Violator Spaces: Structure and Algorithms

Sharir and Welzl introduced an abstract framework for optimization problems, called LP-type problems or also generalized linear programming problems, which proved useful in algorithm design. We define a new, and as we believe, simpler and more natural framework: violator spaces, which constitute a proper generalization of LP-type problems. We show that Clarkson's randomized algorithms for low-dimensional linear programming work in the context of violator spaces. For example, in this way we obtain the fastest known algorithm for the P-matrix generalized linear complementarity problem with a constant number of blocks. We also give two new characterizations of LP-type problems: they are equivalent to acyclic violator spaces, as well as to concrete LP-type problems (informally, the constraints in a concrete LP-type problem are subsets of a linearly ordered ground set, and the value of a set of constraints is the minimum of its intersection).Comment: 28 pages, 5 figures, extended abstract was presented at ESA 2006; author spelling fixe

Drug combination and repurposing for cancer therapy: the example of breast cancer

Cancer is a set of extremely complex diseases, which are increasingly prominent today, as it affects and kills millions of people worldwide, being the subject of intense study both in its pathophysiology and therapy. Especially in women, breast cancer is still a cancer with a high incidence and mortality. Even though mortality rates for this type of cancer have declined in recent years, it remains challenging at the treatment level, especially the metastatic type. Due to all the impact on health, cancer therapy is the subject of costly and intense research. To enrich this therapy, as well as decrease its underlying high associated costs, drug repurposing and drug combinations are strategies that have been increasingly studied and addressed. As the name implies, drug repurposing presupposes giving new purposes to agents which, in this case, are approved for the therapy of other diseases (for example, cardiovascular or metabolic diseases), but are not approved for cancer therapy. Therefore, a better knowledge of these therapeutic modalities for breast cancer therapy is crucial for improved therapy. In this particular review, we will discuss some relevant aspects of cancer and, particularly, breast cancer and its therapy. Also, drug combination and repurposing will be highlighted, together with relevant examples. Despite some limitations that need to be overcome, these methodologies are extremely important and advantageous in combating several current problems of cancer therapy, namely in terms of costs and resistance to current therapeutic modalities. These approaches will be explored with a special focus on breast cancer.This work was supported by FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT - Fundação para a Ciência e a Tecnologia , in the framework of the projects supported by National Funds through FCT, within CINTESIS, R&D Unit (reference UIDB/4255/2020). N. Vale was supported by FCT and FEDER (European Union), award number IF/00092/2014/CP1255/CT0004

A system for production of defective interfering particles in the absence of infectious influenza A virus

<div><p>Influenza A virus (IAV) infection poses a serious health threat and novel antiviral strategies are needed. Defective interfering particles (DIPs) can be generated in IAV infected cells due to errors of the viral polymerase and may suppress spread of wild type (wt) virus. The antiviral activity of DIPs is exerted by a DI genomic RNA segment that usually contains a large deletion and suppresses amplification of wt segments, potentially by competing for cellular and viral resources. DI-244 is a naturally occurring prototypic segment 1-derived DI RNA in which most of the PB2 open reading frame has been deleted and which is currently developed for antiviral therapy. At present, coinfection with wt virus is required for production of DI-244 particles which raises concerns regarding biosafety and may complicate interpretation of research results. Here, we show that cocultures of 293T and MDCK cell lines stably expressing codon optimized PB2 allow production of DI-244 particles solely from plasmids and in the absence of helper virus. Moreover, we demonstrate that infectivity of these particles can be quantified using MDCK-PB2 cells. Finally, we report that the DI-244 particles produced in this novel system exert potent antiviral activity against H1N1 and H3N2 IAV but not against the unrelated vesicular stomatitis virus. This is the first report of DIP production in the absence of infectious IAV and may spur efforts to develop DIPs for antiviral therapy.</p></div

Extending local features with contextual information in graph kernels

Graph kernels are usually defined in terms of simpler kernels over local substructures of the original graphs. Different kernels consider different types of substructures. However, in some cases they have similar predictive performances, probably because the substructures can be interpreted as approximations of the subgraphs they induce. In this paper, we propose to associate to each feature a piece of information about the context in which the feature appears in the graph. A substructure appearing in two different graphs will match only if it appears with the same context in both graphs. We propose a kernel based on this idea that considers trees as substructures, and where the contexts are features too. The kernel is inspired from the framework in [6], even if it is not part of it. We give an efficient algorithm for computing the kernel and show promising results on real-world graph classification datasets.Comment: To appear in ICONIP 201

New insight into breast cancer cells involving drug combinations for dopamine and serotonin receptors

The breast cancer therapies available are insufficient, especially since first-line treatments, such as paclitaxel, result in drug resistance and their toxicity often limits their concentration. Strategies like drug repurposing are beneficial, and novel treatments can emerge by repurposing drugs that interfere with the dopamine and serotonin receptors, and thus influence tumor growth. In this study, the MTT assay was used to test the efficacy of such repurposed drugs commonly used for neurodegenerative disorders that act on the dopamine and serotonin receptors to reduce the MCF7 cell’s viability, either by their single use or in combination with the reference drug paclitaxel. Furthermore, the expression of vimentin and E-cadherin was assayed by immunofluorescence. The dopamine receptor-altering drugs benztropine and thioridazine resulted in the strongest reduction of cell viability when combined with paclitaxel, which may be connected to the alteration of E-cadherin rather than vimentin expression. More studies are needed to understand the mechanism of action of the combinations tested and the efficacious role of dopamine and serotonin.This work was supported by Fundação para a Ciência e Tecnologia (FCT, Portugal) and FEDER (Fundo Europeu de Desenvolvimento Regional) funds through the COMPETE 2020 Operational Programme for Competitiveness and Internationalisation (POCI), Portugal, in the framework of the project IF/00092/2014/CP1255/CT0004. N.V. thanks Fundação para a Ciência e a Tecnologia (FCT, Portugal) for supporting these studies through nationally-funded projects within the CINTESIS R&D unit (reference UIDB/4255/2020). The contents of this report are solely the responsibility of the authors and do not necessarily represent the official view of the FCT

Inhibition of the formation in vitro of putatively carcinogenic metabolites derived from S. Haematobium and O. Viverrini by Combination of Drugs with Antioxidants

Infections caused by Schistosoma haematobium and Opisthorchis viverrini are classified as carcinogenic. Although carcinogenesis might be a multifactorial process, it has been postulated that these helminth produce/excrete oxysterols and estrogen-like metabolites that might act as initiators of their infection-associated carcinogenesis. Current treatment and control of these infections rely on a single drug, praziquantel, that mainly targets the parasites and not the pathologies related to the infection including cancer. Thus, there is a need to search for novel therapeutic alternatives that might include combinations of drugs and drug repurposing. Based on these concepts, we propose a novel therapeutic strategy that combines drugs with molecule antioxidants. We evaluate the efficacy of a novel therapeutic strategy to prevent the formation of putative carcinogenic metabolites precursors and DNA adducts. Firstly, we used a methodology previously established to synthesize metabolites precursors and DNA adducts in the presence of CYP450. Then, we evaluated the inhibition of their formation induced by drugs and antioxidants alone or in combination. Drugs and resveratrol alone did not show a significant inhibitory effect while N-acetylcysteine inhibited the formation of most metabolite precursors and DNA adducts. Moreover, the combinations of classical drugs with antioxidants were more effective rather than compounds alone. This strategy might be a valuable tool to prevent the initiation of helminth infection-associated carcinogenesis.This work was financed by FEDER-Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020-Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT-Fundação para a Ciência e a Tecnologia, in the framework of the projects "Institute for Research and Innovation in Health Sciences" (POCI-01-0145-FEDER-007274). N.V. also acknowledges support from FCT and FEDER (European Union), award number IF/00092/2014/CP1255/CT0004. FUNDING TEXT 2: Funding: This work was financed by FEDER-Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020-Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT-Fundação para a Ciência e a Tecnologia, in the framework of the projects “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274). N.V. also acknowledges support from FCT and FEDER (European Union), award number IF/00092/2014/CP1255/CT0004

The antioxidants resveratrol and N-acetylcysteine enhance anthelmintic activity of praziquantel and artesunate against Schistosoma mansoni

Background: Treatment of schistosomiasis has relied on the anthelmintic drug praziquantel (PZQ) for more than a generation. Despite its celebrated performance for treatment and control of schistosomiasis and other platyhelminth infections, praziquantel has some shortcomings and the inability of this drug to counteract disease sequelae prompts the need for novel therapeutic strategies. Methods: Using a host-parasite model involving Biomphalaria glabrata and Schistosoma mansoni we established mechanical transformation of S. mansoni cercariae into newly transformed schistosomula (NTS) and characterized optimal culture conditions. Thereafter, we investigated the antischistosomal activity and ability of the antioxidants N-acetylcysteine (NAC) and resveratrol (RESV) to augment the performance of praziquantel and/or artesunate (AS) against larval stages of the parasite. Drug effects were evaluated by using an automated microscopical system to study live and fixed parasites and by transmission electron microscopy (TEM). Results: Transformation rates of cercariae to schistosomula reached ~ 70% when the manipulation process was optimized. Several culture media were tested, with M199 supplemented with HEPES found to be suitable for S. mansoni NTS. Among the antioxidants studied, RESV alone or combined with anthelminthic drugs achieved better results rather N-acetylcysteine (NAC). TEM observations demonstrated that the combination of AS + RESV induced severe, extensive alterations to the tegument and subtegument of NTS when compared to the constituent compounds alone. Two anthelmintic-antioxidant combinations, praziquantel-resveratrol [combination index (CI) = 0.74] and artesunate-resveratrol (CI = 0.34) displayed moderate and strong synergy, respectively. Conclusions: The use of viability markers including staining with propidium iodide increased the accuracy of drug screening assays against S. mansoni NTS. The synergies observed might be the consequence of increased action by RESV on targets of AS and PZQ and/or they may act through concomitantly on discrete targets to enhance overall antischistosomal action. Combinations of active agents, preferably with discrete modes of action including activity against developmental stages and/or the potential to ameliorate infection-associated pathology, might be pursued in order to identify novel therapeutic interventions.We express our deepest appreciation to Mrs. Maria Lurdes Delgado for expert maintenance of the schistosome life-cycle and her technical support NV acknowledges support from the Fundação para a Ciência e Tecnologia (FCT, Portugal) and FEDER (European Union) through Project Number IF/00092/2014/CP1255/CT0004. NV thanks FCT by IF position, Fundação Manuel António da Mota (FMAM, Portugal) and Pfizer Portugal for research group support. JMCC thanks FCT for UID/Multi/00211/2019 and Strategic Project UI211. PJB acknowledges support from award RO1CA164719 from the National Cancer Institute (NCI), National Institutes of Health (NIH), USA. The contents of this report are solely the responsibility of the authors and do not necessarily represent the official views of the FCT, FMAM, the NCI, or the NIH