The predominance of M2-polarized macrophages in the stroma of low-hypoxic bladder tumors is associated with BCG immunotherapy failure

OBJECTIVE: Bacillus Calmette-Guérin (BCG) immunotherapy is the gold standard treatment for superficial bladder tumors with intermediate/high risk of recurrence or progression. However, approximately 30% of patients fail to respond to the treatment. Effective BCG therapy needs precise activation of the type 1 helper cells immune pathway. Tumor-associated macrophages (TAMs) often assume an immunoregulatory M2 phenotype and may directly interfere with the BCG-induced antitumor immune response. Thus, we aim to clarify the influence of TAMs, in particular of the M2 phenotype in stroma and tumor areas, in BCG treatment outcome. PATIENTS AND METHODS: The study included 99 patients with bladder cancer treated with BCG. Tumors resected before treatment were evaluated using immunohistochemistry for CD68 and CD163 antigens, which identify a lineage macrophage marker and a M2-polarized specific cell surface receptor, respectively. CD68+ and CD163+ macrophages were evaluated within the stroma and tumor areas, and high density of infiltrating cells spots were selected for counting. Hypoxia, an event known to modulate macrophage phenotype, was also assessed through hypoxia induced factor (HIF)-1α expression. RESULTS: Patients in whom BCG failed had high stroma-predominant CD163+ macrophage counts (high stroma but low tumor CD163+ macrophages counts) when compared with the ones with a successful treatment (71% vs. 47%, P = 0.017). Furthermore, patients presenting this phenotype showed decreased recurrence-free survival (log rank, P = 0.008) and a clear 2-fold increased risk of BCG treatment failure was observed in univariate analysis (hazard ratio = 2.343; 95% CI: 1.197-4.587; P = 0.013). Even when adjusted for potential confounders, such as age and therapeutic scheme, multivariate analysis revealed 2.6-fold increased risk of recurrence (hazard ratio = 2.627; 95% CI: 1.340-5.150; P = 0.005). High stroma-predominant CD163+ macrophage counts were also associated with low expression of HIF-1α in tumor areas, whereas high counts of CD163+ in the tumor presented high expression of HIF-1α in tumor nests. CONCLUSIONS: TAMs evaluation using CD163 is a good indicator of BCG treatment failure. Moreover, elevated infiltration of CD163+ macrophages, predominantly in stroma areas but not in the tumor, may be a useful indicator of BCG treatment outcome, possibly owing to its immunosuppressive phenotype.

Efeitos auditivos em doentes com tumores de cabeça e pescoço e tumores cerebrais sujeitos a Radioterapia e terapia combinada

Introdução: A capacidade auditiva dos doentes com neoplasias de cabeça e pescoço e tumores cerebrais pode ser comprometida com os tratamentos antineoplásicos realizados. A Quimioterapia com cisplatina pode provocar perda auditiva de condução ou neurossensorial, podendo agravar-se quando combinada com Radioterapia (RT). O objectivo deste trabalho foi a análise da relação entre a Terapia Combinada (Cisplatina+RT) e a Radioterapia isolada, e os seus efeitos adversos sobre a audição tendo em consideração a inclusão das estruturas do ouvido no campo de tratamento de RT. Métodos: Foram seguidos 10 doentes submetidos a Terapia Combinada (grupo TC) e 11 a Radioterapia isolada (grupo RT). A avaliação audiológica realizou-se antes do inicio (M1), no fim (M2) e um mês após (M3) o termo dos tratamentos e incluiu anamnese audiológica, otoscopia e audiometria tonal. Resultados: No grupo TC, 94,4% dos doentes apresentaram uma relação directamente proporcional entre a dose de radiação na cóclea e a perda auditiva. Esta relação só se verificou em 31% dos doentes do grupo RT, tendo-se verificado diferenças significativas entre grupos (p <0,001). Conclusões: Verificou-se maior incidência da perda auditiva no grupo TC relativamente ao grupo RT. Sugere-se um melhor planeamento do tratamento de RT, reduz - indo a dose à cóclea com o objectivo de minimizar a perda auditiva neurossensorial irreversível, sobretudo quando são utilizadas as duas modalidades de tratamento.

Angolan cymbopogon citratus used for therapeutic benefits: nutritional composition and influence of solvents in phytochemicals content and antioxidant activity of leaf extracts

Folk medicine is a relevant and effective part of indigenous healthcare systems which are, in practice, totally dependent on traditional healers. An outstanding coincidence between indigenous medicinal plant uses and scientifically proved pharmacological properties of several phytochemicals has been observed along the years. This work focused on the leaves of a medicinal plant traditionally used for therapeutic benefits (Angolan Cymbopogon citratus), in order to evaluate their nutritional value. The bioactive phytochemical composition and antioxidant activity of leaf extracts prepared with different solvents (water, methanol and ethanol) were also evaluated. The plant leaves contained ~60% of carbohydrates, protein (~20%), fat (~5%), ash (~4%) and moisture (~9%). The phytochemicals screening revealed the presence of tannins, flavonoids, and terpenoids in all extracts. Methanolic extracts also contained alkaloids and steroids. Several methods were used to evaluate total antioxidant capacity of the different extracts (DPPH; NO; and H2O2 scavenging assays, reducing power, and FRAP). Ethanolic extracts presented a significantly higher antioxidant activity (p < 0.05) except for FRAP, in which the best results were achieved by the aqueous extracts. Methanolic extracts showed the lowest radical scavenging activities for both DPPH; and NO; radicals.

Evaluation of distinct input methods of an intelligent wheelchair in simulated and real environments: a performance and usability study

This paper focuses on evaluating the usability of an Intelligent Wheelchair (IW) in both real and simulated environments. The wheelchair is controlled at a high-level by a flexible multimodal interface, using voice commands, facial expressions, head movements and joystick as its main inputs. A Quasi-experimental design was applied including a deterministic sample with a questionnaire that enabled to apply the System Usability Scale. The subjects were divided in two independent samples: 46 individuals performing the experiment with an Intelligent Wheelchair in a simulated environment (28 using different commands in a sequential way and 18 with the liberty to choose the command); 12 individuals performing the experiment with a real IW. The main conclusion achieved by this study is that the usability of the Intelligent Wheelchair in a real environment is higher than in the simulated environment. However there were not statistical evidences to affirm that there are differences between the real and simulated wheelchairs in terms of safety and control. Also, most of users considered the multimodal way of driving the wheelchair very practical and satisfactory. Thus, it may be concluded that the multimodal interfaces enables very easy and safe control of the IW both in simulated and real environments.

Local fractional variational iteration and decomposition methods for wave equation on cantor sets within local fractional operators

We perform a comparison between the fractional iteration and decomposition methods applied to the wave equation on Cantor set. The operators are taken in the local sense. The results illustrate the significant features of the two methods which are both very effective and straightforward for solving the differential equations with local fractional derivative.

Neurokinin-1 receptor, a new modulator of lymphangiogenesis in obese-asthma phenotype

Aims: Obesity and asthma are widely prevalent and associated disorders. Recent studies of our group revealed that Substance P (SP) is involved in pathophysiology of obese-asthma phenotype in mice through its selective NK1 receptor (NK1-R). Lymphangiogenesis is impaired in asthma and obesity, and SP activates contractile and inflammatory pathways in lymphatics. Our aim was to study whether NK1-R expression was involved in lymphangiogenesis on visceral (VAT) and subcutaneous (SAT) adipose tissues and in the lungs, in obeseallergen sensitized mice. Main methods: Diet-induced obese and ovalbumin (OVA)-sensitized Balb/c mice were treated with a selective NK1-R antagonist (CJ 12,255, Pfizer Inc., USA) or placebo. Lymphatic structures (LYVE-1+) and NK1-R expression were analyzed by immunohistochemistry. A semi-quantitative score methodology was used for NK1-R expression. Key findings: Obesity and allergen-sensitization together increased the number of LYVE-1+ lymphatics in VAT and decreased it in SAT and lungs. NK1-R was mainly expressed on adipocyte membranes of VAT, blood vessel areas of SAT, and in lung epithelium. Obesity and allergen-sensitization combined increased the expression of NK1-R in VAT, SAT and lungs. NK1-R antagonist treatment reversed the effects observed in lymphangiogenesis in those tissues. Significance: The obese-asthma phenotype in mice is accompanied by increased expression of NK1-R on adipose tissues and lung epithelium, reflecting that SP released during inflammation may act directly on these tissues. Blocking NK1-R affects lymphangiogenesis, implying a role of SP, with opposite physiological consequences in VAT, and in SAT and lungs. Our results provide a clue for a novel SP role in the obese-asthma phenotype.

Classification of some penalty methods

Optimization problems arise in science, engineering, economy, etc. and we need to find the best solutions for each reality. The methods used to solve these problems depend on several factors, including the amount and type of accessible information, the available algorithms for solving them, and, obviously, the intrinsic characteristics of the problem. There are many kinds of optimization problems and, consequently, many kinds of methods to solve them. When the involved functions are nonlinear and their derivatives are not known or are very difficult to calculate, these methods are more rare. These kinds of functions are frequently called black box functions. To solve such problems without constraints (unconstrained optimization), we can use direct search methods. These methods do not require any derivatives or approximations of them. But when the problem has constraints (nonlinear programming problems) and, additionally, the constraint functions are black box functions, it is much more difficult to find the most appropriate method. Penalty methods can then be used. They transform the original problem into a sequence of other problems, derived from the initial, all without constraints. Then this sequence of problems (without constraints) can be solved using the methods available for unconstrained optimization. In this chapter, we present a classification of some of the existing penalty methods and describe some of their assumptions and limitations. These methods allow the solving of optimization problems with continuous, discrete, and mixing constraints, without requiring continuity, differentiability, or convexity. Thus, penalty methods can be used as the first step in the resolution of constrained problems, by means of methods that typically are used by unconstrained problems. We also discuss a new class of penalty methods for nonlinear optimization, which adjust the penalty parameter dynamically.

Damage evaluation of drilled carbon/epoxy laminates based on area assessment methods

The characteristics of carbon fibre reinforced laminates had widened their use, from aerospace to domestic appliances. A common characteristic is the need of drilling for assembly purposes. It is known that a drilling process that reduces the drill thrust force can decrease the risk of delamination. In this work, delamination assessment methods based on radiographic data are compared and correlated with mechanical test results (bearing test).

A web-based tool to evaluate the iterative processes of direct search methods

Constrained and unconstrained Nonlinear Optimization Problems often appear in many engineering areas. In some of these cases it is not possible to use derivative based optimization methods because the objective function is not known or it is too complex or the objective function is non-smooth. In these cases derivative based methods cannot be used and Direct Search Methods might be the most suitable optimization methods. An Application Programming Interface (API) including some of these methods was implemented using Java Technology. This API can be accessed either by applications running in the same computer where it is installed or, it can be remotely accessed through a LAN or the Internet, using webservices. From the engineering point of view, the information needed from the API is the solution for the provided problem. On the other hand, from the optimization methods researchers’ point of view, not only the solution for the problem is needed. Also additional information about the iterative process is useful, such as: the number of iterations; the value of the solution at each iteration; the stopping criteria, etc. In this paper are presented the features added to the API to allow users to access to the iterative process data.

Direct-search penalty/barrier methods

In Nonlinear Optimization Penalty and Barrier Methods are normally used to solve Constrained Problems. There are several Penalty/Barrier Methods and they are used in several areas from Engineering to Economy, through Biology, Chemistry, Physics among others. In these areas it often appears Optimization Problems in which the involved functions (objective and constraints) are non-smooth and/or their derivatives are not know. In this work some Penalty/Barrier functions are tested and compared, using in the internal process, Derivative-free, namely Direct Search, methods. This work is a part of a bigger project involving the development of an Application Programming Interface, that implements several Optimization Methods, to be used in applications that need to solve constrained and/or unconstrained Nonlinear Optimization Problems. Besides the use of it in applied mathematics research it is also to be used in engineering software packages.

Root locus of fractional linear systems

In this paper an algorithm for the calculation of the root locus of fractional linear systems is presented. The proposed algorithm takes advantage of present day computational resources and processes directly the characteristic equation, avoiding the limitations revealed by standard methods. The results demonstrate the good performance for different types of expressions.

A comparative analysis of fault injection methods via enhanced on-chip debug infrastructures

On-chip debug (OCD) features are frequently available in modern microprocessors. Their contribution to shorten the time-to-market justifies the industry investment in this area, where a number of competing or complementary proposals are available or under development, e.g. NEXUS, CJTAG, IJTAG. The controllability and observability features provided by OCD infrastructures provide a valuable toolbox that can be used well beyond the debugging arena, improving the return on investment rate by diluting its cost across a wider spectrum of application areas. This paper discusses the use of OCD features for validating fault tolerant architectures, and in particular the efficiency of various fault injection methods provided by enhanced OCD infrastructures. The reference data for our comparative study was captured on a workbench comprising the 32-bit Freescale MPC-565 microprocessor, an iSYSTEM IC3000 debugger (iTracePro version) and the Winidea 2005 debugging package. All enhanced OCD infrastructures were implemented in VHDL and the results were obtained by simulation within the same fault injection environment. The focus of this paper is on the comparative analysis of the experimental results obtained for various OCD configurations and debugging scenarios.

Privatization and government preference in a public Stackelberg leader duopoly

We analyse the relationship between the privatization of a public firm and government preferences for tax revenue in a Stackelberg duopoly with the public firm as the leader. We assume that the government payoff is given by a weighted sum of tax revenue and the sum of consumer and producer surplus. We get that if the government puts a sufficiently larger weight on tax revenue than on the sum of both surpluses, it will not privatize the public firm. In contrast, if the government puts a moderately larger weight on tax revenue than on the sum of both surpluses, it will privatize the public firm.

People counting system using existing surveillance video camera

The Casa da Música Foundation, responsible for the management of Casa da Música do Porto building, has the need to obtain statistical data related to the number of building’s visitors. This information is a valuable tool for the elaboration of periodical reports concerning the success of this cultural institution. For this reason it was necessary to develop a system capable of returning the number of visitors for a requested period of time. This represents a complex task due to the building’s unique architectural design, characterized by very large doors and halls, and the sudden large number of people that pass through them in moments preceding and proceeding the different activities occurring in the building. To achieve the technical solution for this challenge, several image processing methods, for people detection with still cameras, were first studied. The next step was the development of a real time algorithm, using OpenCV libraries and computer vision concepts,to count individuals with the desired accuracy. This algorithm includes the scientific and technical knowledge acquired in the study of the previous methods. The themes developed in this thesis comprise the fields of background maintenance, shadow and highlight detection, and blob detection and tracking. A graphical interface was also built, to help on the development, test and tunning of the proposed system, as a complement to the work. Furthermore, tests to the system were also performed, to certify the proposed techniques against a set of limited circumstances. The results obtained revealed that the algorithm was successfully applied to count the number of people in complex environments with reliable accuracy.

O empreendedorismo social como promotor da integração socioprofissional: um estudo exploratório

Dissertação de Mestrado apresentado ao Instituto de Contabilidade e Administração do Porto para a obtenção do grau de Mestre em Empreendedorismo e Internacionalização, sob orientação de Dra. Susana Bernardino e Professor Doutor José Freitas Santos