Potentiating vascular-targeted photodynamic therapy through CSF-1R modulation of myeloid cells in a preclinical model of prostate cancer

Vascular-targeted photodynamic therapy (VTP) induces rapid destruction of targeted tissues and is a promising therapy for prostate cancer. However, the resulting immune response, which may play an important role in either potentiating or blunting the effects of VTP, is still incompletely understood. Myeloid cells such as myeloid-derived suppressor cells (MDSCs) and macrophages are often found in tumors and are widely reported to be associated with cancer angiogenesis, tissue remodeling, and immunosuppression. These cells are also known to play a critical role in wound-healing, which is induced by rapid tissue destruction. In this study, we investigated the effects of VTP on the recruitment of tumor-infiltrating myeloid cells, specifically MDSCs and tumor-associated macrophages (TAMs), in the Myc-Cap and TRAMP C2 murine prostate cancer models. We report that VTP increased the infiltration of myeloid cells into the tumors, as well as their expression of CSF1R, a receptor required for myeloid differentiation, proliferation, and tumor migration. As anti-CSF1R treatment has previously been used to deplete these cells types in other murine models of prostate cancer, we hypothesized that combining anti-CSF1R with VTP therapy would lead to decreased tumor regrowth and improved survival. Importantly, we found that targeting myeloid cells using anti-CSF1R in combination with VTP therapy decreased the number of tumor MDSCs and TAMs, especially M2 macrophages, as well as increased CD8 T cell infiltration, decreased tumor growth and improved overall survival. These results suggest that targeting myeloid cells via CSF1R targeting is a promising strategy to potentiate the anti-tumor effects of VTP

Neoantigen quality predicts immunoediting in survivors of pancreatic cancer.

Cancer immunoediting1 is a hallmark of cancer2 that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice1,3, whether immunoediting occurs naturally in human cancers remains unclear. Here, to address this, we investigate how 70 human pancreatic cancers evolved over 10 years. We find that, despite having more time to accumulate mutations, rare long-term survivors of pancreatic cancer who have stronger T cell activity in primary tumours develop genetically less heterogeneous recurrent tumours with fewer immunogenic mutations (neoantigens). To quantify whether immunoediting underlies these observations, we infer that a neoantigen is immunogenic (high-quality) by two features-'non-selfness'  based on neoantigen similarity to known antigens4,5, and 'selfness'  based on the antigenic distance required for a neoantigen to differentially bind to the MHC or activate a T cell compared with its wild-type peptide. Using these features, we estimate cancer clone fitness as the aggregate cost of T cells recognizing high-quality neoantigens offset by gains from oncogenic mutations. With this model, we predict the clonal evolution of tumours to reveal that long-term survivors of pancreatic cancer develop recurrent tumours with fewer high-quality neoantigens. Thus, we submit evidence that that the human immune system naturally edits neoantigens. Furthermore, we present a model to predict how immune pressure induces cancer cell populations to evolve over time. More broadly, our results argue that the immune system fundamentally surveils host genetic changes to suppress cancer

ICOS regulates the generation and function of human CD4+ Treg in a CTLA-4 dependent manner

Inducible co-stimulator (ICOS) is a member of CD28/Cytotoxic T-lymphocyte Antigen-4 (CTLA-4) family and broadly expressed in activated CD4+ T cells and induced regulatory CD4+ T cells (CD4+ iTreg). ICOS-related signal pathway could be activated by the interaction between ICOS and its ligand (ICOSL). In our previous work, we established a cost-effective system to generate a novel human allo-antigen specific CD4hi Treg by co-culturing their naïve precursors with allogeneic CD40-activated B cells in vitro. Here we investigate the role of ICOS in the generation and function of CD4hi Treg by interrupting ICOS-ICOSL interaction with ICOS-Ig. It is found that blockade of ICOS-ICOSL interaction impairs the induction and expansion of CD4hi Treg induced by allogeneic CD40-activated B cells. More importantly, CD4hi Treg induced with the addition of ICOS-Ig exhibits decreased suppressive capacity on alloantigen-specific responses. Dysfunction of CD4hi Treg induced with ICOS-Ig is accompanied with its decreased exocytosis and surface CTLA-4 expression. Through inhibiting endocytosis with E64 and pepstatin A, surface CTLA-4 expression and suppressive functions of induced CD4hi Treg could be partly reversed. Conclusively, our results demonstrate the beneficial role of ICOS-ICOSL signal pathway in the generation and function of CD4hi Treg and uncover a novel relationship between ICOS and CTLA-4. © 2013 zheng et al.published_or_final_versio

Aurora-A overexpression enhances cell-aggregation of Ha-ras transformants through the MEK/ERK signaling pathway

<p>Abstract</p> <p>Background</p> <p>Overexpression of Aurora-A and mutant Ras (Ras^V12) together has been detected in human bladder cancer tissue. However, it is not clear whether this phenomenon is a general event or not. Although crosstalk between Aurora-A and Ras signaling pathways has been reported, the role of these two genes acting together in tumorigenesis remains unclear.</p> <p>Methods</p> <p>Real-time PCR and sequence analysis were utilized to identify Ha- and Ki-<it>ras </it>mutation (Gly -> Val). Immunohistochemistry staining was used to measure the level of Aurora-A expression in bladder and colon cancer specimens. To reveal the effect of overexpression of the above two genes on cellular responses, mouse NIH3T3 fibroblast derived cell lines over-expressing either Ras^V12and wild-type Aurora-A (designated WT) or Ras^V12and kinase-inactivated Aurora-A (KD) were established. MTT and focus formation assays were conducted to measure proliferation rate and focus formation capability of the cells. Small interfering RNA, pharmacological inhibitors and dominant negative genes were used to dissect the signaling pathways involved.</p> <p>Results</p> <p>Overexpression of wild-type Aurora-A and mutation of Ras^V12were detected in human bladder and colon cancer tissues. Wild-type Aurora-A induces focus formation and aggregation of the Ras^V12transformants. Aurora-A activates Ral A and the phosphorylation of AKT as well as enhances the phosphorylation of MEK, ERK of WT cells. Finally, the Ras/MEK/ERK signaling pathway is responsible for Aurora-A induced aggregation of the Ras^V12transformants.</p> <p>Conclusion</p> <p>Wild-type-Aurora-A enhances focus formation and aggregation of the Ras^V12transformants and the latter occurs through modulating the Ras/MEK/ERK signaling pathway.</p

PI3Kδ and primary immunodeficiencies.

Primary immunodeficiencies are inherited disorders of the immune system, often caused by the mutation of genes required for lymphocyte development and activation. Recently, several studies have identified gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (which encodes p110δ) and PIK3R1 (which encodes p85α) that cause a combined immunodeficiency syndrome, referred to as activated PI3Kδ syndrome (APDS; also known as p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI)). Paradoxically, both loss-of-function and gain-of-function mutations that affect these genes lead to immunosuppression, albeit via different mechanisms. Here, we review the roles of PI3Kδ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3Kδ gleaned from these patients, as well as implications of these findings for clinical therapy

The 1990 Calan/Tololo Supernova Search

We have started a search for supernovae as a collaboration between the University of Chile and the Cerro Tololo Inter-American Observatory, with the aim of producing a moderately distant (0.01 < z <0.10) sample of Type Ia and Type II supernovae suitable for cosmological studies. The project began in mid-1990 and continues to the present. This paper reports on the Calan/Tololo discoveries in the course of 1990, and on the spectroscopic and photometric observations gathered for these objects. All of these observations were obtained with CCDs, with the extensive collaboration of visiting astronomers. Great care was exercised in the reduction of the light curves in order to properly correct for the background light of the host galaxy of each supernova. Of the four supernovae found in 1990, one proved to be a SN II-n; the remaining three were members of the Type Ia class at redshifts that ranged between z = 0.04-0.05. One of the Type Ia events, SN 1990af, was found in the elusive premaximum phase at a redshift of z = 0.0503, and was observed through maximum light. Peak magnitudes for the other two SNe Ia, which were not observed at maximum light, were derived using a χ^2^ minimization technique to fit the data with various template curves that represent a broad range of SNe Ia light curves. In future papers we will make use of these estimates in order to discuss the Hubble diagram of SNe Ia

Enfermedades crónicas

Adherencia al tratamiento farmacol&oacute;gico y relaci&oacute;n con el control metab&oacute;lico en pacientes con DM2Aluminio en pacientes con terapia de reemplazo renal cr&oacute;nico con hemodi&aacute;lisis en Bogot&aacute;, ColombiaAmputaci&oacute;n de extremidades inferiores: &iquest;est&aacute;n aumentando las tasas?Consumo de edulcorantes artificiales en j&oacute;venes universitariosC&oacute;mo crecen ni&ntilde;os normales de 2 a&ntilde;os que son sobrepeso a los 7 a&ntilde;osDiagn&oacute;stico con enfoque territorial de salud cardiovascular en la Regi&oacute;n MetropolitanaEfecto a corto plazo de una intervenci&oacute;n con ejercicio f&iacute;sico, en ni&ntilde;os con sobrepesoEfectos de la cirug&iacute;a bari&aacute;trica en pacientes con s&iacute;ndrome metab&oacute;lico e IMC &lt; 35 KG/M2Encuesta mundial de tabaquismo en estudiantes de profesiones de saludEnfermedades cr&oacute;nicas no transmisibles: Consecuencias sociales-sanitarias de comunidades rurales en ChileEpidemiolog&iacute;a de las muertes hospitalarias por patolog&iacute;as relacionadas a muerte encef&aacute;lica, Chile 2003-2007Estado nutricional y conductas alimentarias en adolescentes de 4&ordm; medio de la Regi&oacute;n de CoquimboEstudio de calidad de vida en una muestra del plan piloto para hepatitis CEvaluaci&oacute;n del proceso asistencial y de resultados de salud del GES de diabetes mellitus 2Factores de riesgo cardiovascular en poblaci&oacute;n universitaria de la Facsal, universidad de Tarapac&aacute;Implicancias psicosociales en la g&eacute;nesis, evoluci&oacute;n y tratamiento de pacientes con hipertensi&oacute;n arterial esencialInfarto agudo al miocardio (IAM): Realidad en el Hospital de Puerto Natales, 2009-2010Introducci&oacute;n de nuevas TIC y mejor&iacute;a de la asistencia a un programa de saludNi&ntilde;os obesos atendidos en el Cesfam de Puerto Natales y su entorno familiarPerfil de la mortalidad por c&aacute;ncer de cuello uterino en R&iacute;o de JaneiroPerfil del paciente primo-consultante del Programa de Salud Cardiovascular, Consultorio Cordillera Andina, Los AndesPrevalencia de automedicaci&oacute;n en mujeres beneficiarias del Hospital Comunitario de Til-TiPrevalencia de caries en poblaci&oacute;n preescolar y su relaci&oacute;n con malnutrici&oacute;n por excesoPrevalencia de retinopat&iacute;a diab&eacute;tica en comunas dependientes del Servicio de Salud Metropolitano Occidente (SSMOC)Problemas de adherencia farmacol&oacute;gica antihipertensiva en poblaci&oacute;n mapuche: Un estudio cualitativoRol biol&oacute;gico de los antioxidantes innatos en pacientes portadores de VIH/SidaSobrepeso en empleados de un restaurante de una universidad p&uacute;blica del estado de S&atilde;o Paul

The cellular geography of Aurora kinases

Aurora is the name given to a family of highly conserved protein kinases with essential roles in many aspects of cell division. Yeasts have a single Aurora kinase, whereas mammals have three: Aurora A, B and C. During mitosis, Aurora kinases regulate the structure and function of the cytoskeleton and chromosomes and the interactions between these two at the kinetochore. They also regulate signalling by the spindle-assembly checkpoint pathway and cytokinesis. Perturbation of Aurora kinase expression or function might lead to cancer

Anestesia para el trabajo de parto

El nacimiento de un hijo es una experiencia maravillosa y dolorosa. Los mitos que rodean a la anestesia del trabajo de parto surgen tanto desde la ciencia y la sociedad como de las personas. En el presente artículo se revisa el estado actual del conocimiento sobre el efecto de la anestesia en el trabajo de parto, tomando alguno de sus aspectos más relevantes. Aunque la anestesia epidural estándar tiene algunos efectos negativos (partos instrumentales, paresia, retención de orina), las técnicas modernas (combinada espinal-epidural o epidural dosis bajas) han mejorado mucho estos aspectos. Por ello, la anestesia neuroaxial es la mejor alternativa en analgesia para parto. Sin embargo, a pesar de todo este avance poco ha cambiado la satisfacción materna, indicando que el dolor es sólo una parte de algo mucho más complejo