ID4-dependent reprogramming of tumor associated macrophages in triple negative breast cancer

Breast cancer is one of the most common cancer affecting especially women worldwide and it shows a particularly aggressive behavior in the triple negative (TNBC) and basal-like breast cancer (BLBC) subtypes that are characterized by poor prognosis and by the lack of targeted therapies. Moreover, it is well established that the presence of a massive leukocyte infiltrate, is involved in the promotion of tumor progression, contributing in particular to the angiogenic switch that occurs in the early phases of tumor progression. Among the variety of cells infiltrating breast tumors, macrophages have been extensively shown to tightly control the angiogenic onset and progression to malignancy. Here, we investigated whether ID4 protein, previously reported to enhance the angiogenic potential of breast cancer cells, exerts its function also modulating the activity of tumor-associated macrophages. We first assessed the significant association between the expression of ID4 and the macrophages marker CD68 in series of triple negative breast tumors. Of note, high ID4 mRNA expression in presence of a high macrophage infiltrate (determined as the expression of 8 macrophage markers) in BLBC is a strong predictor of poor survival. In vitro and in vivo migration assays evidenced that expression of ID4 in breast cancer cells is able to influence macrophages motility. At gene expression level we observed induction of ID4 itself, in macrophages co-cultured with breast cancer cells, induction that was impaired when breast cancer cells were depleted of ID4 expression. The same ID4-dependent behavior was observed for HIF-1A and for an angiogenesis-related signature in macrophages. Expression of angiogenesis-related genes was further controlled by miR-107, down-regulated in macrophages in ID4-dependent manner. Altogether our results highlight a key role for ID4 in dictating the angiogenic behavior of tumor-associated macrophages in breast cancer

Multi-Criteria Optimal Planning for Energy Policies in CLP

In the policy making process a number of disparate and diverse issues such as economic development, environmental aspects, as well as the social acceptance of the policy, need to be considered. A single person might not have all the required expertises, and decision support systems featuring optimization components can help to assess policies. Leveraging on previous work on Strategic Environmental Assessment, we developed a fully-fledged system that is able to provide optimal plans with respect to a given objective, to perform multi-objective optimization and provide sets of Pareto optimal plans, and to visually compare them. Each plan is environmentally assessed and its footprint is evaluated. The heart of the system is an application developed in a popular Constraint Logic Programming system on the Reals sort. It has been equipped with a web service module that can be queried through standard interfaces, and an intuitive graphic user interface.Comment: Accepted at ICLP2014 Conference as Technical Communication, due to appear in Theory and Practice of Logic Programming (TPLP

Expression of ID4 protein in breast cancer cells induces reprogramming of tumour-associated macrophages

Background: As crucial regulators of the immune response against pathogens, macrophages have been extensively shown also to be important players in several diseases, including cancer. Specifically, breast cancer macrophages tightly control the angiogenic switch and progression to malignancy. ID4, a member of the ID (inhibitors of differentiation) family of proteins, is associated with a stem-like phenotype and poor prognosis in basal-like breast cancer. Moreover, ID4 favours angiogenesis by enhancing the expression of pro-angiogenic cytokines interleukin-8, CXCL1 and vascular endothelial growth factor. In the present study, we investigated whether ID4 protein exerts its pro-angiogenic function while also modulating the activity of tumour-associated macrophages in breast cancer. Methods: We performed IHC analysis of ID4 protein and macrophage marker CD68 in a triple-negative breast cancer series. Next, we used cell migration assays to evaluate the effect of ID4 expression modulation in breast cancer cells on the motility of co-cultured macrophages. The analysis of breast cancer gene expression data repositories allowed us to evaluate the ability of ID4 to predict survival in subsets of tumours showing high or low macrophage infiltration. By culturing macrophages in conditioned media obtained from breast cancer cells in which ID4 expression was modulated by overexpression or depletion, we identified changes in the expression of ID4-dependent angiogenesis-related transcripts and microRNAs (miRNAs, miRs) in macrophages by RT-qPCR. Results: We determined that ID4 and macrophage marker CD68 protein expression were significantly associated in a series of triple-negative breast tumours. Interestingly, ID4 messenger RNA (mRNA) levels robustly predicted survival, specifically in the subset of tumours showing high macrophage infiltration. In vitro and in vivo migration assays demonstrated that expression of ID4 in breast cancer cells stimulates macrophage motility. At the molecular level, ID4 protein expression in breast cancer cells controls, through paracrine signalling, the activation of an angiogenic programme in macrophages. This programme includes both the increase of angiogenesis-related mRNAs and the decrease of members of the anti-angiogenic miR-15b/107 group. Intriguingly, these miRNAs control the expression of the cytokine granulin, whose enhanced expression in macrophages confers increased angiogenic potential. Conclusions: These results uncover a key role for ID4 in dictating the behaviour of tumour-associated macrophages in breast cancer

The contribution of italian linguistics to saussurian studies

O presente artigo apresenta uma abordagem exploratória inicial da linguística saussuriana italiana. Para tanto, partiu-se da contextualização do autor que é o marco para os estudos saussurianos na Itália, Tullio De Mauro. Especial destaque é dado à originalidade da interpretação produzida por De Mauro em relação ao clássico livro Curso de linguística geral, resultando em contribuições que são definidoras da forma com que a teoria é até hoje interpretada. Termos como langue e parole ilustram essa posição de interpretação da teoria em De Mauro e em outros autores saussurianos italianos contemporâneos.This article presents an initial exploratory approach to Italian Saussurean linguistics. To do so, we begin with a contextualization of the author whose work is the landmark for Saussurean studies in Italy, Tullio De Mauro. Special emphasis is given to the originality of the interpretation produced by De Mauro in relation to the classic book Course in general linguistics, resulting in contributions that define the way in which Saussurean theory is interpreted until today. Terms such as langue and parole illustrate De Mauro’s approach to the theory, followed by other contemporary Italian Saussurean authors

Paracrine signaling from breast cancer cells causes activation of ID4 expression in tumor-associated macrophages

Background: Tumor-associated macrophages (TAMs) constitute a major portion of the leukocyte infiltrate found in breast cancer (BC). BC cells may reprogram TAMs in a pro-angiogenic and immunosuppressive sense. We previously showed that high expression of the ID4 protein in triple-negative BC cells leads to the induction of a proangiogenic program in TAMs also through the downregulation of miR-107. Here, we investigated the expression and function of the ID4 protein in TAMs. Methods: Human macrophages obtained from peripheral blood-derived monocytes (PBDM) and mouse RAW264.7 cells were used as macrophage experimental systems. ID4-correlated mRNAs of the TCGA and E-GEOD-18295 datasets were analyzed. Results: We observed that BC cells determine a paracrine induction of ID4 expression and activation of the ID4 promoter in neighboring macrophages. Interestingly, ID4 expression is higher in macrophages associated with invasive tumor cells compared to general TAMs, and ID4-correlated mRNAs are involved in various pathways that were previously reported as relevant for TAM functions. Selective depletion of ID4 expression in macrophages enabled validation of the ability of ID4 to control the expression of YAP1 and of its downstream targets CTGF and CYR61. Conclusion: Collectively, our results show that activation of ID4 expression in TAMs is observed as a consequence of BC cell paracrine activity and could participate in macrophage reprogramming in BC

Salum after half a century : a presentation of the saussurian sources to the Brazilian reader

Este artigo propõe-se a apresentar um panorama das fontes saussurianas aos leitores brasileiros. Com o intuito de organizar tão vasto material, optou-se por dividi-lo em seis seções: publicações em vida; publicações disponíveis em língua portuguesa; edições complementares ao Cours; manuscritos autográficos editados; publicações sobre léxico e terminologia; cartas e biografia. Para além da apresentação do conjunto de fontes, é necessária uma introdução ao corpus à disposição dos pesquisadores atualmente, visto sua complexidade e diversidade. Além disso, este artigo pretende homenagear a primeira edição brasileira do Curso de linguística geral a partir de seu prefácio, que já à época de sua publicação foi responsável por apresentar ao público o contexto e a natureza da obra, assim como indicar aos leitores fontes de leitura então disponíveis, recomendação que seguimos e que buscamos complementar.This article intends to present an overview of Saussurean research sources to Brazilian readers. To organize such vast material, there are six sections: publications during his lifetime; publications available in Portuguese; complementary editions to the Course; edited autograph manuscripts; publications on the lexicon and terminology; letters and biographies. In addition to presenting this set of works, this article introduces the Saussurean corpus currently available for research, given its complexity and diversity. Besides, this article intends to pay tribute to the first Brazilian edition of the Course in general linguistics from its preface, which, at the time of its first appearance, was responsible for presenting the context and nature of the book to the public, as well as indicating to readers available reading sources, indication that we seek to complement

The mutant p53-ID4 complex controls VEGFA isoforms by recruiting lncRNA MALAT1

The abundant, nuclear-retained, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been associated with a poorly differentiated and aggressive phenotype of mammary carcinomas. This long non-coding RNA (lncRNA) localizes to nuclear speckles, where it interacts with a subset of splicing factors and modulates their activity. In this study, we demonstrate that oncogenic splicing factor SRSF1 bridges MALAT1 to mutant p53 and ID4 proteins in breast cancer cells. Mutant p53 and ID4 delocalize MALAT1 from nuclear speckles and favor its association with chromatin. This enables aberrant recruitment of MALAT1 on VEGFA pre-mRNA and modulation of VEGFA isoforms expression. Interestingly, VEGFA-dependent expression signatures associate with ID4 expression specifically in basal-like breast cancers carrying TP53 mutations. Our results highlight the key role for MALAT1 in control of VEGFA isoforms expression in breast cancer cells expressing gain-of-function mutant p53 and ID4 proteins

Whole Lung Irradiation after High-Dose Busulfan/Melphalan in Ewing Sarcoma with Lung Metastases: An Italian Sarcoma Group and Associazione Italiana Ematologia Oncologia Pediatrica Joint Study

SIMPLE SUMMARY: The lung is the most frequent site of metastasis in Ewing sarcoma, the second most common bone cancer affecting children, adolescents and young adults. The five-year overall survival of patients with isolated lung metastasis is approximately 50% after multimodal treatments including chemotherapy, surgery and radiotherapy. This retrospective study aimed to investigate the feasibility and the predictors of survival in 68 Ewing sarcoma patients with lung metastases who received high-dose chemotherapy with busulfan and melphalan, followed by reduced dose whole-lung irradiation, as part of two prospective and consecutive treatment protocols. This combined treatment strategy is feasible and might contribute to the disease control in lung metastatic Ewing sarcoma with responsive disease. Furthermore, the results of this study provide support to explore the treatment stratification for lung metastatic Ewing sarcoma based on the histological response of the primary tumor. ABSTRACT: Purpose: To analyze toxicity and outcome predictors in Ewing sarcoma patients with lung metastases treated with busulfan and melphalan (BU-MEL) followed by whole-lung irradiation (WLI). Methods: This retrospective study included 68 lung metastatic Ewing Sarcoma patients who underwent WLI after BU-MEL with autologous stem cell transplantation, as part of two prospective and consecutive treatment protocols. WLI 12 Gy for <14 years old and 15 Gy for ≥14 years old patients were applied at least eight weeks after BU-MEL. Toxicity, overall survival (OS), event-free survival (EFS) and pulmonary relapse-free survival (PRFS) were estimated and analyzed. Results: After WLI, grade 1–2 and grade 3 clinical toxicity was reported in 16.2% and 5.9% patients, respectively. The five-year OS, EFS and PRFS with 95% confidence interval (CI) were 69.8% (57.1–79.3), 61.2% (48.4–71.7) and 70.5% (56.3–80.8), respectively. Patients with good histological necrosis of the primary tumor after neoadjuvant chemotherapy showed a significant decreased risk of pulmonary relapse or death compared to patients with poor histological necrosis. Conclusions: WLI at recommended doses and time interval after BU-MEL is feasible and might contribute to the disease control in Ewing sarcoma with lung metastases and responsive disease. Further studies are needed to explore the treatment stratification based on the histological response of the primary tumor

Severe dyspnea due to a giant antrochoanal polyp

[ES] Disnea severa por pólipo gigante antrocoanal Autores: Susana Martín Batista, Marina Madrigal Revuelta, Luis Angel Vallejo Valdezate, Milagros Coloma Milano, Elisa Gil-Carcedo Sañudo, Luis María Gil-Carcedo García Localización: Otorrinolaringológica de Castilla y León, Cantabria y La Rioja, ISSN-e 2171-9381, Vol. 3, 2012 , págs. 186-189 Idioma: español Títulos paralelos: Severe dyspnea due to a giant antrochoanal polyp Texto completo (pdf) Resumen español Introducción: El pólipo antrocoanal es una patología prevalente en adolescentes y adultos jóvenes, normalmente se presentan con sintomatología de obstrucción nasal. Paciente y método: Describimos el caso de un paciente de 80 años con encepalopatía alcohólica, broncopatía crónica no filiada y rinosinusitis crónica polipoidea. Acude a urgencias con disnea severa de características no laringeas y carácter posicional. A la exploración se aprecia masa polipoidea en fosa nasal izquierda que impide pogresar el nasofibroscopio, observándose también gran tumoración en orofaringe que parece depender de rinofaringe y se extiende hacia cara laríngea de epiglotis. Se solicita TC urgente. Resultados: La TC informa de lesión de gran tamaño que ocupa celdas etmoidales izquierdas toda la fosa nasal y seno maxilar izquierdo y se extiende posteriormente a naso y orofaringe sobrepasando la línea media y condicionando estenosis de la vía aérea. Se decide exéresis quirúrgica mediante cirugía endoscópica nasosinusal urgente tras la que remite la clínica del paciente. Discusión/conclusión: Ante un paciente con disnea severa debemos determinar la causa y localización de la misma para planificar el tratamiento adecuado. Las características de la disnea desestimaron el asiento laríngeo, las pruebas complementarias aportan datos referidos a la extensión del proceso. El pólipo antrocoanal es una causa rara de disnea pero debemos pensar en la misma, o en la posible presencia de formaciones faríngeas, ante una disnea dudosamente laríngea que mejora con la extensión cervical.Introducción: El pólipo antrocoanal es una patología prevalente en adolescentes y adultos jóvenes, normalmente se presentan con sintomatología de obstrucción nasal. Paciente y método: Describimos el caso de un paciente de 80 años con encepalopatía alcohólica, broncopatía crónica no filiada y rinosinusitis crónica polipoidea. Acude a urgencias con disnea severa de características no laringeas y carácter posicional. A la exploración se aprecia masa polipoidea en fosa nasal izquierda que impide pogresar el nasofibroscopio, observándose también gran tumoración en orofaringe que parece depender de rinofaringe y se extiende hacia cara laríngea de epiglotis. Se solicita TC urgente. Resultados: La TC informa de lesión de gran tamaño que ocupa celdas etmoidales izquierdas toda la fosa nasal y seno maxilar izquierdo y se extiende posteriormente a naso y orofaringe sobrepasando la línea media y condicionando estenosis de la vía aérea. Se decide exéresis quirúrgica mediante cirugía endoscópica nasosinusal urgente tras la que remite la clínica del paciente. Discusión/conclusión: Ante un paciente con disnea severa debemos determinar la causa y localización de la misma para planificar el tratamiento adecuado. Las características de la disnea desestimaron el asiento laríngeo, las pruebas complementarias aportan datos referidos a la extensión del proceso. El pólipo antrocoanal es una causa rara de disnea pero debemos pensar en la misma, o en la posible presencia de formaciones faríngeas, ante una disnea dudosamente laríngea que mejora con la extensión cervical. [EN] Introduction: The antrochoanal polyp is a prevalent pathology in teenagers and young adults. It usually presents with nasal obstruction. Patient and method: Case report: An 80-year-old male with alcoholic encephalopathy, chronic bronchial disease of unknown etiology and polypoid chronic rhinosinusitis came to the emergency service with severe dyspnea without laryngeal features. Anterior rhinoscopy showed a polypoid mass in left nostril that prevented the visualization with nasal endoscopy.Examination of the mouth revealed a large polypoid mass involving nasopharynx and extends to hypopharynx until the laryngeal side of epiglottis. CT was requested urgently. Results CT demonstrated an almost complete opacification of the left maxillary sinus, left complex ethmoid cells and the presence of a soft-tissue mass, passing through the maxilary ostium into the posterior nasal cavity and choana. Mass caudal extention was located close to the laryngeal surface of the epiglottis and partially occupying the laryngeal vestibule conditioning the air way. Functional endoscopic sinus surgery was performed urgently with clinical remission. Conclusions In case we are treating a patient with severe dyspnea, we must determinate the etiology and localization of it, in order to decide the best treatment option. Dyspnea´s features dismissed the laryngeal site.Complementary image studies give us information about the extension. Antrochoanal polyp cases causing dyspnea are unsual, but we must think of it, or in pharyngeal formations, every time dyspnea improves with a cervical extention