of anti-GAPDH1–22 antibodies, suggesting good induction of LM-specific memory, This study was supported by IDIVAL grants API2010/03/SAF2009-08695, AIP13/2014/SAF2012- 34203 and INNVAL15/01 (to C. A-D and J.F), the Spanish Government through Plan Nacional (MINECO) (SAF2012-34203), FIPSE (ISCIII) (00-00002755-16) and CIBER-BNN (CIB16-NM009) (to C. A-D and I. G), RED RICET RD12/0018/0004 and BIOMID (ISCIII), SAF2013-42850-R (MINECO), HOMIN-317057- FP7-PEOPLE-2012-ITN (EU) (to M.F) and by the Spanish Government through Plan Nacional (MINECO) (CTQ2011-27268) (to S.P).

Gold glyconanoparticles loaded with the listeriolysin O peptide 91-99 (GNP-LLO91-99), a bacterial peptide with anti-metastatic properties, are vaccine delivery platforms facilitating immune cell targeting and increasing antigen loading. Here, we present proof of concept analyses for the consideration of GNP-LLO91-99 nanovaccines as a novel immunotherapy for cutaneous melanoma. Studies using mouse models of subcutaneous melanoma indicated that GNP-LLO91-99 nanovaccines recruite and modulate dendritic cell (DC) function within the tumour, alter tumour immunotolerance inducing melanoma-specific cytotoxic T cells, cause complete remission and improve survival. GNP-LLO91-99 nanovaccines showed superior tumour regression and survival benefits, when combined with anti-PD-1 or anti-CTLA-4 checkpoint inhibitors, resulting in an improvement in the efficacy of these immunotherapies. Studies on monocyte-derived DCs from patients with stage IA, IB or IIIB melanoma confirmed the ability of GNP-LLO91-99 nanovaccines to complement the action of checkpoint inhibitors, by not only reducing the expression of cell-death markers on DCs, but also potentiating DC antigen-presentation. We propose that GNP-LLO91-99 nanovaccines function as immune stimulators and immune effectors and serve as safe cancer therapies, alone or in combination with other immunotherapies.

Humans constantly lose epithelial cells, and these biological traces are frequently studied in the context of criminal investigations. The objective of this work was to examine the genetic profile in samples of forensic interest (nail and skin epithelial cells) of bone marrow transplant patients and discuss its forensic and clinical implications. The genetic profile of nail, epidermal cells and blood samples of patients receiving HSCT was analyzed by the amplification and sequencing of 38 insertion/deletion polymorphisms and 15 short tandem repeat polymorphisms. In this analysis, the age of patients and donors, the time elapsed from the transplant, the type of conditioning prior to the transplant and whether the patient suffered graft-versus-host disease were considered. Donor chimerism can be detected in the DNA extracted from nail and skin epithelial cells of transplant patients. No statistically significant correlation was found between the type of conditioning and the percentage of donor DNA in nail (p > 0.05). A positive correlation, without statistical significance, was encountered when we analyzed the relationship between the time elapsed from the transplant with the percent donor chimerism found in epithelial cells of the epidermis and in nails. We conclude that within a judicial context (e.g. when testifying as an expert witness) it is necessary to consider whether we are facing a possible transplant patient or a person who has been a bone marrow donor.

The indirect calculation from acceleration of transversal displacement of the piston inside the body of a double effect linear hydraulic cylinder during its operating cycle is assessed. Currently an extensive effort exists in the improvement of the mechanical and electronic design of the highly sophisticated MEMS accelerometers. Nevertheless, the predictable presence of measurement errors in the current commercial accelerometers is the main origin of velocity and displacement measurement deviations during integration of the acceleration. A bond graph numerical simulation model of the electromechanical system has been developed in order to forecast the effect of several measurement errors in the use of low cost two axes accelerometers. The level of influence is assessed using quality indicators and visual signal evaluation, for both simulations and experimental results. The obtained displacements results are highly influenced by the diverse dynamic characteristics of each measuring axis. The small measuring errors of a simulated extremely high performance sensor generate only moderate effects in longitudinal displacement but deep deviations in the reconstruction of piston transversal movements. The bias error has been identified as the source of the higher deviations of displacement results, although, its consequences can be easily corrected.

Vaccination with dendritic cells (DCs) is proposed to induce lasting responses against melanoma but its survival benefit in patients needs to be demonstrated. We propose a DC-targeted vaccine loaded with a Listeria peptide with exceptional anti-tumour activity to prevent metastasis of melanoma. Mice vaccinated with vaccines based on DCs loaded with listeriolysin O peptide (91–99) (LLO91–99) showed clear reduction of metastatic B16OVA melanoma size and adhesion, prevention of lung metastasis, enhanced survival, and reversion of immune tolerance. Robust innate and specific immune responses explained the efficiency of DC-LLO91–99 vaccines against B16OVA melanoma. The noTable features of this vaccine related to melanoma reduction were: expansion of immune-dominant LLO91–99-specific CD8 T cells that helped to expand melanoma-specific CD8+ T cells; high numbers of tumour-infiltrating lymphocytes with a cytotoxic phenotype; and a decrease in CD4+CD25high regulatory T cells. This vaccine might be a useful alternative treatment for advanced melanoma, alone or in combination with other therapies.

Gold glyconanoparticles loaded with the listeriolysin O peptide 91–99 (GNP-LLO(91-99)), a bacterial peptide with anti-metastatic properties, are vaccine delivery platforms facilitating immune cell targeting and increasing antigen loading. Here, we present proof of concept analyses for the consideration of GNP-LLO(91-99) nanovaccines as a novel immunotherapy for cutaneous melanoma. Studies using mouse models of subcutaneous melanoma indicated that GNP-LLO(91-99) nanovaccines recruite and modulate dendritic cell (DC) function within the tumour, alter tumour immunotolerance inducing melanoma-specific cytotoxic T cells, cause complete remission and improve survival. GNP-LLO(91-99) nanovaccines showed superior tumour regression and survival benefits, when combined with anti-PD-1 or anti-CTLA-4 checkpoint inhibitors, resulting in an improvement in the efficacy of these immunotherapies. Studies on monocyte-derived DCs from patients with stage IA, IB or IIIB melanoma confirmed the ability of GNP-LLO(91-99) nanovaccines to complement the action of checkpoint inhibitors, by not only reducing the expression of cell-death markers on DCs, but also potentiating DC antigen-presentation. We propose that GNP-LLO(91-99) nanovaccines function as immune stimulators and immune effectors and serve as safe cancer therapies, alone or in combination with other immunotherapies.

El objetivo de este estudio ha sido la comprobación de las variables Comunicación Familiar, en relación al Grooming, mediante la fundamentación del paradigma socio-crí­tico para estudiar la autorreflexión crí­tica en los procesos del conocimiento a razón de que su finalidad es la transformación de la estructura de las relaciones sociales y dar respuestas a determinados problemas generados por éstas. Para ello se contó con la colaboración de 49 estudiantes de los segundos de bachillerato de la Unidad Educativa Picaihua, donde los resultados parecen encontrar una leve presencia de indicadores, a través de las redes sociales donde posiblemente se podrí­a estar originando el grooming, en una minorí­a de los estudiantes, pero que si no se interviene rápidamente desembocará en situaciones fatales para la ví­ctima, sus padres, y a la institución como tal poniendo en duda su accionar ante éstas situaciones. Con este estudio se deberí­a abrir nuevas lí­neas de investigación que permitirí­an profundizar en la comprensión del grooming.

Dendritic cell (DC) vaccines are cancer vaccines used currently as melanoma therapies. They act as adjuvants initiating the immune responses, but not only as they can also have effector activities redirecting cytotoxic CD8+ T cells against melanoma. Ex vivo preparation of monocyte derived DCs has been implemented to produce large numbers of DCs for clinical therapy, highlighting the necessity of activate DC s to produce Th1 cytokines, especially TNF-a and IL-12 with potent anti-tumour actions. Several clinical trials both in the European Union and USA are open currently using DC vaccines, alone or in combination with other immunotherapies. The type of antigen is also an active area of investigation involving tumour antigens and bacterial epitopes, both providing good responses. Bacterial epitopes presented the advantage versus tumour antigens that they can prepare the vaccination site as they induce innate and specific immune responses as they are potent recall antigens that expand cytotoxic responses.

The technology of gerotor pumps is progressing towards cutting-edge applications in emerging sectors, which are more demanding for pump performance. Moreover, recent environmental standards are heading towards leakage-free and noiseless hydraulic systems. Hence, in order to respond to these demands, this study, which will be referred to as the GeroMAG concept, aims to make a leap from the standard gerotor pump technology: a sealed, compact, non-shaft-driven gerotor pump with a magnetically-driving outer rotor. The GeroMAG pump is conceived as a variable-flow pump to accomplish a standard volumetric flow rate at low rotational speed with satisfactory volumetric efficiency. By following the authors’ methodology based on a catalogue of best-practice rules, a custom trochoidal gear set is designed. Then, two main technological challenges are encountered: how to generate the rotational movement of the driving outer rotor and how to produce the guide of rotation of the gear set once there is no drive shaft. To confront them, a quiet magnet brushless motor powers the driving outer rotor through pole pieces placed in its external sideway and the rotational movement is guided by the inner edgewise pads carved on it. Subsequently, GeroMAG pump architecture, prototype, housing, methodology, materials and manufacture will be presented. As a principal conclusion, the GeroMAG proof of concept and pump prototype are feasible, which is corroborated by experimental results and performance indexes.

A pulmonary Langerhans cell histiocytosis is presented in a 40 year-old woman two years after bilateral lung transplantation for emphysema without any signs of Langerhans cells proliferation in the explanted lungs. A microsatellite molecular analysis showed the proliferating cells were generated in a recipient cellular clone. The patient did not quit smoking after transplantation. No signs of disease were detected in the implanted lungs before surgery. Strict control of immunosupressive drug levels stabilized the disease. A "de novo" monoclonal origin of stem cells, probably from the bone marrow is suggested. The reason she did not develop disease in the native lungs is unknown, although we suggest an interaction between tobacco or some other antigens and local cellular receptors.

The trochoidal-gear technology has been growing in groundbreaking fields. Forthcoming applications are demanding to this technology a step forward in the conceiving stage of positive displacement machines. The compendium of the qualities and the inherent characteristics of trochoidal-gear technology, especially towards the gerotor pump, together with scale/size factor and magnetic-driven transmission has led to the idea of a magnet-sleeve-sealed variable flow mini trochoidal-gear pump. From its original concept, to the last phase of the design development, the proof of concept, this new product will intend to overcome problems such as noise, vibration, maintenance, materials, and dimensions. The paper aims to show the technological path followed from the concept, design, and model, to the manufacture of the first prototype, where the theoretical and numerical approaches are not always directly reflected in the prototype performance results. Early in the design process, from a standard-commercial sintered metal mini trochoidal-gear unit, fundamental characteristics and dimensional limitations have been evaluated becoming the strategic parameters that led to its configuration. The main technical challenge to confront is being sealed with non-exterior driveshaft, ensuring that the whole interior is filled and wetted with working fluid and helping the hydrodynamic film formation, the pumping effect, and the heat dissipation. Subsequently, the mini pump architecture, embodiment, methodology, materials, and manufacture are presented. The trend of applications of polymer composite materials and their benefits wanted to be examined with this new mini pump prototype, and a pure polyoxymethylene mini trochoidal-gear set has been designed and manufactured. Finally, both the sintered and the polymer trochoidal-gear units have been experimentally tested in an in-house full-instrumented mini test bench. Although the main goal of the presented work is the development of a new mini trochoidal-gear pump prototype rather than a numerical study, the results have been compared with numerical simulation. Subsequently, the prototype of the mini trochoidal-gear pump is a feasible proof of concept supported by functional indexes and the experimental results.

Clinical cases of neonatal listeriosis are associated with brain disease and fetal loss due to complications in early or late pregnancy, which suggests that microglial function is altered. This is believed to be the first study to link microglial apoptosis with neonatal listeriosis and listeriosis-associated brain disease, and to propose a new nanovaccine formulation that reverses all effects of listeriosis and confers Listeria monocytogenes (LM)-specific immunity. We examined clinical cases of neonatal listeriosis in 2013–2015 and defined two useful prognostic immune biomarkers to design listeriosis vaccines: high anti-GAPDH1-22 titres and tumor necrosis factor (TNF)/interleukin (IL)-6 ratios. Therefore, we developed a nanovaccine with gold glyco-nanoparticles conjugated to LM peptide 1-22 of GAPDH (Lmo2459), GNP-GAPDH1-22 nanovaccinesformulated with a pro-inflammatory Toll-like receptor 2/4-targeted adjuvant. Neonates born to non-vaccinated pregnant mice with listeriosis, showed brain and vascular diseases and significant microglial dysfunction by induction of TNF-α-mediated apoptosis. This programmed TNF-mediated suicide explains LM dissemination in brains and livers and blocks production of early pro-inflammatory cytokines such as IL-1β and interferon-α/β. In contrast, neonates born to GNP-GAPDH1–22-vaccinated mothers before LM infection, did not develop listeriosis or brain diseases and had functional microglia. In nanovaccinated mothers, immune responses shifted towards Th1/IL-12 pro-inflammatory cytokine profiles and high production of anti-GAPDH1–22 antibodies, suggesting good induction of LM-specific memory.

The work presented in this article demonstrates the use of an empirical and simplified approach based on an optical technique and a home-made ad hoc code that give knowledge of the shape and falling velocity of a free-falling non-submerged liquid stream to predict its typology and flow rate. The visualization photographic technique is a non-intrusive robust technique which can be applied to high-temperature liquids in harsh environments, such as an iron stream in a foundry. This technique allows predicting the liquid stream boundaries and contours without any type of treatment on the fluid. As a result of employing this empirical methodology, three flow typologies for a water stream are proposed and demonstrated experimentally. Comparisons with experimental data reveal satisfactory estimations of mean flow quantities. Finally, the approach used based on experimental visualization is carried out in an iron stream of a foundry, not being disruptive to in-situ foundry operations and showing its potential to improve performance of the cast parts’ properties during the casting phase and revealing to be a useful tool for process optimization.

Listeriosis is a fatal infection for fetuses and newborns with two clinical main morbidities in the neonatal period, meningitis and diffused cutaneous lesions. In this study, we vaccinated pregnant females with two gold glyconanoparticles (GNP) loaded with two peptides, listeriolysin peptide 91-99 (LLO91-99) or glyceraldehyde-3-phosphate dehydrogenase 1-22 peptide (GAPDH1-22). Neonates born to vaccinated mothers were free of bacteria and healthy, while non-vaccinated mice presented clear brain affections and cutaneous diminishment of melanocytes. Therefore, these nanoparticle vaccines are effective measures to offer pregnant mothers at high risk of listeriosis interesting therapies that cross the placenta.

// Maria Villalba 1, 2, * , Angel Diaz-Lagares 3, * , Miriam Redrado 2 , Arrate L. de Aberasturi 1, 2 , Victor Segura 4 , Maria Elena Bodegas 1 , Maria J. Pajares 1, 2 , Ruben Pio 2, 5 , Javier Freire 6 , Javier Gomez-Roman 6 , Luis M. Montuenga 1, 2 , Manel Esteller 3 , Juan Sandoval 7, # , Alfonso Calvo 1, 2, # 1 Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Navarra, Spain 2 IDISNA and Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain 3 Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet, Catalonia, Spain 4 IDISNA and Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain 5 Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Navarra, Spain 6 Department of Pathology, University Hospital Marques de Valdecilla, IDIVAL, Santander, Spain 7 Department of Personalized Medicine, Epigenomics Unit, Medical Research Institute La Fe, Valencia, Spain * Both authors should be considered as first authors # Both authors should be considered as senior authors Correspondence to: Juan Sandoval, e-mail: epigenomica@iislafe.es Alfonso Calvo, e-mail: acalvo@unav.es Keywords: TMPRSS4, epigenetics, promoter hypomethylation, squamous cell carcinoma, prognosis Abbreviations: NSCLC, non-small cell lung cancer; SCC, squamous cell carcinoma; ADC, adenocarcinoma; TCGA, The Cancer Genome Atlas; TSS, Transcription Start Site Received: December 02, 2015 Accepted: February 18, 2016 Published: March 14, 2016 ABSTRACT Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, which highlights the need of innovative therapeutic options. Although targeted therapies can be successfully used in a subset of patients with lung adenocarcinomas (ADC), they are not appropriate for patients with squamous cell carcinomas (SCC). In addition, there is an unmet need for the identification of prognostic biomarkers that can select patients at risk of relapse in early stages. Here, we have used several cohorts of NSCLC patients to analyze the prognostic value of both protein expression and DNA promoter methylation status of the prometastatic serine protease TMPRSS4. Moreover, expression and promoter methylation was evaluated in a panel of 46 lung cancer cell lines. We have demonstrated that a high TMPRSS4 expression is an independent prognostic factor in SCC. Similarly, aberrant hypomethylation in tumors, which correlates with high TMPRSS4 expression, is an independent prognostic predictor in SCC. The inverse correlation between expression and methylation status was also observed in cell lines. In vitro studies showed that treatment of cells lacking TMPRSS4 expression with a demethylating agent significantly increased TMPRSS4 levels. In conclusion, TMPRSS4 is a novel independent prognostic biomarker regulated by epigenetic changes in SCC and a potential therapeutic target in this tumor type, where targeted therapy is still underdeveloped.

Analytical and experimental investigations of typical hydraulic cylinders have indicated that their load capacities are significantly different from those obtained from simple buckling analysis of idealized systems. In any case, an increase in the friction coefficient at the restrained ends changes the actuator's limit load, while an increase in the initial maximum deflection (initial misalignment) decreases the limit load. A common practice of most cylinder manufacturers is to use a safety factor (between 2.5 and 4) to determine the service load after the critical load (buckling) is obtained by simple analytical procedures treating the cylinder as a perfect stepped column. The intricate aspects of friction effects have been deliberately left aside in this present work. Nevertheless, friction and interaction between mechanism and actuator in the buckling characteristics will be presented in the ongoing paper, which will follow this work. Authors know that, in a real system, the cylinder tube–rod interface is not rigid. Due to the flexibility of guide rings and clearances between components, misalignment (an angular deflection which increases with increasing axial load) exits at the interface. When initial imperfection angle exists, there is no sudden buckling. Then, stresses and deflections increase with increasing load. After repetitive use, the tolerance between the parts will become larger, consequently increasing the initial deflection, which has been proved to considerably decrease the load capacities of the power cylinders. From this analysis, a theoretical and experimental work has been carried out in order to show the advantages and disadvantages of the current design methods, characterizing the critical factors that cause the collapse and proposing useful design criterions. The present work aims to describe the behaviour of actuators under load capacity with experimental validation.

Over the last years, a better comprehension of hydraulic cylinder performance is observed to be a prime objective of many owing to demanding applications. By observing these hydraulic cylinder applications, we see currently proposed models and design criteria do not take into account real factors, and further there are misalignment and boundary conditions in the end supports, mechanism interaction, dust, clearance and imperfections. Since these boundary conditions can develop progressive moments, the ideal simple supported bi-articulated configuration of the actuator is no longer valid, and virtual clamped configuration appears with friction moments that substantially modify the buckling analysis. In a previous work, misalignment effects were studied and discussed. In the present work a study of the influence of friction moments when misalignment effects are deliberately left aside is carried out. In order to separate these two phenomena (friction and misalignment) boundary conditions in a column are analysed. From this analysis, a theoretical and experimental work has been carried out for columns and an actuator characterizing the critical factors that cause the collapse. The aim of this paper is to describe the behaviour of actuators under load capacity with experimental validation when friction moment is taken into account and becomes an unknown variable. Experimental and theoretical results point out the importance and influence of the friction effects in columns and hydraulic cylinders. Then, it is recommended that knowledge of the hydraulic cylinder application to predict its load capacity owing to that direct extrapolation of results from current theories and criterions could lead to incorrect estimations.

Despite the progress achieved in the treatment of breast cancer, there are still many unsolved clinical issues, being the diagnosis, prognosis, and treatment of papillary diseases, one of the highest challenges. Because of its unpredictable clinical behavior, treatment of intraductal papilloma has generated a great controversy. Even though considered as a benign lesion, it presents high rate of malignant recurrence. This is the reason why there are clinicians supporting a complete excision of the lesion, while others support an only expectant follow-up. Previous results of our group suggested that procollagen 11 alpha 1 (pro-COL11A1) expression correlates with infiltrating phenotype in breast lesions. We analyzed the correlation between expression of pro-COL11A1 in intraductal papilloma and their risk of malignant recurrence. Immunohistochemistry of pro-COL11A1 was performed in 62 samples of intraductal papilloma. Ten out 11 cases relapsed as carcinoma presents positive staining for COL11A1, while just 17 out of 51 cases with benign behaviour present immunostaining. There were significant differences (P<0.0001) when comparing patients with malignant recurrence versus nonmalignant relapse patients. These data suggest that pro-COL11A1 expression is a highly sensitive biomarker to predict malignant relapse of intraductal papilloma and it can be used as indicative factor for prevention programs.

Trochoidal gear pumps produce significant flow pulsations that result in pressure pulsations, which interact with the system where they are connected, shortening the life of both the pump and circuit components. The complicated aspects of the operation of a gerotor pump make computational fluid dynamics the proper tool for modelling and simulating its flow characteristics. A three-dimensional model with deforming mesh computational fluid dynamics is presented, including the effects of the manufacturing tolerance and the leakage inside the pump. A new boundary condition is created for the simulation of the solid contact in the interteeth radial clearance. The experimental study of the pump is carried out by means of time-resolved particle image velocimetry, and results are qualitatively evaluated, thanks to the numerical simulation results. Time-resolved particle image velocimetry is developed in order to adapt it to the gerotor pump, and it is proved to be a feasible alternative to obtain the instantaneous flow of the pump in a direct mode, which would allow the determination of geometries that minimize the non-desired flow pulsations. Thus, a new methodology involving computational fluid dynamics and time-resolved particle image velocimetry is presented, which allows the obtaining of the instantaneous flow of the pump in a direct mode without altering its behaviour significantly.

An improvement methodology is proposed for the design process in construction projects. Based on concepts and principles of lean production, the methodology considers the design process as a set of three different models—conversion, flow, and value. Four stages are necessary to produce improvements and changes— ~1! diagnosis/evaluation; ~2! changes implementation; ~3! control; and ~4! standardization. The methodology suggests the application of seven tools in accordance to specific needs ~detected and desired! on five potential areas of improvement—client, administration, project, resources, and information. Results of an application included an increase of 31% in the share of value adding activities, 44% reduction of unit errors in the products, up to 58% decrease of waiting times in the process, and an expansion of the utilization in the cycle times. In this manner, not only did the efficiency and effectiveness of internal engineering products improve, but also the whole project, by improving one of the main suppliers of construction.

New mouse models with specific drivers of genetic alterations are needed for preclinical studies. Herein, we created and characterized at the genetic level a new syngeneic model for lung cancer and metastasis in Balb-c mice. Tumor cell lines were obtained from a silica-mediated airway chronic inflammation that promotes tumorigenesis when combined with low doses of N-nitrosodimethylamine, a tobacco smoke carcinogen. Orthotopic transplantation of these cells induced lung adenocarcinomas, and their intracardiac injection led to prominent colonization of various organs (bone, lung, liver and brain). Driver gene alterations included a mutation in the codon 12 of KRAS (G-A transition), accompanied by a homozygous deletion of the WW domain-containing oxidoreductase (WWOX) gene. The mutant form of WWOX lacked exons 5-8 and displayed reduced protein expression level and activity. WWOX gene restoration decreased the in vitro and in vivo tumorigenicity, confirming the tumor suppressor function of this gene in this particular model. Interestingly, we found that cells displayed remarkable sphere formation ability with expression of specific lung cancer stem cell markers. Study of non-small-cell lung cancer patient cohorts demonstrated a deletion of WWOX in 30% of cases, with significant reduction in protein levels as compared to normal tissues. Overall, our new syngeneic mouse model provides a most valuable tool to study lung cancer metastasis in balb-c mice background and highlights the importance of WWOX deletion in lung carcinogenesis.