Quercetin in Cancer Treatment, Alone or in Combination with Conventional Therapeutics?

Cancer is a problem of global importance, since the incidence is increasing worldwide and therapeutic options are generally limited. Thus, it becomes imperative to find new therapeutic targets as well as new molecules with therapeutic potential for tumors. Flavonoids are polyphenolic compounds that may be potential therapeutic agents. Several studies have shown that these compounds have a higher anticancer potential. Among the flavonoids in the human diet, quercetin is one of the most important. In the last decades, several anticancer properties of quercetin have been described, such as cell signaling, pro-apoptotic, anti-proliferative and anti-oxidant effects, growth suppression. In fact, it is now well known that quercetin has diverse biological effects, inhibiting multiple enzymes involved in cell proliferation, as well as, in signal transduction pathways. On the other hand, there are also studies reporting potential synergistic effects when combined quercetin with chemotherapeutic agents or radiotherapy. In fact, several studies which aim to explore the anticancer potential of these combined treatments have already been published, the majority with promising results. Actually it is well known that quercetin can act on the chemosensitization and radiosensitization but also as chemoprotective and radioprotective, protecting normal cells of the side effects that results from chemotherapy and radiotherapy, which obviously provides notable advantages in their use in anticancer treatment. Thus, all these data indicate that quercetin may have a key role in anticancer treatment. In this context, this review is focused on the relationship between flavonoids and cancer, with special emphasis on the role of quercetin.

(Re)criar ambientes pedagógicos alternativos : o lúdico ao serviço da aprendizagem

Relatório de Estágio apresentado à Escola Superior de Educação de Paula Frassinetti para obtenção do grau de Mestre em Educação Pré-Escolar e Ensino do 1º Ciclo do Ensino Básico,sob orientação Doutora Daniela Alexandra Ramos Gonçalves | Mestre Irene Zuzarte Cortesão Melo Costa

Playing for Real: Designing Alternate Reality Games in Learning Contexts

Alternate Reality Game (ARG) represent a new genre of transmedia practice where players hunt for scattered clues, make sense of disparate information, and solve puzzles to advance an ever-evolving storyline. Players participate in ARGs using multiple communications technologies, ranging from print materials to mobile devices. However, many interaction design challenges must be addressed to weave these everyday communication tools together into an immersive, participatory experience. Transmedia design is not an everyday process. Designers must create and connect story bits across multiple media (video, audio, text) and multiple platforms (phones, computers, physical spaces). Furthermore, they must engage with players of varying skill levels. Few studies to-date have explored the design process of ARGs in learning contexts. Fewer still have focused on challenges involved in designing for youth (13-17 years old). In this study, I explore the process of designing ARGs as vehicles for promoting information literacy and participatory culture for adolescents (13-17 years old). Two ARG design scenarios, distinguished by target learning environment (formal and informal context) and target audience (adolescents), comprise the two cases that I examine. Through my analysis of these two design cases, I articulate several unique challenges faced by designers who create interactive, transmedia stories for – and with – youth. Drawing from these design challenges, I derive a repertoire of design strategies that future designers and researchers may use to create and implement ARGs for teens in learning contexts. In particular, I propose a narrative design framework that allows for the categorization of ARGs as storytelling constructs that lie along a continuum of participation and interaction. The framework can serve as an analytic tool for researchers and a guide for designers. In addition, I establish a framework of social roles that designers may employ to craft transmedia narratives before live launch and to promote and scaffold player participation after play begins. Overall, the contributions of my study include theoretical insights that may advance our understanding of narrative design and analysis as well as more practical design implications for designers and practitioners seeking to incorporate transmedia features into learning experiences that target youth.

Investigating disease persistence in host vector systems: dengue as a case study

The investigation of pathogen persistence in vector-borne diseases is important in different ecological and epidemiological contexts. In this thesis, I have developed deterministic and stochastic models to help investigating the pathogen persistence in host-vector systems by using efficient modelling paradigms. A general introduction with aims and objectives of the studies conducted in the thesis are provided in Chapter 1. The mathematical treatment of models used in the thesis is provided in Chapter 2 where the models are found locally asymptotically stable. The models used in the rest of the thesis are based on either the same or similar mathematical structure studied in this chapter. After that, there are three different experiments that are conducted in this thesis to study the pathogen persistence. In Chapter 3, I characterize pathogen persistence in terms of the Critical Community Size (CCS) and find its relationship with the model parameters. In this study, the stochastic versions of two epidemiologically different host-vector models are used for estimating CCS. I note that the model parameters and their algebraic combination, in addition to the seroprevalence level of the host population, can be used to quantify CCS. The study undertaken in Chapter 4 is used to estimate pathogen persistence using both deterministic and stochastic versions of a model with seasonal birth rate of the vectors. Through stochastic simulations we investigate the pattern of epidemics after the introduction of an infectious individual at different times of the year. The results show that the disease dynamics are altered by the seasonal variation. The higher levels of pre-existing seroprevalence reduces the probability of invasion of dengue. In Chapter 5, I considered two alternate ways to represent the dynamics of a host-vector model. Both of the approximate models are investigated for the parameter regions where the approximation fails to hold. Moreover, three metrics are used to compare them with the Full model. In addition to the computational benefits, these approximations are used to investigate to what degree the inclusion of the vector population in the dynamics of the system is important. Finally, in Chapter 6, I present the summary of studies undertaken and possible extensions for the future work.

Combination of Evolutionary Algorithms with Experimental Design, Traditional Optimization and Machine Learning

Evolutionary algorithms alone cannot solve optimization problems very efficiently since there are many random (not very rational) decisions in these algorithms. Combination of evolutionary algorithms and other techniques have been proven to be an efficient optimization methodology. In this talk, I will explain the basic ideas of our three algorithms along this line (1): Orthogonal genetic algorithm which treats crossover/mutation as an experimental design problem, (2) Multiobjective evolutionary algorithm based on decomposition (MOEA/D) which uses decomposition techniques from traditional mathematical programming in multiobjective optimization evolutionary algorithm, and (3) Regular model based multiobjective estimation of distribution algorithms (RM-MEDA) which uses the regular property and machine learning methods for improving multiobjective evolutionary algorithms.

Robust Stereo Visual Odometry through a Probabilistic Combination of Points and Line Segments

Most approaches to stereo visual odometry reconstruct the motion based on the tracking of point features along a sequence of images. However, in low-textured scenes it is often difficult to encounter a large set of point features, or it may happen that they are not well distributed over the image, so that the behavior of these algorithms deteriorates. This paper proposes a probabilistic approach to stereo visual odometry based on the combination of both point and line segment that works robustly in a wide variety of scenarios. The camera motion is recovered through non-linear minimization of the projection errors of both point and line segment features. In order to effectively combine both types of features, their associated errors are weighted according to their covariance matrices, computed from the propagation of Gaussian distribution errors in the sensor measurements. The method, of course, is computationally more expensive that using only one type of feature, but still can run in real-time on a standard computer and provides interesting advantages, including a straightforward integration into any probabilistic framework commonly employed in mobile robotics.

Alternate Conformations Regulate Ribosomal Recoding in a Positive-sense RNA Virus

Positive-sense RNA viruses are important animal, plant, insect and bacteria pathogens and constitute the largest group of RNA viruses. Due to the relatively small size of their genomes, these viruses have evolved a variety of non-canonical translation mechanisms to optimize coding capacity expanding their proteome diversity. One such strategy is codon redefinition or recoding. First described in viruses, recoding is a programmed translation event in which codon alterations are context dependent. Recoding takes place in a subset of messenger RNA (mRNAs) with some products reflecting new, and some reflecting standard, meanings. The ratio between the two is both critical and highly regulated. While a variety of recoding mechanisms have been documented, (ribosome shunting, stop-carry on, termination-reinitiation, and translational bypassing), the two most extensively employed by RNA viruses are Programmed Ribosomal Frameshifting (PRF) and Programmed Ribosomal Readthrough (PRT). While both PRT and PRF subvert normal decoding for expression of C-terminal extension products, the former involves an alteration of reading frame, and the latter requires decoding of a non-sense codon. Both processes occur at a low but defined frequency, and both require Recoding Stimulatory Elements (RSE) for regulation and optimum functionality. These stimulatory signals can be embedded in the RNA in the form of sequence or secondary structure, or trans-acting factors outside the mRNA such as proteins or micro RNAs (miRNA). Despite 40+ years of study, the precise mechanisms by which viral RSE mediate ribosome recoding for the synthesis of their proteins, or how the ratio of these products is maintained, is poorly defined. This study reveals that in addition to a long distance RNA:RNA interaction, three alternate conformations and a phylogenetically conserved pseudoknot regulate PRT in the carmovirus Turnip crinkle virus (TCV).

EACS: Effective Avoidance Combination Strategy

International audience

HBsAg seroclearance or seroconversion induced by peg-interferon alpha and lamivudine or adefovir combination therapy in chronic hepatitis B treatment: a meta-analysis and systematic review

Background and aims: Seroclearance or seroconversion of hepatitis B surface antigen (HBsAg) is generally considered as a clinical endpoint. The purpose of the present meta-analysis was to evaluate the effect of combined therapy with pegylated interferon alpha (PEG-IFNα) with or without lamivudine (LAM) or adefovir (ADV) on HBsAg seroclearance or seroconversion in subjects with chronic hepatitis B (CHB). Methods: Randomized controlled trials performed through May 30th 2015 in adults with CHB receiving PEG-IFNα and LAM or ADV combination therapy or monotherapy for 48-52 weeks were included. The Review Manager Software 5.2.0 was used for the meta-analysis. Results: No statistical differences in HBsAg seroclearance (9.9% vs. 7.1%, OR = 1.47, 95% CI: 0.75, 2.90; p = 0.26) or HBsAg seroconversion (4.2% vs. 3.7%, OR = 1.17, 95% CI: 0.57, 2.37; p = 0.67) rates were noticed between PEG-IFNα + LAM and PEG-IFN α + placebo during post-treatment follow-up for 24-26-weeks in subjects with hepatitis Be antigen (HBeAg)-positive CHB. No statistical differences in HBsAg clearance (10.5% vs. 6.4%, OR = 1.68, 95% CI: 0.75, 3.76; p = 0.21) were seen, but statistical differences in HBsAg seroconversion (6.3% vs. 0%, OR = 7.22, 95% CI: 1.23, 42.40; p = 0.03) were observed, between PEG-IFNα + ADV and PEG-IFNα for 48-52 weeks of treatment in subjects with HBeAg-positive CHB. A systematic evaluation showed no differences in HBsAg disappearance and seroconversion rates between PEG-IFNα + placebo and PEG-IFNα + LAM for 48-52 weeks in subjects with HBeAg-positive CHB. A systematic assessment found no differences in HBsAg disappearance and seroconversion rates between PEG-IFNα + placebo and PEG-IFNα + LAM during 24 weeks' to 3 years' follow-up after treatment in subjects with HBeAg-negative CHB. Conclusion: Combined therapy with PEG-IFNα and LAM or ADV was not superior to monotherapy with PEG-IFNα in terms of HBsAg seroclearance or seroconversion.

Using a Combination of Phylogenetic Comparative and Paleobotanical Methods to Elucidate Patterns of Lineage Selection in Rosales (Plantae: Anthophyta)

An increasing focus in evolutionary biology is on the interplay between mesoscale ecological and evolutionary processes such as population demographics, habitat tolerance, and especially geographic distribution, as potential drivers responsible for patterns of diversification and extinction over geologic time. However, few studies to date connect organismal processes such as survival and reproduction through mesoscale patterns to long-term macroevolutionary trends. In my dissertation, I investigate how mechanism of seed dispersal, mediated through geographic range size, influences diversification rates in the Rosales (Plantae: Anthophyta). In my first chapter, I validate the phylogenetic comparative methods that I use in my second and third chapters. Available state speciation and extinction (SSE) models assumptions about evolution known to be false through fossil data. I show, however, that as long as net diversification rates remain positive – a condition likely true for the Rosales – these violations of SSE’s assumptions do not cause significantly biased results. With SSE methods validated, my second chapter reconstructs three associations that appear to increase diversification rate for Rosalean genera: (1) herbaceous habit; (2) a three-way interaction combining animal dispersal, high within-genus species richness, and geographic range on multiple continents; (3) a four-way interaction combining woody habit with the other three characteristics of (2). I suggest that the three- and four-way interactions represent colonization ability and resulting extinction resistance in the face of late Cenozoic climate change; however, there are other possibilities as well that I hope to investigate in future research. My third chapter reconstructs the phylogeographic history of the Rosales using both non-fossil-assisted SSE methods as well as fossil-informed traditional phylogeographic analysis. Ancestral state reconstructions indicate that the Rosaceae diversified in North America while the other Rosalean families diversified elsewhere, possibly in Eurasia. SSE is able to successfully identify groups of genera that were likely to have been ancestrally widespread, but has poorer taxonomic resolution than methods that use fossil data. In conclusion, these chapters together suggest several potential causal links between organismal, mesoscale, and geologic scale processes, but further work will be needed to test the hypotheses that I raise here.

EFFECT OF BAP, NAA AND GA3, EITHER ALONE OR IN COMBINATION, ON MERISTEM CULTURE AND PLANTLET ESTABLISHMENT IN SWEET POTATO (CV BRONDAL)

In Zimbabwe, the average sweet potato yield (6 t/ha) is relatively low when compared to Asian counterparts (17 t/ha). These low crop yields have been blamed on weevil infestations and viral infections which account for 60-90% of sweet potato yield losses in Africa. Meristem tip culture, a Centre for Potato Improvement (CIP) initiated tissue culture technique, has been widely used to eradicate viruses from clonally propagated crops and has been noted to be one of the instrumental techniques that helped China to increase sweet potato yields. In an effort to adopt the meristem tip culture technique for the production of virus-free planting material of a local sweet potato (cv Brondal), a study was conducted to evaluate the effect of Benzylamino purine (BAP), 1-Naphthaleneacetic acid (NAA) and Gibberellic acid (GA3) (either alone or in combination) on cultured Brondal meristems. The different hormonal treatments were assessed on the following parameters: plantlet regenerative capacity, multiple plantlet production, shoot height, average leaf number per shoot and average node number per shoot, ten weeks after meristem culture. All treatments containing a combination of BAP (1 mg-L) and GA3 (at either 5 mg-L, 10 mg-L, or 20 mg-L) had a significantly (p<0.01) higher plantlet regenerative capacity of 33-66% when compared to other treatment combinations. Only treatments, 10 mg-L GA3 + 1 mg-L BAP and 20 mg-L GA3 + 1 mg-L BAP were capable of inducing multiple plantlet formation, producing an average of three plantlets/meristem and two plantlets/meristem respectively. Overall, treatment 10 mg-L GA3 + 1 mg-L BAP gave rise to significantly (p<0.01) taller shoots (20 mm) compared to the rest of the treatments used. For average leaf number per shoot, all GA3 treatments (5 mg-L, 10 mg-L, or 20 mg-L) supplemented with 1 mg-L BAP gave significantly (p<0.01) higher numbers of leaves (six leaves/shoot) than the rest of the treatments. Treatments 10 mg-L GA3 + 1 mg-L BAP and 20 mg-L GA3 + 1 mg-L BAP gave rise to the highest number of nodes per shoot, producing an average of three nodes per shoot. In sharp contrast to treatments containing a combination of BAP and GA3, all treatments containing a combination of BAP and NAA performed poorly in all parameters tested for plant regeneration of Brondal sweet potato variety. In conclusion, the best hormonal treatment for culturing Brondal meristems proved to be 10 mg-L GA3 + 1 mg-L BAP.

INTEGRATED THRESHOLD-ACTIVATED FEEDBACK MICROSYSTEM FOR REAL-TIME CHARACTERIZATION, SENSING AND TREATMENT OF BACTERIAL BIOFILMS

Biofilms are the primary cause of clinical bacterial infections and are impervious to typical amounts of antibiotics, necessitating very high doses for treatment. Therefore, it is highly desirable to develop new alternate methods of treatment that can complement or replace existing approaches using significantly lower doses of antibiotics. Current standards for studying biofilms are based on end-point studies that are invasive and destroy the biofilm during characterization. This dissertation presents the development of a novel real-time sensing and treatment technology to aid in the non-invasive characterization, monitoring and treatment of bacterial biofilms. The technology is demonstrated through the use of a high-throughput bifurcation based microfluidic reactor that enables simulation of flow conditions similar to indwelling medical devices. The integrated microsystem developed in this work incorporates the advantages of previous in vitro platforms while attempting to overcome some of their limitations. Biofilm formation is extremely sensitive to various growth parameters that cause large variability in biofilms between repeated experiments. In this work we investigate the use of microfluidic bifurcations for the reduction in biofilm growth variance. The microfluidic flow cell designed here spatially sections a single biofilm into multiple channels using microfluidic flow bifurcation. Biofilms grown in the bifurcated device were evaluated and verified for reduced biofilm growth variance using standard techniques like confocal microscopy. This uniformity in biofilm growth allows for reliable comparison and evaluation of new treatments with integrated controls on a single device. Biofilm partitioning was demonstrated using the bifurcation device by exposing three of the four channels to various treatments. We studied a novel bacterial biofilm treatment independent of traditional antibiotics using only small molecule inhibitors of bacterial quorum sensing (analogs) in combination with low electric fields. Studies using the bifurcation-based microfluidic flow cell integrated with real-time transduction methods and macro-scale end-point testing of the combination treatment showed a significant decrease in biomass compared to the untreated controls and well-known treatments such as antibiotics. To understand the possible mechanism of action of electric field-based treatments, fundamental treatment efficacy studies focusing on the effect of the energy of the applied electrical signal were performed. It was shown that the total energy and not the type of the applied electrical signal affects the effectiveness of the treatment. The linear dependence of the treatment efficacy on the applied electrical energy was also demonstrated. The integrated bifurcation-based microfluidic platform is the first microsystem that enables biofilm growth with reduced variance, as well as continuous real-time threshold-activated feedback monitoring and treatment using low electric fields. The sensors detect biofilm growth by monitoring the change in impedance across the interdigitated electrodes. Using the measured impedance change and user inputs provided through a convenient and simple graphical interface, a custom-built MATLAB control module intelligently switches the system into and out of treatment mode. Using this self-governing microsystem, in situ biofilm treatment based on the principles of the bioelectric effect was demonstrated by exposing two of the channels of the integrated bifurcation device to low doses of antibiotics.

Arsenic bioleaching in medical realgar ore and arsenicbearing refractory gold ore by combination of Acidithiobacillus ferrooxidans and Acidithiobacillus thiooxidans

Purpose: To develop a novel biotechnological method for removing toxic arsenic from two kinds of representative arsenic-containing ores using different mixed mesophilic acidophiles. Methods: Bioleaching of the two types of arsenic-containing ores by mixed arsenic-unadapted Acidithiobacillus ferrooxidans and Acidithiobacillus thiooxidans or mixed arsenic-adapted cultures, were carried out. Arsenic bioleaching ratios in the various leachates were determined and compared. Results: The results showed that the maximum arsenic leaching ratio obtained from realgar in the presence of mixed adapted cultures was 28.6 %. However, the maximum arsenic leaching ratio from realgar in the presence of mixed unadapted strains was only 12.4 %. Besides, maximum arsenic leaching ratios from arsenic-bearing refractory gold ore by mixed adapted strains or unadapted strains were 45.0 and 22.9 %, respectively. Oxidation of these two ores by sulfuric acid was insignificant, as maximum arsenic leaching ratios of realgar and arsenic-bearing refractory gold ore in the absence of any bacterium were only 2.8 and 11.2 %, respectively. Conclusion: Arsenic leaching ratio of realgar and refractory gold ore can be enhanced significantly in the presence of arsenic-adapted mesophilic acidophiles.

Feeding strategy with alternate fasting and refeeding: effects on farmed pacu production

P>A 36-day trial was conducted to determine the effects of repetitive periods of food restriction and refeeding on growth and energy metabolism in pacu (Piaractus mesopotamicus). A total 264 juvenile fish (36.9 +/- 2.8 g) were fed with the experimental diet for 36 days using three regimes: (i) feeding daily to satiation (FD); (ii) no feed for 3 days, then feeding the same amount offered to the control groups for the next 3 days (NF/R controlled); and (iii) no feed for 3 days, then feeding to apparent satiation for the next 3 days (NF/R at satiation). The treatments were distributed into four tanks each. WG and SGR were higher in FD group. Fish refed showed hyperphagia just up to the second day of refeeding. The worst feed conversion rate and the lowest protein efficiency ratio were found in fish NF/R controlled. The lowest values of visceral fat somatic index were found in both fasted fish groups, particularly in NF/R at satiation. The LL and glycogen concentrations, and the hepatosomatic index were all elevated in both feed restricted fish. Muscle lipid showed a tendency to decrease after the cycle of fasting and refeeding. Plasma free fatty acids and glucose levels were elevated in fish subjected to feeding restrictions while serum triglycerides levels were reduced. Triiodothyronine levels were significantly depressed in fish from the NF/R-controlled group and remained at the same levels as the control fish in fish NF/R at satiation. Results indicated that fish subjected to cyclic periods of 3-day satiation or controlled feeding after 3-days of fasting were unable to achieve the final body weight of fish fed to satiation after 36 days.

Therapeutic effects of ciprofloxacin/bushenhuazhuo combination on chronic prostatitis

Purpose: To evaluate the clinical effect of bushenhuazhuo (a Chinese traditional medicine) in combination with ciprofloxacin (an orthodox medicine) in chronic prostatitis (CP) therapy. Methods: A total of 160 patients who suffered from CP and received treatment in the People’s Hospital of Zhengzhou between April 2012 and June 2014 were selected and divided randomly into treatment and control groups, with 80 patients in each group. Control group was given 0.25 g ciprofloxacin hydrochloride tablets twice a day for 4 weeks. In addition to ciprofloxacin administration, patients in the treatment group also received a dose of bushenhuazhuo preparation twice daily for 4 weeks. Clinical outcomes, quality of life as well as lecithin body and white blood cell (WBC) count in expressed prostatic secretions (EPS-WBC) were evaluated. Results: Cure rates in the treatment and control groups were 90 and 72.50 %, respectively; this difference was significant (p < 0.05). Scores for National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), WBC, and lecithin bodies in the treatment group (8.20 ± 2.20 points, 4.50 ± 1.20 points, and 28.10 ± 2.10 points, respectively) were higher (p < 0.05) than for the control group (12.20 ± 2.20, 6.30 ± 2.20, and 23.30 ± 2.90 points, respectively). The levels of interferon (IFN)-γ and tumour necrosis factor (TNF)-α in the treatment group (26.20 ± 3.30 and 33.80 ± 5.40 mg/L, respectively) were lower than those in the control group (37.70 ± 3.90 and 48.40 ± 3.70 mg/L, respectively), whereas the level of interleukin (IL)-10 in the treatment group (292.60 ± 23.70 mg/L) was higher (p < 0.05) than that in control group (235.80 ± 25.90 mg/L). Conclusion: Ciprofloxacin combined with the Chinese traditional medicine, bushenhuazhuo preparation, demonstrates a marked therapeutic effect in CP. Its mechanism of action may be related to decreased levels of IFN-γ and TNF-α and increased IL-10.