Targeting the tumor microenvironment: An unexplored strategy for mutant KRAS tumors

Current evidence strongly suggests that cancer cells depend on the microenvironment in order to thrive. In fact, signals from the surrounding tumor microenvironment are crucial for cancer cells´ aggressiveness, altering their expression profile and favoring their metastatic potential. As such, targeting the tumor microenvironment to impair cancer progression became an attractive therapeutic option. Interestingly, it has been shown that oncogenic KRAS signaling promotes a pro-tumorigenic microenvironment, and the associated crosstalk alters the expression profile of cancer cells. These findings award KRAS a key role in controlling the interactions between cancer cells and the microenvironment, granting cancer a poor prognosis. Given the lack of effective approaches to target KRAS itself or its downstream effectors in the clinic, exploring such interactions may open new perspectives on possible therapeutic strategies to hinder mutant KRAS tumors. This review highlights those communications and their implications for the development of effective therapies or to provide insights regarding response to existing regimens.This work was supported through FEDER funds through the Operational Programme for Competitiveness Factors (COMPETE 2020), Programa Operacional de Competitividade e Internacionalização (POCI), Programa Operacional Regional do Norte (Norte 2020), European Regional Development Fund (ERDF), and by National Funds through the Portuguese Foundation for Science and Technology (FCT) (PTDC/MED-ONC/31354/2017). PDC is a PhD student from Doctoral Program in Pathology and Molecular Genetics from the Institute of Biomedical Sciences Abel Salazar (ICBAS) and she is funded through a PhD fellowship (SFRH/BD/131156/2017) awarded by Portuguese Foundation for Science and Technology (FCT). FM is a PhD student from Doctoral Programme in Biomedicine from the Faculty of Medicine of the University of Porto and she is funded through NORTE-01-0145-FEDER-000029. ALM is funded through NORTE-01-0145-FEDER-000012. SV is hired by IPATIMUP under norma transitória do DL n.º 57/2016 alterada pela lei n.º 57/2017. This work was supported through FEDER funds through the Operational Programme for Competitiveness Factors (COMPETE 2020), Programa Operacional de Competitividade e Internacionaliza??o (POCI), Programa Operacional Regional do Norte (Norte 2020), European Regional Development Fund (ERDF), and by National Funds through the Portuguese Foundation for Science and Technology (FCT) (PTDC/MED-ONC/31354/2017). PDC is a PhD student from Doctoral Program in Pathology and Molecular Genetics from the Institute of Biomedical Sciences Abel Salazar (ICBAS) and she is funded through a PhD fellowship (SFRH/BD/131156/2017) awarded by Portuguese Foundation for Science and Technology (FCT). FM is a PhD student from Doctoral Programme in Biomedicine from the Faculty of Medicine of the University of Porto and she is funded through NORTE-01-0145-FEDER-000029. ALM is funded through NORTE-01-0145-FEDER-000012. SV is hired by IPATIMUP under norma transitória do DL n.° 57/2016 alterada pela lei n.° 57/2017

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Translational research into gut microbiota: new horizons on obesity treatment: updated 2014

Obesity is currently a pandemic of worldwide proportions affecting millions of people. Recent studies have proposed the hypothesis that mechanisms not directly related to the human genome could be involved in the genesis of obesity, due to the fact that, when a population undergoes the same nutritional stress, not all individuals present weight gain related to the diet or become hyperglycemic. The human intestine is colonized by millions of bacteria which form the intestinal flora, known as gut flora. Studies show that lean and overweight human may present a difference in the composition of their intestinal flora; these studies suggest that the intestinal flora could be involved in the development of obesity. Several mechanisms explain the correlation between intestinal flora and obesity. The intestinal flora would increase the energetic extraction of non-digestible polysaccharides. In addition, the lipopolysaccharide from intestinal flora bacteria could trigger a chronic sub-clinical inflammatory process, leading to obesity and diabetes. Another mechanism through which the intestinal flora could lead to obesity would be through the regulation of genes of the host involved in energy storage and expenditure. In the past five years data coming from different sources established causal effects between intestinal microbiota and obesity/insulin resistance, and it is clear that this area will open new avenues of therapeutic to obesity, insulin resistance and DM2

Body mass index as a predictor of the presence but not the severity of coronary artery disease evaluated by cardiac computed tomography

Background The relation between body mass index (BMI) and coronary artery disease (CAD) extension remains controversial. The aim of this study was to evaluate the correlation between BMI and CAD extension documented by coronary computed tomography angiography (CCTA). Methods and results Prospective registry including 1706 consecutive stable patients that performed CCTA (dual source scanner) for the evaluation of CAD. The population was stratified by BMI: normal 530 (31.1\%), overweight 802 (47.0\%) and obesity 374 (21.9\%). BMI was significantly higher in patients with CAD (27.74.3vs 26.8 +/- 4.3kg/m(2), p5 segments with plaque (15.4\% patients). The prevalence of SIS >5 among the BMI classes was: 18.7\%, 13.7\% and 13.6\% for normal, overweight and obesity respectively (p values for the specific classes versus all other patients: 0.241, 0.450 and 0.663). Conclusions In this population of stable patients undergoing CCTA for suspected CAD, BMI was an independent predictor of its presence, but was not correlated with the coronary disease severity.publishersversionpublishe

Optimized Enzymatic Synthesis of Hesperidin Fatty Acid Esters in a Two-Phase System Containing Ionic Liquid

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Response surface methodology (RSM) based on a five-level, three-variable central composite design (CCD) was employed for modeling and optimizing the conversion yield of the enzymatic acylation of hesperidin with decanoic acid using immobilized Candida antarctica lipase B (CALB) in a two-phase system containing [bmim]BF(4). The three variables studied (molar ratio of hesperidin to decanoic acid, [bmim]BF(4)/acetone ratio and lipase concentration) significantly affected the conversion yield of acylated hesperidin derivative. Verification experiments confirmed the validity of the predicted model. The lipase showed higher conversion degree in a two-phase system using [bmim] BF4 and acetone compared to that in pure acetone. Under the optimal reaction conditions carried out in a single-step biocatalytic process when the water content was kept lower than 200 ppm, the maximum acylation yield was 53.6%.16871717182Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [09/09224-3

Predictors of response to TNF blockers in patients with polyarticular psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory rheumatic disease with a broad clinical spectrum. PsA can affect the axialskeleton, peripheral joints, entheses, synovial sheaths of tendons, skin, nails and extra-articular organs. Tumour necrosis factor alpha blockers (TNF blockers) were a breakthrough development in the treatment of PsA. Identifying predictors of response to biological therapiesin patients with PsA is of utmost importance, especially in view of the costs and potential side effects of these agents. The aims of the present study were to determine baseline predictive factors of response to biological therapies, at 3 and 6 months, in PsA patients with polyarticular involvement (with or without axial involvement). Data were collected from the RheumaticDiseases Portuguese Register(Reuma.pt). Eligible patients had to be anti-TNF-naive at baseline and to have at least 3 months of follow-up after the beginning of TNF blocker therapy. Only patients with information on at least one of the response measures (at 3 or 6 months of follow-up) were included in the analysis. Univariable logistic regression analysis of potential baseline predictors of European League Against Rheu-matism (EULAR) good clinical response, EULAR good/ /moderate response, 28-joint Disease Activity Score with three variables including the erythrocyte sedimentation rate (DAS28-3V-ESR) remission and Health Assessment Questionnaire (HAQ) response were performed. Multivariable logistic regression using a forward selection procedure was used until the best-fit model was obtained, taking confounding effects into account. A total of 180 patients were eligible for the study (mean age 52 years, 54% women). In multivariable analysis at 3 months, females were less likely to attain a good EULAR response [OR=0.082 (95% CI=0.024, 0.278)], a DAS28-3V-ESR remission [OR=0.083 (95% CI=0.017, 0.416)], a moderate or good EULAR response [OR=0.091 (95% CI=0.011, 0.091)] and a HAQ response [OR=0.074 (95% CI=0.009, 0.608)]. At 6 months, female gender was also less likely to achieve a good EULAR response [OR=0.060 (95% CI=0.011, 0.325)], DAS28-3V-ESR remission [OR=0.060 (95% CI=0.012, 0.297)], and a HAQ response [OR=0.138 (95% CI= 0.029, 0.654)]. In this study we found that gender was the most consistent predictor of response to TNF blocker therapy in patients with polyarticular PsA, with females having a lower probability ofresponse compared to males. These findings suggest that gender-related biochemical, hormonal and psychological factors could play an importantrole in the response to TNF blockertherapy in PsA

Selective inhibition of cancer cell self-renewal through a Quisinostat-histone H1.0 axis

Continuous cancer growth is driven by subsets of self-renewing malignant cells. Targeting of uncontrolled self-renewal through inhibition of stem cell-related signaling pathways has proven challenging. Here, we show that cancer cells can be selectively deprived of self-renewal ability by interfering with their epigenetic state. Re-expression of histone H1.0, a tumor-suppressive factor that inhibits cancer cell self-renewal in many cancer types, can be broadly induced by the clinically well-tolerated compound Quisinostat. Through H1.0, Quisinostat inhibits cancer cell self-renewal and halts tumor maintenance without affecting normal stem cell function. Quisinostat also hinders expansion of cells surviving targeted therapy, independently of the cancer types and the resistance mechanism, and inhibits disease relapse in mouse models of lung cancer. Our results identify H1.0 as a major mediator of Quisinostat's antitumor effect and suggest that sequential administration of targeted therapy and Quisinostat may be a broadly applicable strategy to induce a prolonged response in patients

Genetic susceptibility to aspergillosis in allogeneic stem-cell transplantation

Invasive aspergillosis (IA) is a major threat to positive outcomes for allogeneic stem-cell transplantation (allo-SCT) patients. Despite presenting similar degrees of immunosuppression, not all individuals at-risk ultimately develop infection. Therefore, the traditional view of neutropenia as a key risk factor for aspergillosis needs to be accommodated within new conceptual advances on host immunity and its relationship to infection. Polymorphisms in innate immune genes, such as those encoding TLRs, cytokines and cytokine receptors, have recently been associated with susceptibility to IA in allo-SCT recipients. This suggests that understanding host-pathogen interactions at the level of host genetic susceptibility will allow the formulation of new targeted and patient-tailored antifungal therapeutics, including improved donor screening.Fundação para a Ciência e a Tecnologia (FCT) - SFRH/BD/65962/2009, SFRH/BPD/46292/2008Specific Targeted Research Projects MANASP (LSHE-CT-2006), contract number 037899 (FP6), Italian Project PRIN2007KLCKP8_004

An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly

Erythropoetin-producing hepatoma (Eph) receptors are cell-surface protein tyrosine kinases mediating cell-cell communication. Upon activation, they form signaling clusters. We report crystal structures of the full ectodomain of human EphA2 (eEphA2) both alone and in complex with the receptor-binding domain of the ligand ephrinA5 (ephrinA5 RBD). Unliganded eEphA2 forms linear arrays of staggered parallel receptors involving two patches of residues conserved across A-class Ephs. eEphA2-ephrinA5 RBD forms a more elaborate assembly, whose interfaces include the same conserved regions on eEphA2, but rearranged to accommodate ephrinA5 RBD. Cell-surface expression of mutant EphA2s showed that these interfaces are critical for localization at cell-cell contacts and activation-dependent degradation. Our results suggest a 'nucleation' mechanism whereby a limited number of ligand-receptor interactions 'seed' an arrangement of receptors which can propagate into extended signaling arrays