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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.

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].

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).

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.

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.

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.

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.

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 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.

// 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.

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.

Accurate diagnosis of invasive breast lesions, when analyzed by Core Needle Biopsy, may suppose a major challenge for the pathologist. Various markers of invasiveness such as laminin, S-100 protein, P63 or calponin have been described; however, none of them is completely reliable. The use of a specific marker of the infiltrating tumor microenvironment seems vital to support the diagnosis of invasive against in situ lesions. At this point, Collagen, type XI, alpha 1 (COL11A1), might be helpful since it has been described to be associated to cancer associated fibroblasts in other tumors such as lung, pancreas or colorectal. This paper aims to analyze the role of COL11A1 as a marker of invasiveness in breast tumor lesions. Two hundred and one breast Core Needle Biopsy samples were analyzed by immunohistochemistry against pro-COL11A1. The results show a significant difference (p < 0.0001) when comparing the expression in infiltrative tumors (93%) versus immunostaining of non-invasive lesions (4%). Forty cases of underestimated DCIS were also stained for COL11A1, presenting a sensitivity of 90% when compared with p63 and calponin which not tagged invasion. In conclusion, pro-COL11A1 expression is a promising marker of invasive breast lesions, and may be included in immunohistochemical panels aiming at identifying infiltration in problematic breast lesions.

Prothymosin α (ProTα) is a nuclear protein that is widely distributed in mammalian tissues, and is thought to play a role in cell proliferation. In an attempt to shed light on this role, affinity chromatography on ProTα-Sepharose columns was used to identify proteins in subcellular extracts of transformed human lymphocytes (NC37 cells) that interact with ProTα in vitro, and thus may interact with ProTα in vivo. Immunoblotting techniques were used to screen the ProTα-binding fractions for histones and other proteins involved in nuclear transport and cell-cycle control. The most abundant ProTα-binding proteins were histones H2A, H2B, H3, and H4. Of the nuclear-transport proteins, karyopherin β1, Rch-1, Ran, and RCC1 were detected at high concentrations; NTF2, nucleoporin p62, and Hsp70 were detected at low concentrations; while tranportin, CAS, and Ran BP1 were not detected. Of the cell-cycle control proteins, PCNA, Cdk2, and cyclin A were detected at high concentrations; cdc2, Cdk4, and cyclin B were detected at very low concentrations; while cyclin D1, cyclin D3, Cip1, and Kip1 were not detected. These results suggest (i) that ProTα is transported into the nucleus by the karyopherin β1- Rch-1 complex, and (ii) that ProTα may interact in the nucleus with proteins involved in DNA metabolism and cell-cycle control.Key words: prothymosin α, histone-binding proteins, nuclear transport proteins, cell-cycle proteins, chromatin remodeling.

The prothymosin a kinase (ProTαK) is an apparently novel enzyme that is responsible for the phosphorylation of prothymosin α (ProTα), involved in the proliferation of mammalian cells. The present study investigated the properties of this enzyme. ProTαK is more effectively activated by Mn2+ than by other divalent cations, and its activity is unaffected by RNA. Its principal substrate in proliferating cells appears to be ProTa. Both in vivo and in vitro, it is unable to phosphorylate the peptides thymosin α1 and thymosin α11, derived from the amino terminus of ProTα, despite the fact that the sites of phosphorylation of ProTα are contained within this part of its sequence. In trials in vivo, inhibition of gene expression abolished both phosphorylation of ProTα and ProTαK activity. ProTαK is located in the cytosolic fractions throughout the cell cycle. Its activity, which is dependent on cell proliferation, increases markedly during S phase and begins to decline as the cell enters G2. Studies of the effects of activators and inhibitors of protein kinases involved in signal transduction pathways suggest that ProTαK is activated by phosphorylation in a mitogen-initiated pathway that is dependent on PKC; however, PKC does not itself phosphorylate ProTαK, which is therefore presumably phosphorylated by another kinase.

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.

As trochoidal-gear pump specifications become more demanding and design cycles shorter, the use of an innovative tool for modeling and simulation can be a cost effective and valuable guide to a more effective experimental work. The existing methodologies and software fail to thoroughly address the design by taking into account real effects to maximize efficiency and reduce flow fluctuation. Two new modules are added to the structured methodology of GeroLAB: minimum clearance module, teeth clearance related to leakage phenomenon, and relief groove effective port area module, modeling sharp rims with relief grooves in the porting plate which are related to flow performance. An analysis of the manufactured tolerance is conducted in four gear sets and results are compared and contrast. By using the bond graph model of a specific gerotor pump, flow performance is studied in nine cases with different relief grooves geometries and significant results are drawn. As a conclusion, these new modules aim to continue leading the designer to enhance the efficiency of a gerotor pump and the manufacturer to reduce costs by reducing time in experimental stage.

Background Clear cell carcinoma (CCC) is the most prevalent malignancy of the kidney. Sarcomatoid differentiation can occur in all others histologic subtypes, and it is associated with a significant poor prognosis and grade 4 in Fuhrman scoring. The recent use of core needle biopsies (CNB) has hindered the correct diagnosis of RCC sarcomatoid differentiation. Our hypothesis is that the presence of COL11A1 in the tumor can be a reliable sarcomatoid differentiation predictor, as it plays an important role in ephitelial-mesenchymal transition program. Methods Immunohistochemistry of proCOL11A1 was performed (as previously described) in samples of 122 renal cell carcinomas of different histological subtypes. Results Our results showed a significant difference ( p Conclusion COL11A1 expression renal cell carcinoma may predict sarcomatoid differentiation even in samples with low numbers of cells, as may occur in a CNB, so it can be beneficial to clinicians in order to modify treatment options and follow-up protocols.

Listeria monocytogenes is a gram-positive bacteria and human pathogen widely used in cancer immunotherapy because of its capacity to induce a specific cytotoxic T cell response in tumours. This bacterial pathogen strongly induces innate and specific immunity with the potential to overcome tumour induced tolerance and weak immunogenicity. Here, we propose a Listeria based vaccination for melanoma based in its tropism for these tumour cells and its ability to transform in vitro and in vivo melanoma cells into matured and activated dendritic cells with competent microbicidal and antigen processing abilities. This Listeria based vaccination using low doses of the pathogen caused melanoma regression by apoptosis as well as bacterial clearance. Vaccination efficacy is LLO dependent and implies the reduction of LLO-specific CD4+ T cell responses, strong stimulation of innate pro-inflammatory immune cells and a prevalence of LLO-specific CD8+ T cells involved in tumour regression and Listeria elimination. These results support the use of low doses of pathogenic Listeria as safe melanoma therapeutic vaccines that do not require antibiotics for bacterial removal.

Understanding the behavior of system with flexible elements is increasingly important in modern day technology. Reducing the mass of machine elements leads to a remarkable improvement in dynamic performance. However, a loss of precision also occurs with such an increase in flexibility. In order to arrive at a better understanding of systems with flexible elements, we are investigating the particular behavior of a hydraulic servo driven rotating flexible beam with the aim of obtaining a methodology that could be applied to a real application. To investigate this behavior, a set of models has been developed. In this paper, a theoretical model, using classical modal analysis methodology, is presented. The flexible beam is modeled in a standard way and the hydraulic servo drive is modeled as a boundary condition. Only normal modes will be investigated. This approach allows considering the servo proportional constant and the cylinder mass. It will be show that the servo proportional constant has low influence in the system eigen frequencies. The theoretical model predictions are validated experimentally.Copyright © 2003 by ASME

Background As described previously in high impact studies,1 patients with other activating RAS out of codon 2 of kras mutations may also be negative predictive biomarkers for anti-EGFR therapy. Here we present the description of a new series in which has been performed the analysis of mutations in KRAS and NRAS genes. Methods Samples of 108 patients with colorectal cancer were used. DNA were extracted from formalin fixed paraffin embedded samples using COBAS DNA sample preparation kit (Roche). Mutation status was determined by targeted pyrosequencing with N/K RAS Pyro Kit (Qiagen). Results Sixty-four out of 108 samples were wild type (WT) both for KRAS and NRAS. Thirty-five patients presented mutation on KRAS (27 in codon 12, 4 in 13, 1 in 117, and 3 in 146). The rest of the patients (9) presented alterations in NRAS (1 in codon 12, 3 in 13, and 5 in 61). Conclusion Our results closely resemble those published to date,2 but due to small sample size are not fully comparable. Further studies must be done to determine the real distribution of the new RAS mutations.

Background Breast cancer in men is rare, but mortality is slightly higher than women because of their most delayed detection. A greater understanding of this tumor will lead us to an earlier detection. The purpose of this study is to retrospectively evaluate 10 year experience with male breast cancer at Cantabria. Methods The clinical data from male patients who had presented to a physician with suspicion of breast tumor were retrospectively analysed. Results 131 patients sought medical consultation for breast affectation; 58 were diagnosed with gynecomastia and 29 showed no tumor lesions. Twenty-three of 45 patients presenting tumoral lesions were benign, while 21 where malignant. Except for an intracystic papillary carcinoma and apocrine carcinoma the other patients presented infiltrative ductal carcinoma. The median patient age was 70 years (range 50–91). Estrogen receptor was positive in 16 patients (94%, 4 patients were non-valorable), while progesterone receptor and C-erbB2 were positive in 14 (82%) and 1 (6%) patient, respectively. Forty patients (82%) had both ER(+) and PR(+). 15 patients (71 %) presented metastasis in sentinel lymph node, three patients (14%) in skin, while one (5%) in lung. Conclusion Large cooperative studies are needed to advance the understanding of this disease.

Background Pulmonary Langerhans cell histiocytosis (PLCH) is a distinctive form of tobacco associated interstitial lung disease. Therapeutic options other than lung transplantation are scarce when a fibrotic phase has been reached. One severe complication is the emergence of pulmonary hypertension that has been related to chronic hypoxia. A few papers describe its morphological characteristics focusing on arterial lesions. Otherwise, BRAF mutations have been recently described in systemic Langerhans cell histiocytosisandonlyone paperwithfivecaseshasbeen publishedonPLCH. Methods We have revised morphological changes associated with pulmonary vasculature and the presence of Langerhans cells by routine and immunohistochemical methods (S100 protein, CD1a and Langerin) in 22 PLCH cases. We have used real time PCR to detect BRAF mutations in Langerhans cells using manual macrodisection in paraffin embedded tissue. Results Six out of 22 patients (27%) showed some grade of capillary haemangiomatosis-like changes. Aggregates of Langer-hans cells were located in interlobular septa in those cases. Two BRAF mutated cases were found, both of them in cellular/mixed lesions. Conclusion We present six patients with capillary haemangiomatosis-like changes with infrequent located Langerhans cells in pulmonary Langerhans cell histiocytosis. We confirm the occurrence of BRAF mutations in this kind of disease.

Background Bladder cancer is one of the most prevalent neoplasias; although it does not have a high mortality, its great incidence causes a large number of deaths. This is why a proper diagnosis is necessary. Currently, transurethral resection (TUR) based biopsy provides the best tool for the diagnosis of bladder carcinoma. However, technical problems inherent to the resection1 sometimes make the diagnosis inaccurate, especially when there is lack of muscularis propria or fulguration artifacts are present. Our hypothesis is that the presence of COL11A1 in the tumor stroma can be a reliable infiltrative growth predictor, as it has been shown in other tumors such as breast, lung, stomach or pancreas. Methods Immunohistochemistry of COL11A12 was performed in TUR samples of 43 patients. We finally examined 11 pTa, 15 pT1, 11 pT2 and 6 non-neoplastic lesions. Results Our results showed a significant difference ( p Conclusion These data suggest that fibroblast expression of COL11 1 is an accurate malignant marker, with high levels of sensitivity and specificity greater than 90%, which could be used as a predictive marker of muscular infiltration.

En vista a la importante inversion que requiere Chile para el Programa de Concesiones de Obras Publicas, estimada en US$ 4.000 millones dentro de los proximos diez anos, surgio un estudio para analizar las estructuras de endeudamiento utilizadas por las sociedades concesionarias para el financiamiento de sus proyectos. Este estudio fue llevado a cabo por el Comite de Mercado de Capitales junto al sector privado y a los Ministerios de Hacienda y de Obras Publicas. El resultado del trabajo fue la creacion de un nuevo instrumento financiero: el Bono de Infraestructura. Los bonos serian emitidos por las mismas sociedades concesionarias y tienen como objetivo ser clasificados con grado de inversion para facilitar la participacion de los inversionistas institucionales.

540 Background: Breast cancer is currently the most frequent tumor among women. Despite the huge progress achieved in its early diagnosis, there are still many unsolved clinical issues, being the diagnosis, prognosis and treatment of papillary diseases (and specifically intraductal papilloma), 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 papillary lesion, while others support an only expectant follow up. Previous results of our group have suggested that pro-Collagen 11 alpha 1 (pro-COL11A1) expression in cancer associated fibroblasts (CAFs) correlates with an infiltrating phenotype in breast lesions. We have analyzed the correlation between the differential expression of pro-COL11A1 in intraductal papilloma and their risk of malignant recurrence. Methods: Immunohistochemistry of pro-COL11A1 (clone 1E8.33, ONCOMATRIX, Bilbao, SPAIN) was performed in formalin fixed, paraffin embedded Core Needle Biopsy samples of 51 patients with intraductal papilloma. All patients had a minimum follow-up of 5 years. Results: Twenty-three out of 51 cases showed positive staining for COL11A1. Nine patients out of the positive cases relapsed as infiltrating carcinoma, two as intraductal papilloma and the rest had not recurred after five years of follow up. Only one case out of the 28 negative cases relapsed as invasive carcinoma. There were significant differences (p=0.0013) when comparing staining of individuals with malignant recurrence versus non recurrence and benign relapse patients, with a sensitivity of 90% and specificity of 66%. Conclusions: These data suggest that COL11A1 expression in CAFs is a highly sensitive biomarker to predict malignant relapse of intraductal papilloma. The low specificity might be biased by the complete excision of this lesion as the routine treatment or by a short follow-up of the patients.

The molecular hallmarks of inflammation-mediated lung carcinogenesis have not been fully clarified, mainly due to the scarcity of appropriate animal models. We have used a silica-induced multistep lung carcinogenesis model driven by chronic inflammation to study the evolution of molecular markers and genetic alterations. We analyzed markers of DNA damage response (DDR), proliferative stress, and telomeric stress: gamma-H2AX, p16, p53, and TERT. Lung cancer-related epigenetic and genetic alterations, including promoter hypermethylation status of p16(CDKN2A), APC, CDH13, Rassf1, and Nore1A, as well as mutations of Tp53, epidermal growth factor receptor, K-ras, N-ras, and c-H-ras, have been also studied. Our results showed DDR pathway activation in preneoplastic lesions, in association with inducible nitric oxide synthase and p53 induction. p16 was also induced in early tumorigenic progression and was inactivated in bronchiolar dysplasias and tumors. Remarkably, lack of mutations of Ras and epidermal growth factor receptor, and a very low frequency of Tp53 mutations suggest that they are not required for tumorigenesis in this model. In contrast, epigenetic alterations in p16(CDKN2A), CDH13, and APC, but not in Rassf1 and Nore1A, were clearly observed. These data suggest the existence of a specific molecular signature of inflammation-driven lung carcinogenesis that shares some, but not all, of the molecular landmarks of chemically induced lung cancer.

A mRNA fraction purified by preparative polyacrylamide disc gel electrophoresis from calf thymus polysomes codes for a polypeptide(s) having a mass of 16,000-17,000 daltons. This polypeptide contains amino acid sequences corresponding to residues 11-18 and 19-25 of thymosin alpha 1. The yield of the octapeptide indicates that the 16,000-dalton peptide is the major product formed in the cell-free synthesis system containing the purified mRNA.