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Resumo Diante da complexidade dos fenômenos que levam à evasão, foi sistematizado um método que simplifica a elaboração de um diagnóstico, permitindo estruturar e agrupar as dificuldades mais relatadas, possibilitando relacionar as estratégias mais adequadas para contribuir com a permanência e a conclusão de estudantes. A pesquisa caracteriza-se como exploratória e descritiva, utilizando a análise documental para subsidiar a elaboração de questionários estruturados e objetivos. Para aplicação, empregou-se um método não probabilístico, no qual obteveram-se 5.041 respondentes de todos os cursos de graduação da UFMT (33% desvinculados, 37% vinculados e 29% egressos), totalizando cerca de 10% da população entre 2013 e 2019. A ponderação e o agrupamento de dificuldades possibilitou capturar diferentes perspectivas dos discentes. As dificuldades relacionadas com o aprendizado, a estrutura do curso e com o corpo docente foram muito citadas, permitindo a priorização de estratégias para gestores dos cursos e da instituição. Abstract In view of the complexity of the phenomena that lead to dropout, this paper systematized a method that simplifies the elaboration of a diagnosis, allowing to structure and group the most reported difficulties, making it possible to relate the most appropriate strategies to contribute to the permanence and completion of undergraduate degrees by students. The research is characterized as exploratory and descriptive, using documentary analysis to support the development of structured and objective questionnaires. For application, a non-probabilistic method was used, in which 5,041 respondents were obtained from all undergraduate courses at UFMT (33% disenrolled, 37% enrolled and 29% alumni), totaling about 10% of the population between 2013 and 2019. The weighting and aggregation of difficulties made it possible to capture different perspectives of the students. Difficulties related to learning, course structure and teaching staff were often mentioned, allowing the prioritization of strategies for managers of the courses and the institution. Resumen Ante la complejidad de los fenómenos que conducen a la deserción, se sistematizó un método que simplifica la elaboración de un diagnóstico, permitiendo estructurar y agrupar las dificultades más reportadas, posibilitando enumerar las estrategias más adecuadas para contribuir a la permanencia y culminación de la graduación. La investigación se caracteriza por ser exploratoria y descriptiva, utilizando el análisis de documentos para apoyar el desarrollo de cuestionarios estructurados y objetivos. Para la aplicación se utilizó un método no probabilístico, en el que se obtuvieron 5.041 encuestados de todas las carreras de grado de la UFMT (33% no afines, 37% vinculados y 29% egresados), totalizando cerca del 10% de la población entre 2013 y 2019. La ponderación y agrupación de las dificultades permitió captar diferentes perspectivas de los estudiantes. Dificultades relacionadas con el aprendizaje, la estructura de la carrera y el cuerpo docente fueron mencionadas con frecuencia, lo que permitió priorizar estrategias para los gestores de las carreras y de la institución.

Throughout life, macrophages are located in every tissue of the body, where their main roles are to phagocytose cellular debris and recycle aging red blood cells. In the tissue niche, they promote homeostasis through trophic, regulatory, and repair functions by responding to internal and external stimuli. This in turn polarizes macrophages into a broad spectrum of functional activation states, also reflected in their iron-regulated gene profile. The fast adaptation to the environment in which they are located helps to maintain tissue homeostasis under physiological conditions.

Iron is an essential co-factor for cellular processes. In the immune system, it can activate macrophages and represents a potential therapeutic for various diseases. To specifically deliver iron to macrophages, iron oxide nanoparticles are embedded in polymeric micelles of reactive polysarcosine-block-poly(S-ethylsulfonyl-l-cysteine). Upon surface functionalization via dihydrolipoic acid, iron oxide cores act as crosslinker themselves and undergo chemoselective disulfide bond formation with the surrounding poly(S-ethylsulfonyl-l-cysteine) block, yielding glutathione-responsive core cross-linked polymeric micelles (CCPMs). When applied to primary murine and human macrophages, these nanoparticles display preferential uptake, sustained intracellular iron release, and induce a strong inflammatory response. This response is also demonstrated in vivo when nanoparticles are intratracheally administered to wild-type C57Bl/6N mice. Most importantly, the controlled release concept to deliver iron oxide in redox-responsive CCPMs induces significantly stronger macrophage activation than any other iron source at identical iron levels (e.g., Feraheme), directing to a new class of immune therapeutics.

Iron is an essential micronutrient and a critical cofactor for proteins involved in fundamental processes such as oxygen transport, energy production and DNA synthesis. However, iron levels need to be tightly balanced to avoid pathological consequences of iron overload or deficiency. Genetically engineered mouse models with alterations in systemic or cellular iron handling advanced our knowledge how systemic and cellular iron homeostasis is maintained. Here, we prepared a comprehensive overview of mouse models that provide insight into mechanisms of iron regulation and/or rare or frequent iron-related disorders.

Lipocalin-2 (Lcn-2) is rapidly upregulated in macrophages after renal tubular injury and acts as renoprotective and pro-regenerative agent. Lcn-2 possesses the ability to bind and transport iron with high affinity. Therefore, the present study focuses on the decisive role of the Lcn-2 iron-load for its pro-regenerative function. Primary mouse tubular epithelial cells were isolated from kidney tissue of wildtype mice and incubated with 5&mu, M Cisplatin for 24h to induce injury. Bone marrow-derived macrophages of wildtype and Lcn-2-/- mice were isolated and polarized with IL-10 towards an anti-inflammatory, iron-release phenotype. Their supernatants as well as recombinant iron-loaded holo-Lcn-2 was used for stimulation of Cisplatin-injured tubular epithelial cells. Incubation of tubular epithelial cells with wildtype supernatants resulted in less damage and induced cellular proliferation, whereas in absence of Lcn-2 no protective effect was observed. Epithelial integrity as well as cellular proliferation showed a clear protection upon rescue experiments applying holo-Lcn-2. Notably, we detected a positive correlation between total iron amounts in tubular epithelial cells and cellular proliferation, which, in turn, reinforced the assumed link between availability of Lcn-2-bound iron and recovery. We hypothesize that macrophage-released Lcn-2-bound iron is provided to tubular epithelial cells during toxic cell damage, whereby injury is limited and recovery is favored.

Objective The neurophysiological processes involved in the generation of medically-unexplained symptoms (MUS) remain unclear. This study tested three assumptions of the perception-filter model contributing to MUS: (I.) increased bodily signal strength (II.) decreased filter function, (III.) increased perception. Methods In this cross-sectional, observational study, trait MUS were assessed by a web-based survey (N = 486). The upper and lower decile were identified as extreme groups of high (HSR; n = 29; 26 women; Mage = 26.0 years) and low symptom reporters (LSR; n = 29; 21 women; Mage = 28.4 years). Mean heart rate (HR) and heart rate variability (HRV), and cortisol awakening response (CAR) were assessed as indicators of bodily signal strength (I.). Heartbeat-evoked potentials (HEPs) were assessed during rest and a heartbeat perception task. HEPs reflect attentional resources allocated towards heartbeats and served as index of filter function (II.). Interoceptive accuracy (IAc) in heartbeat perception was assessed as an indicator of perception (III.). Results HSR showed higher HR and lower HRV (RMSSD) than LSR (I.), but no differences in CAR. HSR exhibited a stronger increase of HEPs when attention was focused on heartbeats than LSR (II.); there were no group differences in IAc (III.). Conclusions The perception-filter model was partially confirmed in that HSR showed altered bodily signals suggesting higher sympathetic activity (I.); higher HEP increases indicated increased filter function for bodily signals (II.). As more attentional resources are mobilized to process heartbeats, but perception accuracy remains unchanged (III.), this overflow could be responsible for detecting minor bodily changes associated with MUS.

The inflammatory response after myocardial infarction (MI) is a precisely regulated process that greatly affects subsequent remodeling. Here, we show that basophil granulocytes infiltrated infarcted murine hearts, with a peak occurring between days 3 and 7. Antibody-mediated and genetic depletion of basophils deteriorated cardiac function and resulted in enhanced scar thinning after MI. Mechanistically, we found that basophil depletion was associated with a shift from reparative Ly6C(lo) macrophages toward increased numbers of inflammatory Ly6C(hi) monocytes in the infarcted myocardium. Restoration of basophils in basophil-deficient mice by adoptive transfer reversed this proinflammatory phenotype. Cellular alterations in the absence of basophils were accompanied by lower cardiac levels of IL-4 and IL-13, two major cytokines secreted by basophils. Mice with basophil-specific IL-4/IL-13 deficiency exhibited a similarly altered myeloid response with an increased fraction of Ly6C(hi) monocytes and aggravated cardiac function after MI. In contrast, IL-4 induction in basophils via administration of the glycoprotein IPSE/α-1 led to improved post-MI healing. These results in mice were corroborated by the finding that initially low counts of blood basophils in patients with acute MI were associated with a worse cardiac outcome after 1 year, characterized by a larger scar size. In conclusion, we show that basophils promoted tissue repair after MI by increasing cardiac IL-4 and IL-13 levels.

Background We aimed at clarifying the role of lipocalin-2 (LCN-2) in clear-cell renal cell carcinoma (ccRCC). Since LCN-2 was recently identified as a novel iron transporter, we explored its iron load as a decisive factor in conferring its biological function. Methods LCN-2 expression was analysed at the mRNA and protein level by using immunohistochemistry, RNAscope® and qRT-PCR in patients diagnosed with clear-cell renal cell carcinoma compared with adjacent healthy tissue. We measured LCN-2-bound iron by atomic absorption spectrometry from patient-derived samples and applied functional assays by using ccRCC cell lines, primary cells, and 3D tumour spheroids to verify the role of the LCN-2 iron load in tumour progression. Results LCN-2 was associated with poor patient survival and LCN-2 mRNA clustered in high- and low-expressing ccRCC patients. LCN-2 protein was found overexpressed in tumour compared with adjacent healthy tissue, whereby LCN-2 was iron loaded. In vitro, the iron load determines the biological function of LCN-2. Iron-loaded LCN-2 showed pro-tumour functions, whereas iron-free LCN-2 produced adverse effects. Conclusions We provide new insights into the pro-tumour function of LCN-2. LCN-2 donates iron to cells to promote migration and matrix adhesion. Since the iron load of LCN-2 determines its pro-tumour characteristics, targeting either its iron load or its receptor interaction might represent new therapeutic options.

Introduction: Survival in gastric cancer is often limited by peritoneal carcinomatosis, which supposedly develops from serosal tumor infiltration or tumor cell spread during gastrectomy with lymphadenectomy. To eliminate peritoneal tumor cells, extensive intraperitoneal lavage (EIPL) has been suggested. Impressive results have been achieved in Japanese trials. In this trial, we assessed EIPL in Western patients. Methods: This prospective trial included patients with non-metastatic gastric adenocarcinoma undergoing gastrectomy with D2 lymphadenectomy. Peritoneal fluid samples at laparotomy, after lymphadenectomy, and after EIPL were analyzed for tumor cells using cytology and EpCAM antibodies. The primary endpoint was peritoneal conversion rate (PCR; proportion of patients in whom EIPL eliminated tumor cells after lymphadenectomy). Secondary endpoints were peritoneal release rate (PRR; proportion of patients with peritoneal tumor cells after gastrectomy/lymphadenectomy among all patients without cells before gastrectomy/lymphadenectomy) and prevalence of peritoneal tumor cells before resection. EIPL was considered ineffective if PCR ⩽ 0.2 and warranted further exploration if PCR ⩾ 0.5. Clinicaltrials.gov identifier is NCT01476553. Results: The trial was stopped early because tumor cells after gastrectomy/lymphadenectomy were detected in only 3/27 (11.1%) patients. In none of these did EIPL eliminate tumor cells (PCR 0, 95% confidence interval [CI] 0%–12.5%). In 8/27 (29.6%) patients, tumor cells were detected after EIPL. PRR was 11.1% (95% CI 2.4%–29.2%). There were no perioperative complications higher than Clavien-Dindo grade 3a. Conclusions: In Western patients, free peritoneal tumor cells after gastrectomy with D2 lymphadenectomy for gastric cancer were detected only sporadically. Although based on few cases, the findings suggest that EIPL spreads tumor cells into the peritoneal cavity, thus being potentially harmful. Therefore, EIPL cannot be generally recommended.

Jietacins, an azoxy antibiotic class of chemicals, were isolated from the culture broth of Streptomyces sp. KP-197. They have a unique structural motif, including a vinyl azoxy group and a long acyclic aliphatic chain, which is usually branched but non-branched in the case of jietacin C. During a drug discovery program, we found that jietacins display potent anthelmintic activity against parasitic nematodes and that jietacin A has a moderate or low acute toxicity (LD50 > 300 mg/kg) and no mutagenic potential in a mini Ames screen. This suggests that jietacins have potential for drug discovery research. In order to create a novel anthelmintic agent, we performed design, synthesis, and biological evaluation of jietacin derivatives against parasitic nematodes. Of these derivatives, we found that a fully synthesized simplified derivative exhibited better anthelmintic activity against three parasitic nematodes than natural jietacins. In addition, it had a better efficacy in vivo through oral administration against a mouse nematode. This indicated that the azoxy motif could prove useful as a template for anthelmintic discovery, possibly creating a class of anthelmintic with novel skeletons, a potential new mode of action, and providing further insight for rational drug design.

Purpose Optimal perfusion of the gastric conduit during esophagectomy is elementary for the anastomotic healing since poor perfusion has been associated with increased morbidity due to anastomotic leaks. Until recently surgical experience was the main tool to assess the perfusion of the anastomosis. We hypothesized that anastomoses located in the zone of optimal ICG perfusion of the gastric conduit ("optizone") have a reduced anastomotic leakage rate after esophagectomy. Methods Indocyanine green (ICG) fluorescence tissue angiography was used to evaluate the anastomotic perfusion in 35 patients undergoing esophagectomy with gastric conduit reconstruction. The transition point of the "optizone" to the malperfused area of the conduit was defined macroscopically and with the use of ICG angiography during the operation. The anastomosis was performed in the optizone whenever possible. The results of the ICG patients were retrospectively reviewed and compared with 55 patients previously operated without ICG angiography. Results The visual assessment of the conduit perfusion concurred with the ICG angiography in 27 cases. In 8 cases (22.8%) the ICG angiography deviated from the visual aspect. One case of anastomotic leakage was observed in the group of patients in which the anastomosis could be performed in the optizone (1/33; 3%) compared with 10 cases in the control group (18%; p = 0.04). In two cases we had to perform the anastomosis in an area of compromised ICG perfusion. Both patients developed an anastomotic leakage. Conclusions ICG tissue angiography represents a feasible and reliable technical support in the evaluation of the anastomotic perfusion after esophagectomy. In this retrospective analysis we observed a significant decrease in anastomotic leakage rate when the anastomosis could be placed in the zone of good perfusion defined by ICG fluorescence. A prospective trial is needed in order to provide higher level evidence for the use of ICG fluorescence in reducing leakage rates after esophagectomy.

Iron is an essential element for virtually all organisms. It facilitates cell proliferation and growth but also contributes to major hallmarks of cancer such as tumor initiation, growth, and metastasis. Often, iron handling of tumor cells is disturbed, with altered iron acquisition, efflux, and storage. Targeting perturbed iron metabolic pathways might open opportunities towards novel approaches in cancer treatment. It is becoming clear that cells of the tumor microenvironment such as macrophages contribute to tumor progression. Since macrophages evolved a multitude of mechanisms to sequester, transport, store, and release iron it can be speculated that tumor cells educate them to supply iron to support tumor growth. Recent evidence supports the existence of transferrin-independent iron transport mechanisms in the tumor microenvironment, which points to local iron transport proteins such as lipocalin-2 and/or low molecular weight iron-trafficking substances such as siderophores. We hypothesize that tumor cells educate immune cells, i.e. macrophages in their neighborhood to make them delivering iron for the benefit of cancer progression. In particular, we pay attention to recent developments, pointing to lipocalin-2 and siderophores as alternative iron transport molecules in the tumor microenvironment.

Iron is an essential element for virtually all organisms. On the one hand, it facilitates cell proliferation and growth. On the other hand, iron may be detrimental due to its redox abilities, thereby contributing to free radical formation, which in turn may provoke oxidative stress and DNA damage. Iron also plays a crucial role in tumor progression and metastasis due to its major function in tumor cell survival and reprogramming of the tumor microenvironment. Therefore, pathways of iron acquisition, export, and storage are often perturbed in cancers, suggesting that targeting iron metabolic pathways might represent opportunities towards innovative approaches in cancer treatment. Recent evidence points to a crucial role of tumor-associated macrophages (TAMs) as a source of iron within the tumor microenvironment, implying that specifically targeting the TAM iron pool might add to the efficacy of tumor therapy. Here, we provide a brief summary of tumor cell iron metabolism and updated molecular mechanisms that regulate cellular and systemic iron homeostasis with regard to the development of cancer. Since iron adds to shaping major hallmarks of cancer, we emphasize innovative therapeutic strategies to address the iron pool of tumor cells or cells of the tumor microenvironment for the treatment of cancer.

Tumour cell-secreted factors skew infiltrating immune cells towards a tumour-supporting phenotype, expressing pro-tumourigenic mediators. However, the influence of lipocalin-2 (Lcn2) on the metastatic cascade in the tumour micro-environment is still not clearly defined. Here, we explored the role of stroma-derived, especially macrophage-released, Lcn2 in breast cancer progression. Knockdown studies and neutralizing antibody approaches showed that Lcn2 contributes to the early events of metastasis in vitro. The release of Lcn2 from macrophages induced an epithelial-mesenchymal transition programme in MCF-7 breast cancer cells and enhanced local migration as well as invasion into the extracellular matrix, using a three-dimensioanl (3D) spheroid model. Moreover, a global Lcn2 deficiency attenuated breast cancer metastasis in both the MMTV-PyMT breast cancer model and a xenograft model inoculating MCF-7 cells pretreated with supernatants from wild-type and Lcn2-knockdown macrophages. To dissect the role of stroma-derived Lcn2, we employed an orthotopic mammary tumour mouse model. Implantation of wild-type PyMT tumour cells into Lcn2-deficient mice left primary mammary tumour formation unaltered, but specifically reduced tumour cell dissemination into the lung. We conclude that stroma-secreted Lcn2 promotes metastasis in vitro and in vivo, thereby contributing to tumour progression. Our study highlights the tumourigenic potential of stroma-released Lcn2 and suggests Lcn2 as a putative therapeutic target. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

(1) Background: Oncological gastrectomy requires complex multidisciplinary management. Clinical pathways (CPs) can potentially facilitate this task, but evidence related to their use in managing oncological gastrectomy is limited. This study evaluated the effect of a CP for oncological gastrectomy on process and outcome quality. (2) Methods: Consecutive patients undergoing oncological gastrectomy before (n = 64) or after (n = 62) the introduction of a CP were evaluated. Assessed parameters included catheter and drain management, postoperative mobilization, resumption of diet and length of stay. Morbidity, mortality, reoperation and readmission rates were used as indicators of outcome quality. (3) Results: Enteral nutrition was initiated significantly earlier after CP implementation (5.0 vs. 7.0 days, p &lt, 0.0001). Readmission was more frequent before CP implementation (7.8% vs. 0.0%, p = 0.05). Incentive spirometer usage increased following CP implementation (100% vs. 90.6%, p = 0.11). Mortality, morbidity and reoperation rates remained unchanged. (4) Conclusions: After implementation of an oncological gastrectomy CP, process quality improved, while indicators of outcome quality such as mortality and reoperation rates remained unchanged. CPs are a promising tool to standardize perioperative care for oncological gastrectomy.

Este estudo apresenta uma análise sobre a evasão e o tempo de permanência dos alunos do curso de bacharelado em Estatística da Universidade Federal de Mato Grosso - UFMT, que ingressaram no período de 2010 a 2015, por meio da Análise de Sobrevivência, com o objetivo de identificar o tempo até o primeiro trancamento de matrícula e sua dependência com o sexo, o estado civil, a naturalidade, a faixa etária e o tipo de ingresso do estudante (processo seletivo, transferência ou admissão de graduado). Na análise, conclui-se que o trancamento é realizado largamente nos primeiros 3 semestres de curso, sendo que o tempo mediano foi de 3 semestres. Com base no Teste de Logrank, não foram observadas diferenças significativas no tempo de trancamento entre o sexo do estudante, o seu estado civil e nem entre sua naturalidade. Porém observou-se que os estudantes que ingressaram no curso com menos de 25 anos apresentam uma probabilidade menor de realizar o trancamento em todos os semestres e que o fluxo escolar também apresenta dependência com o tipo de ingresso do estudante. De maneira geral, conclui-se que existe uma alta proporção de trancamentos no período em que os alunos ainda estão cursando as disciplinas introdutórias do curso e, portanto, destaca-se a importância de ações preventivas nos semestres iniciais para evitar a ocorrência excessiva de trancamento do curso.

Early and adequate restoration of endothelial and tubular renal function is a substantial step during regeneration after ischemia reperfusion (IR) injury, occurring, e.g., in kidney transplantation, renal surgery, and sepsis. While tubular epithelial cell injury has long been of central importance, recent perception includes the renal vascular endothelium. In this regard, the fibrin cleavage product fibrinopeptide Bβ15-42 mitigate IR injury by stabilizing interendothelial junctions through its affinity to VE-cadherin. Therefore, this study focused on the effect of Bβ15-42 on post-acute physiological renal regeneration. For this, adult male C57BL/6 mice were exposed to a 30 min bilateral renal ischemia and reperfusion for 24 h or 48 h. Animals were randomized in a non-operative control group, two operative groups each treated with i.v. administration of either saline or Bβ15-42 (2.4 mg/kg) immediately prior to reperfusion. Endothelial activation and inflammatory response was attenuated in renal tissue homogenates by single application of Bβ15-42. Meanwhile, Bβ15-42 did not affect acute kidney injury markers. Regarding the angiogenetic players VEGF-A, Angiopoietin-1, Angiopoietin-2, however, we observed significant higher expressions at mRNA and trend to higher protein level in Bβ15-42 treated mice, compared to saline treated mice after 48 h of IR, thus pointing toward an increased angiogenetic activity. Similar dynamics were observed for the intermediate filament vimentin, the cytoprotective protein klotho, stathmin and the proliferation cellular nuclear antigen, which were significantly up-regulated at the same points in time. These results suggest a beneficial effect of anatomical contiguously located endothelial cells on tubular regeneration through stabilization of endothelial integrity. Therefore, it seems that Bβ15-42 represents a novel pharmacological approach in the targeted therapy of acute renal failure in everyday clinical practice.

Many randomized controlled trials in which motivational interviewing (MI) is a key intervention make no provision for the assessment of treatment fidelity. This methodological shortcoming makes it impossible to distinguish between high- and low-quality MI interventions, and, consequently, to know whether MI provision has contributed to any intervention effects. This article makes some practical recommendations for the collection, selection, coding and reporting of MI fidelity data, as measured using the Motivational Interviewing Treatment Integrity Code. We hope that researchers will consider these recommendations and include MI fidelity measures in future studies.

O texto analisa os significados que se têm atribuído ao acesso e aos indicadores para compreensão dos avanços e retrocessos das políticas da educação superior de 2000 a 2012. Adota a pesquisa bibliográfica e documental, e informações estatísticas, indicando condições concretas que determinam e são determinadas pelas políticas nacionais. Conclui que existem avanços, na medida em que as políticas proporcionaram o acesso de diversos grupos sociais na educação superior, e retrocessos, visto que o sistema registra a predominância do ensino privado e, no setor público, a preocupação com a expansão de vagas faz-se acompanhar de poucas ações de permanência estudantil.

O texto tem por objetivo abordar o acesso à educação superior na perspectiva de atribuir-lhe uma significação e propor indicadores para balizá-lo, tendo em vista a democratização do acesso e/ou o pleno acesso. A par disso, traça um panorama das políticas da educação superior e apresenta um quadro da realidade, com base na pesquisa bibliográfica e documental. Conclui que os avanços observados transcorrem sem referência ao acesso democrático, no que esse tem de elevado, substancial, abrangente. The objective of the text is to approach the topic access to higher education in the perspective of giving it a meaning and proposing indicators to delimit it, aiming at the democratization of access and/or total access. With this in mind, the paper traces an overview of the policies of higher education and presents a picture of the reality, based on bibliographic and documental research. The conclusions show that the progress observed does not derive from any reference to democratic access and to what it has of elevated, substantial, and inclusive.

A growing body of evidence suggests that macrophage polarization dictates the expression of iron-regulated genes. Polarization towards iron sequestration depletes the microenvironment, whereby extracellular pathogen growth is limited and inflammation is fostered. In contrast, iron release contributes to cell proliferation, which is important for tissue regeneration. Moreover, macrophages constitute a major component of the infiltrates in most solid tumors. Considering the pivotal role of macrophages for iron homeostasis and their presence in association with poor clinical prognosis in tumors, we approached the possibility to target macrophages with intracellular iron chelators. Analyzing the expression of iron-regulated genes at mRNA and protein level in primary human macrophages, we found that the iron-release phenotype is a characteristic of polarized macrophages that, in turn, stimulate tumor cell growth and progression. The application of the intracellular iron chelator (TC3-S)2 shifted the macrophage phenotype from iron release towards sequestration, as determined by the iron-gene profile and atomic absorption spectroscopy (AAS). Moreover, whereas the addition of macrophage supernatants to tumor cells induced tumor growth and metastatic behavior, the supernatant of chelator-treated macrophages reversed this effect. Iron chelators demonstrated potent anti-neoplastic properties in a number of cancers, both in cell culture and in clinical trials. Our results suggest that iron chelation could affect not only cancer cells but also the tumor microenvironment by altering the iron-release phenotype of tumor-associated macrophages (TAMs). The study of iron chelators in conjunction with the effect of TAMs on tumor growth could lead to an improved understanding of the role of iron in cancer biology and to novel therapeutic avenues for iron chelation approaches.

Tumor cell-derived factors skew macrophages toward a tumor-supporting phenotype associated with the secretion of protumorigenic mediators. Apoptosing tumor cells release sphingosine 1-phosphate (S1P), which stimulates the production of lipocalin 2 (LCN2) in tumor-associated macrophages and is associated with tumor metastasis. We explored the mechanism by which S1P induces LCN2 in macrophages and investigated how this contributed to tumor growth and metastasis. Knockdown of S1P receptor 1 (S1PR1) in primary human macrophages and experiments with bone marrow-derived macrophages from S1PR1-deficient mice showed that S1P signaled through S1PR1 to induce LCN2 expression. The LCN2 promoter contains a consensus sequence for signal transducer and activator of transcription 3 (STAT3), and deletion of the STAT3 recognition sequence reduced expression of an LCN2-controlled reporter gene. Conditioned medium from coculture experiments indicated that the release of LCN2 from macrophages induced tube formation and proliferation in cultures of primary human lymphatic endothelial cells in a manner dependent on the kinase PI3K and subsequent induction of the growth factor VEGFC, which functioned as an autocrine signal stimulating the receptor VEGFR3. Knockout of Lcn2 attenuated tumor-associated lymphangiogenesis and breast tumor metastasis both in the breast cancer model MMTV-PyMT mice and in mice bearing orthotopic wild-type tumors. Our findings indicate that macrophages respond to dying tumor cells by producing signals that promote lymphangiogenesis, which enables metastasis.

BACKGROUND: Content validity, the proper reflection of the concept to be measured, is yet unknown for the Credibility and Expectancy Questionnaire (CEQ). It is frequently used in pain rehabilitation because treatment expectancy is influential on the outcome.OBJECTIVE: To test and improve the content validity of the CEQ in a sample of patients with chronic pain in different phases of their treatment.METHODS: A qualitative observational study design using the Three-Step Test-Interview method was used. Therein, data collection, analyses, and adaptations occur iteratively.RESULTS: Seventeen patients with chronic pain in different stages of treatment participated through convenience sampling from the mother sample of a randomized controlled trial. The main study parameter is content validity, which is defined as (1) interpretations and responses of the participants and (2) the identification of response problems operationalized, and resulting in changes in the CEQ. For patients waiting for treatment, the written instruction of the CEQ allowed different interpretations. After changing the instructions, the CEQ became an easy-to-understand and content-valid questionnaire. For patients who had already undergone treatment, changes regarding time frame and recall period were necessary to overcome interpretation and response problems to the CEQ.DISCUSSION: After small changes, the CEQ appeared to be a content-valid measurement instrument for patients waiting for treatment. However, for patients who had already undergone treatment, the content validity of the CEQ was less, and considerable changes were necessary.

VELOSO, Tereza Christina Mertens Aguiar; SILVA, Maria das Graças Martins da. Avaliação de programas de expansão e ingresso nas universidades federais e os reflexos na permanência do estudante. Revista Educação em Debate, Fortaleza, anos 35-38, v. 38, n.os 66-71, p. 94-104, jul./dez. 2013; jan./jun., jul./dez. 2014; jan./jun., jul./dez. 2015; jan./jun. 2016. The purpose of the current paper is to evaluate indicators of the Programa de Apoio a Planos de Reestruturação e Expansão das Universidades Federais (REUNI) as well as of the Sistema de Seleção Unificada (SISU), establishing a relationship between them and the students’ permanence at federal universities. Quantitative data from INEP/MEC and legislation regarding those programs were consulted. In conclusion, the indicators point out that those programs really increase the possibilities of entrance to university, resulting in admission, nevertheless, they do not resonate at the students’ permanence or graduation at the right time. Therefore, we make suggestions for further qualitative research to better understand the phenomenon of students’ permanence. O presente artigo tem por objetivo avaliar indicadores do Programa de Apoio a Planos de Reestruturação e Expansão das Universidades Federais (REUNI) e do Sistema de Seleção Unificada (SISU), relacionando-os à permanência de estudantes em universidades federais. Utilizam-se dados quantitativos do Instituto Nacional de Estudos e Pesquisas Educacionais Anísio Teixeira (INEP), do Ministério da Educação (MEC), e legislação relacionada aos programas. Conclusivamente, os indicadores apontam que os referidos programas aumentam as possibilidades de acesso às universidades, refletindo em vagas e no ingresso; no entanto, não repercutem na permanência do estudante nem na conclusão do curso no tempo adequado. Diante disso, faz-se necessário agregar aos dados apresentados pesquisas qualitativas para melhor entender o fenômeno da permanência.

Background: Chronically ill patients need to adapt to their impaired life condition. Social (e.g. social support), material (e.g. income) and personal (e.g. mastery) resources are needed to cope with this challenge. It is, however, less clear whether these factors also contribute to 'relatively successful functioning' and whether these effects are disease specific or generic across chronic diseases. Methods: Baseline data from 361 Dutch men and women aged epsilon 60 years who were mildly depressed and diagnosed with type 2 diabetes or chronic obstructive pulmonary disease (COPD) were used. These persons participated in the 'Depression in Elderly with Long-Term Afflictions' (DELTA) study. Logistic regression analyses were used to study the independent association of social support, income and mastery (independent variables) with physical, mental and social functioning (dependent variables). Results: A high level of mastery is significantly associated with physical, mental and social functioning in the total study population, as well as in subgroups of patients with COPD or diabetes. This relationship remained significant after controlling for confounding factors such as gender, age, educational level and the other remaining resources. In diabetes patients, high levels of social support and income also contributed significantly to successful social functioning. Conclusion: Our findings suggest that rather than having good friends and a high income, having a high level of mastery (resilience) might best help chronically ill patients in coping with and adapting to their often co-morbid condition. Further longitudinal research is necessary to unravel the long-term effects of mastery, income and social support on 'relatively successful functioning' in chronically ill patients.

Tumour cell-secreted factors skew infiltrating immune cells towards a tumour-supporting phenotype, expressing pro-tumourigenic mediators. However, the influence of lipocalin-2 (Lcn2) on the metastatic cascade in the tumour micro-environment is still not clearly defined. Here, we explored the role of stroma-derived, especially macrophage-released, Lcn2 in breast cancer progression. Knockdown studies and neutralizing antibody approaches showed that Lcn2 contributes to the early events of metastasis in vitro. The release of Lcn2 from macrophages induced an epithelial-mesenchymal transition programme in MCF-7 breast cancer cells and enhanced local migration as well as invasion into the extracellular matrix, using a three-dimensioanl (3D) spheroid model. Moreover, a global Lcn2 deficiency attenuated breast cancer metastasis in both the MMTV-PyMT breast cancer model and a xenograft model inoculating MCF-7 cells pretreated with supernatants from wild-type and Lcn2-knockdown macrophages. To dissect the role of stroma-derived Lcn2, we employed an orthotopic mammary tumour mouse model. Implantation of wild-type PyMT tumour cells into Lcn2-deficient mice left primary mammary tumour formation unaltered, but specifically reduced tumour cell dissemination into the lung. We conclude that stroma-secreted Lcn2 promotes metastasis in vitro and in vivo, thereby contributing to tumour progression. Our study highlights the tumourigenic potential of stroma-released Lcn2 and suggests Lcn2 as a putative therapeutic target. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John WileySons, Ltd.

Faecal Eimeria oocyst excretion, body weights, humoral antibodies against E. ovinoidalis sporozoite antigen and related heritabilities were determined in housed Merinoland sheep lambs throughout a period of 100 days after birth in Germany. Altogether 10-11 Eimeria spp. were found. Cumulative incidences of E. ovinoidalis and E. weybridgensis/crandallis increased rapidly resulting in almost 100% incidence in 8 weeks old lambs. In the other species, the cumulative incidence increased more continuously. Except for E. granulosa oocysts of all species had been excreted at last once until day 30. By far the highest oocyst counts (OpG) were observed with E. ovinoidalis, followed by E. weybridgensis/crandallis. High counts were limited to the period of 5-8 weeks after birth. In the other Eimeria species oocyst counts persisted at comparatively low levels until the end of the observation period although their proportion of the total counts increased with age of the lambs. Time courses of oocyst excretion suggest an early onset of effective immunity to the major Eimeria spp., which differed for the minor species. Mean and maximum oocyst counts and body weights of the lambs were inversely correlated suggesting negative effects of the infection on the lamb's performance. High mean antibody levels on day 7 after birth dropped until day 40 and increased subsequently again. There were no indications that maternal antibodies were protective. Antibody levels on day 40 after birth were positively correlated with oocyst counts in the faeces whereas those determined on day 80 were independent of infection parameters. Heritabilities of log(10)OpG were not significantly different from 0 up to an age of 60 days. Later estimated values were between 0.54 and 0.79 suggesting that immune protective effects rather than innate effects determining disease susceptibility are under genetic influence.

While the importance of iron for tumor development is widely appreciated, the exact sources of tumor-supporting iron largely remain elusive. The possibility that iron might be provided by stromal cells in the tumor microenvironment was not taken into account so far. In the present study, we show that tumor-associated macrophages (TAM) acquire an iron-release phenotype upon their interaction with tumor cells, thereby increasing the availability of iron in the tumor microenvironment. Mechanistically, TAM expressed elevated levels of the high-affinity iron-binding protein lipocalin-2 (LCN-2), which appeared to be critical for the export of iron from TAM, and in turn enhanced tumor cell proliferation. Moreover, in PyMT-mouse tumors as well as in primary human breast tumors LCN-2 was predominantly expressed in the tumor stroma as compared to tumor cells. LCN-2 expression in the stroma further correlated with enhanced tumor proliferation in vivo. Our data suggest a dominant role of TAM in the tumor iron-management and identify LCN-2 as a critical iron transporter in this context. Targeting the LCN-2 iron export mechanism selectively in stromal cells might open for future iron-targeted tumor therapeutic approaches.

Cytosolic DNA that emerges during infection with a retrovirus or DNA virus triggers antiviral type I interferon responses. So far, only double-stranded DNA (dsDNA) over 40 base pairs (bp) in length has been considered immunostimulatory. Here we found that unpaired DNA nucleotides flanking short base-paired DNA stretches, as in stem-loop structures of single-stranded DNA (ssDNA) derived from human immunodeficiency virus type 1 (HIV-1), activated the type I interferon-inducing DNA sensor cGAS in a sequence-dependent manner. DNA structures containing unpaired guanosines flanking short (12- to 20-bp) dsDNA (Y-form DNA) were highly stimulatory and specifically enhanced the enzymatic activity of cGAS. Furthermore, we found that primary HIV-1 reverse transcripts represented the predominant viral cytosolic DNA species during early infection of macrophages and that these ssDNAs were highly immunostimulatory. Collectively, our study identifies unpaired guanosines in Y-form DNA as a highly active, minimal cGAS recognition motif that enables detection of HIV-1 ssDNA.

Macrophages are central in regulating iron homeostasis, which is tightly linked to their versatile role during innate immunity. They sequester iron by phagocytosis of senescent erythrocytes and represent a major source of available iron in the body. Macrophage iron homeostasis is coupled to the functional heterogeneity and plasticity of these cells, with their extreme roles during inflammation, immune modulation, and resolution of inflammation. It is now appreciated that the macrophage polarization process dictates expression profiles of genes involved in iron metabolism. Therefore, macrophages have evolved a multitude of mechanisms to sequester, transport, store, and release iron. A new, enigmatic protein entering the iron scene and affecting the macrophage phenotype is lipocalin-2. Iron sequestration in macrophages depletes the microenvironment, thereby limiting extracellular pathogen or tumor growth, while fostering inflammation. In contrast, iron release from macrophages contributes to bystander cell proliferation, which is important for tissue regeneration and repair. This dichotomy is also reflected by the dual role of lipocalin-2 in macrophages. Unfortunately, the iron release macrophage phenotype is also a characteristic of tumor-associated macrophages and stimulates tumor cell survival and growth. Iron sequestration versus its release is now appreciated to be associated with the macrophage polarization program and can be used to explain a number of biological functions attributed to distinct macrophage phenotypes. Here we discuss macrophage iron homeostasis with a special focus on lipocalin-2 related to the formation and function of tumor-associated macrophages.

O presente trabalho realiza uma análise documental em torno do discurso da democratização do acesso à educação superior pública internalizado nos mecanismos de seleção, como observado nas novas propostas: Novo Enem e o SiSU. Teve como fonte de análise os documentos definidores de políticas públicas do Brasil – focalizando no campo da educação superior – segundo as décadas de 1980, 1990 e 2000. Foi possível verificar que a democratização do acesso se apresenta muito mais na compreensão do mero “ato de ingressar” sem levar em consideração outros condicionantes para que isso de fato ocorra principalmente direcionados à classe popular da sociedade. Ela ainda ocorre de maneira contraditória devido os limites impostos pelo sistema capitalista.

O texto discute a democratização nas políticas de ingresso na educação superior, segundo a mediação teórica de Marx, Lukács e Wood. São utilizadas fontes documentais e bibliográficas, destacando os formatos seletivos de ingresso. Do estudo extrai-se a complexidade do sentido de democracia, um conceito implicado nas contradições sociais, na transformação da sociedade e na compreensão de ser humano. Igualmente, é possível apreender um discurso de infalibilidade e redenção sobre o ingresso na educação superior, cuja realidade, no entanto, ocorre de forma limitada e contraditória., This text discusses the democratization on admission policies in higher education, according to Marx, Lukács and Wood’s theoretical mediation. It is based on documentary and bibliographic sources, highlighting the selective modes of entry. The study brings to light the complexity of the meaning of democracy, a concept involved in the social contradictions, in the transformation of society and in the understanding of being human. It is also possible to apprehend a discourse of infallibility and redemption regarding admission into higher education, while in reality, it occurs in a limited and contradictory fashion.

Contains fulltext : 125398.pdf (Publisher’s version ) (Open Access) BACKGROUND: Non-adherence and drop-out are major problems in pain rehabilitation. For patients with various health problems, motivational interviewing (MI) has shown promising effects to tackle these problems. In chronic pain patients, the effectiveness of MI is however unknown. Therefore, a MI-based pre-pain rehabilitation intervention (MIP) addressing motivation, expectations, and beliefs has been developed to prepare eligible patients for rehabilitation treatment. METHODS/DESIGN: Study design: A parallel randomized controlled trial including two interventions: a motivational interviewing pre-pain rehabilitation intervention (MIP) and a usual care (UC) control arm. Follow-up will be 6 months after completion of rehabilitation treatment.Study population: One hundred and sixty (n = 80 per arm) patients with chronic non-specific musculoskeletal pain visiting an outpatient rehabilitation department, who are eligible to participate in an outpatient cognitive behavioral pain rehabilitation program.Intervention: MIP consists of two sessions to prepare and motivate the patient for pain rehabilitation treatment and its bio psychosocial approach. UC consists of information and education about the etiology and the general rehabilitation approach of chronic pain. Both the MIP and UC contain two sessions of 45 to 60 minutes each.Objective: The aim of the current study is to evaluate the effectiveness of MIP compared to UC in terms of an increase in the long-term level of societal participation and decrease of drop-out during rehabilitation treatment.Main study endpoints: Primary outcome is the change in level of participation (according to the ICF-definition: 'involvement in a life situation') 6 months after completion of rehabilitation treatment. Secondary outcomes are adherence and treatment drop-out, disability, pain intensity, self-reported main complaints, (pain-specific) self-efficacy, motivation, and quality of life. Costs are calculated including the costs of the pre-treatment intervention, productivity losses, and healthcare utilization. Potential moderators and active ingredients of MI are explored. For the process evaluation, parameters such as MI fidelity, feasibility, and experiences are explored. DISCUSSION: The results of this study will provide evidence on the effectiveness of this MI-based pre-treatment in pain rehabilitation. Furthermore, a cost-effectiveness analysis and exploration of moderating and working mechanisms of MI and an extensive process evaluation takes place. TRIAL REGISTRATION: Nederlands trial register NTR3065.