Peat bogs of the Serra do Espinhaço Meridional - Minas Gerais, Brazil: I - characterization and classification

As turfeiras são ambientes especiais para estudos relacionados com a dinâmica da matéria orgânica, evolução das paisagens, mudanças climáticas e ciclos de poluição atmosférica locais, regionais e globais. Elas contribuem para o sequestro global de carbono, funcionam como reservatórios de água e constituem o ambiente de uma biodiversidade endêmica. A Serra do Espinhaço Meridional (SdEM), Reserva da Biosfera Terrestre, apresenta uma área significativa formada por diferentes tipos de turfeira, que foram descritas em três perfis, situados a 1.250 m (P1), 1.800 m (P2) e 1.350 m (P4) de altitude e classificados respectivamente como Organossolo Háplico Sáprico térrico (P1), Organossolo Háplico Fíbrico típico (P2) e Organossolo Háplico Hêmico típico (P4), de acordo com o Sistema Brasileiro de Classificação de Solos. Os três perfis foram caracterizados morfologicamente e, nas amostras coletadas, foram realizadas análises químicas, físicas e microbiológicas. Verificou-se que a localização, a altitude e a drenagem influenciaram os atributos morfológicos, físicos, químicos e microbiológicos das turfeiras da SdEM. O estádio de decomposição da matéria orgânica é mais avançado com a melhoria da drenagem nas turfeiras. O teor de metais pesados está relacionado com o teor e a composição granulométrica da fração mineral e com a localização das turfeiras. O perfil P1 apresentou os mais elevados teores médios de Ti, Zr e Pb; em P2 foram detectados os teores médios mais elevados de Mn, Zn e Cu; e o teor médio de Fe é mais elevado em P4. A intensidade da atividade microbiológica das turfeiras P2 e P4 relacionou-se com sua drenagem e com o teor de metais pesados de suas camadas.Peat bogs are a special environment for studies related with the dynamics of organic matter, landscape evolution and climatic changes and with local, regional and global cycles of atmospheric pollution. Peat bogs contribute to the global C sequestration, act as water reservoirs and are the habitat of an endemic biodiversity. The Serra do Espinhaço Meridional (Minas Gerais State, Brazil) - SdEM - a terrestrial biosphere reservation area, contains a considerably large area with different types of peat bogs, which were described in three profiles at 1,250, 1,800 and 1,350 m above sea level and classified, respectively, as Organosol Haplic sapric terric (P1), Organosol Haplic fibric typical (P2) and Organosol Haplic Hemic typical (P4), in agreement with the Brazilian System of Soil Classification. The three profiles were characterized morphologically and the samples were chemically, physically and microbiologically analyzed. It was found that the location, altitude and drainage influenced the morphologic, physical, chemical, and biological properties of the peat bogs in SdEM. The decomposition state of organic matter is more advanced when the drainage in the peat bogs is better. The amount of heavy metals is related with the quantity and granulometric composition of the mineral fraction and location of the peat bogs. The highest mean levels of Ti, Zr, Pb were detected in profile P1, highest mean levels of Mn, Zn and Cu in P2, and the highest mean Fe content in P4. The intensity of microbiological activity in the peat bogs P2 and P4 was related with the drainage and heavy-metal content of its layers.(FAPEMIG) Pesquisa do Estado de Minas Gerai

Norepinephrine-evoked pain in fibromyalgia. A randomized pilot study [ISRCTN70707830]

BACKGROUND: Fibromyalgia syndrome displays sympathetically maintained pain features such as frequent post-traumatic onset and stimuli-independent pain accompanied by allodynia and paresthesias. Heart rate variability studies showed that fibromyalgia patients have changes consistent with ongoing sympathetic hyperactivity. Norepinephrine-evoked pain test is used to assess sympathetically maintained pain syndromes. Our objective was to define if fibromyalgia patients have norepinephrine-evoked pain. METHODS: Prospective double blind controlled study. Participants: Twenty FM patients, and two age/sex matched control groups; 20 rheumatoid arthritis patients and 20 healthy controls. Ten micrograms of norepinephrine diluted in 0.1 ml of saline solution were injected in a forearm. The contrasting substance, 0.1 ml of saline solution alone, was injected in the opposite forearm. Maximum local pain elicited during the 5 minutes post-injection was graded on a visual analog scale (VAS). Norepinephrine-evoked pain was diagnosed when norepinephrine injection induced greater pain than placebo injection. Intensity of norepinephrine-evoked pain was calculated as the difference between norepinephrine minus placebo-induced VAS scores. RESULTS: Norepinephrine-evoked pain was seen in 80 % of FM patients (95% confidence intervals 56.3 – 94.3%), in 30 % of rheumatoid arthritis patients and in 30 % of healthy controls (95% confidence intervals 11.9 – 54.3) (p < 0.05). Intensity of norepinephrine-evoked pain was greater in FM patients (mean ± SD 2.5 ± 2.5) when compared to rheumatoid arthritis patients (0.3 ± 0.7), and healthy controls (0.3 ± 0.8) p < 0.0001. CONCLUSIONS: Fibromyalgia patients have norepinephrine-evoked pain. This finding supports the hypothesis that fibromyalgia may be a sympathetically maintained pain syndrome

A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect

Cancer cells possess aberrant proteomes that can arise by the disruption of genes involved in physiological protein degradation. Here we demonstrate the presence of promoter CpG island hypermethylation-linked inactivation of DERL3 (Derlin-3), a key gene in the endoplasmic reticulum-associated protein degradation pathway, in human tumours. The restoration of in vitro and in vivo DERL3 activity highlights the tumour suppressor features of the gene. Using the stable isotopic labelling of amino acids in cell culture workflow for differential proteome analysis, we identify SLC2A1 (glucose transporter 1, GLUT1) as a downstream target of DERL3. Most importantly, SLC2A1 overexpression mediated by DERL3 epigenetic loss contributes to the Warburg effect in the studied cells and pinpoints a subset of human tumours with greater vulnerability to drugs targeting glycolysis.Seventh Framework Programme (European Commission) (Grant HEALTH-F5-2010-258236-SYSCOL)Seventh Framework Programme (European Commission) (Grant HEALTH-F2-2011-259015-COLTHERES)Cellex FoundationOlga Torres FoundationEuropean Research Council (EPINORC Project Grant Agreement 268626)Spain. Ministerio de Economia y Competividad (MINECO Project SAF2011-22803)Institute of Health Carlos III (RTICC Grant RD12/0036/0039

The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase

Purpose: ABTL0812 is a novel first-in-class, small molecule which showed antiproliferative effect on tumor cells in phenotypic assays. Here we describe the mechanism of action of this antitumor drug, which is currently in clinical development. Experimental design: We investigated the effect of ABTL0812 on cancer cell death, proliferation, and modulation of intracellular signaling pathways, using human lung (A549) and pancreatic (MiaPaCa-2) cancer cells and tumor xenografts. To identify cellular targets, we performed in silico high-throughput screening comparing ABTL0812 chemical structure against ChEMBL15 database. Results: ABTL0812 inhibited Akt/mTORC1 axis, resulting in impaired cancer cell proliferation and autophagy-mediated cell death. In silico screening led us to identify PPARs, PPARα and PPARγ as the cellular targets of ABTL0812. We showed that ABTL0812 activates both PPAR receptors, resulting in upregulation of Tribbles-3 pseudokinase (TRIB3) gene expression. Upregulated TRIB3 binds cellular Akt, preventing its activation by upstream kinases, resulting in Akt inhibition and suppression of the Akt/mTORC1 axis. Pharmacologic inhibition of PPARα/γ or TRIB3 silencing prevented ABTL0812-induced cell death. ABTL0812 treatment induced Akt inhibition in cancer cells, tumor xenografts, and peripheral blood mononuclear cells from patients enrolled in phase I/Ib first-in-human clinical trial. Conclusions: ABTL0812 has a unique and novel mechanism of action, that defines a new and drugable cellular route that links PPARs to Akt/mTORC1 axis, where TRIB3 pseudokinase plays a central role. Activation of this route (PPARα/γ-TRIB3-Akt-mTORC1) leads to autophagy-mediated cancer cell death. Given the low toxicity and high tolerability of ABTL0812, our results support further development of ABTL0812 as a promising anticancer therapy

Morbid liver manifestations are intrinsically bound to metabolic syndrome and nutrient intake based on a machine-learning cluster analysis

Metabolic syndrome (MetS) is one of the most important medical problems around the world. Identification of patient ' s singular characteristic could help to reduce the clinical impact and facilitate individualized management. This study aimed to categorize MetS patients using phenotypical and clinical variables habitually collected during health check-ups of individuals considered to have high cardiovascular risk. The selected markers to categorize MetS participants included anthropometric variables as well as clinical data, biochemical parameters and prescribed pharmacological treatment. An exploratory factor analysis was carried out with a subsequent hierarchical cluster analysis using the z-scores from factor analysis. The first step identified three different factors. The first was determined by hypercholesterolemia and associated treatments, the second factor exhibited glycemic disorders and accompanying treatments and the third factor was characterized by hepatic enzymes. Subsequently four clusters of patients were identified, where cluster 1 was characterized by glucose disorders and treatments, cluster 2 presented mild MetS, cluster 3 presented exacerbated levels of hepatic enzymes and cluster 4 highlighted cholesterol and its associated treatments Interestingly, the liver status related cluster was characterized by higher protein consumption and cluster 4 with low polyunsaturated fatty acid intake. This research emphasized the potential clinical relevance of hepatic impairments in addition to MetS traditional characterization for precision and personalized management of MetS patients

The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper

BACKGROUND: The heterogeneity of metastatic breast cancer (MBC) necessitates novel biomarkers allowing stratification of patients for treatment selection and drug development. We propose to use the prognostic utility of circulating tumor cells (CTCs) for stratification of patients with stage IV disease. METHODS: In a retrospective, pooled analysis of individual patient data from 18 cohorts, including 2436 MBC patients, a CTC threshold of 5 cells per 7.5\u2009ml was used for stratification based on molecular subtypes, disease location, and prior treatments. Patients with 65 5 CTCs were classified as Stage IVaggressive, those with < 5 CTCs as Stage IVindolent. Survival was analyzed using Kaplan-Meier curves and the log rank test. RESULTS: For all patients, Stage IVindolent patients had longer median overall survival than those with Stage IVaggressive (36.3 months vs. 16.0 months, P\u2009<\u20090.0001) and similarly for de novo MBC patients (41.4 months Stage IVindolent vs. 18.7 months Stage IVaggressive, p\u2009<\u20090.0001). Moreover, patients with Stage IVindolent disease had significantly longer overall survival across all disease subtypes compared to the aggressive cohort: hormone receptor-positive (44 months vs. 17.3 months, P\u2009<\u20090.0001), HER2-positive (36.7 months vs. 20.4 months, P\u2009<\u20090.0001), and triple negative (23.8 months vs. 9.0 months, P\u2009<\u20090.0001). Similar results were obtained regardless of prior treatment or disease location. CONCLUSIONS: We confirm the identification of two subgroups of MBC, Stage IVindolent and Stage IVaggressive, independent of clinical and molecular variables. Thus, CTC count should be considered an important tool for staging of advanced disease and for disease stratification in prospective clinical trials

Differential body composition effects of protease inhibitors recommended for initial treatment of HIV infection: A randomized clinical trial

This article has been accepted for publication in Clinical Infectious Diseases ©2014 The Authors .Published by Oxford University Press on Clinical Infectious Disease 60.5. DOI: 10.1093/cid/ciu898Background. It is unclear whether metabolic or body composition effects may differ between protease inhibitor-based regimens recommended for initial treatment of HIV infection. Methods. ATADAR is a phase IV, open-label, multicenter randomized clinical trial. Stable antiretroviral-naive HIV-infected adults were randomly assigned to atazanavir/ritonavir 300/100 mg or darunavir/ritonavir 800/100 mg in combination with tenofovir/emtricitabine daily. Pre-defined end-points were treatment or virological failure, drug discontinuation due to adverse effects, and laboratory and body composition changes at 96 weeks. Results. At 96 weeks, 56 (62%) atazanavir/ritonavir and 62 (71%) darunavir/ritonavir patients remained free of treatment failure (estimated difference 8.2%; 95%CI -0.6 to 21.6); and 71 (79%) atazanavir/ritonavir and 75 (85%) darunavir/ritonavir patients remained free of virological failure (estimated difference 6.3%; 95%CI -0.5 to 17.6). Seven vs. five patients discontinued atazanavir/ritonavir or darunavir/ritonavir due to adverse effects. Total and HDL cholesterol similarly increased in both arms, but triglycerides increased more in atazanavir/ritonavir arm. At 96 weeks, body fat (estimated difference 2862.2 gr; 95%CI 726.7 to 4997.7; P=0.0090), limb fat (estimated difference 1403.3 gr; 95%CI 388.4 to 2418.2; P=0.0071), and subcutaneous abdominal adipose tissue (estimated difference 28.4 cm2; 95%CI 1.9 to 55.0; P=0.0362) increased more in atazanavir/ritonavir than in darunavir/ritonavir arm. Body fat changes in atazanavir/ritonavir arm were associated with higher insulin resistance. Conclusions. We found no major differences between atazanavir/ritonavir and darunavir/ritonavir in efficacy, clinically-relevant side effects, or plasma cholesterol fractions. However, atazanavir/ritonavir led to higher triglycerides and total and subcutaneous fat than darunavir/ritonavir and fat gains with atazanavir/ritonavir were associated with insulin resistanceThis is an Investigator Sponsored Research study. It was supported in part by research grants from Bristol‐Myers Squibb and Janssen‐Cilag; Instituto de Salud Carlos III (PI12/01217) and Red Temática Cooperativa de Investigación en SIDA G03/173 (RIS‐EST11), Ministerio de Ciencia e Innovación, Spain. (Registration number: NCT01274780; registry name: ATADAR; EUDRACT; 2010‐021002‐38)

Effect of a Nutritional and Behavioral Intervention on Energy-Reduced Mediterranean Diet Adherence Among Patients With Metabolic Syndrome: Interim Analysis of the PREDIMED-Plus Randomized Clinical Trial

Key PointsQuestionWhat is the effect of a nutritional and behavioral intervention focused on encouraging an energy-reduced Mediterranean diet and physical activity on the dietary pattern of participants after 12 months? FindingsIn this preliminary analysis of an ongoing randomized clinical trial involving 6874 participants, an intervention focused on encouraging an energy-reduced Mediterranean diet and promoting physical activity, compared with advice to follow an energy-unrestricted Mediterranean diet, resulted in a significant increase in a measure of diet adherence, the 17-item energy-reduced Mediterranean diet score, at 12 months (4.7 points vs 2.5 points; score range, 0-17; minimal clinically important difference, 1 point). MeaningA nutritional and behavioral intervention focused on encouraging an energy-reduced Mediterranean diet and physical activity led to a significant improvement in a measure of diet adherence at 12 months. Further evaluation of the effects on long-term cardiovascular and other health outcomes is needed. ImportanceHigh-quality dietary patterns may help prevent chronic disease, but limited data exist from randomized trials about the effects of nutritional and behavioral interventions on dietary changes. ObjectiveTo assess the effect of a nutritional and physical activity education program on dietary quality. Design, Setting, and ParticipantsPreliminary exploratory interim analysis of an ongoing randomized trial. In 23 research centers in Spain, 6874 men and women aged 55 to 75 years with metabolic syndrome and no cardiovascular disease were enrolled in the trial between September 2013 and December 2016, with final data collection in March 2019. InterventionsParticipants were randomized to an intervention group that encouraged an energy-reduced Mediterranean diet, promoted physical activity, and provided behavioral support (n=3406) or to a control group that encouraged an energy-unrestricted Mediterranean diet (n=3468). All participants received allotments of extra-virgin olive oil (1 L/mo) and nuts (125 g/mo) for free. Main Outcomes and MeasuresThe primary outcome was 12-month change in adherence based on the energy-reduced Mediterranean diet (er-MedDiet) score (range, 0-17; higher scores indicate greater adherence; minimal clinically important difference, 1 point). ResultsAmong 6874 randomized participants (mean [SD] age, 65.0 [4.9] years; 3406 [52%] men), 6583 (96%) completed the 12-month follow-up and were included in the main analysis. The mean (SD) er-MedDiet score was 8.5 (2.6) at baseline and 13.2 (2.7) at 12 months in the intervention group (increase, 4.7 [95% CI, 4.6-4.8]) and 8.6 (2.7) at baseline and 11.1 (2.8) at 12 months in the control group (increase, 2.5 [95% CI, 2.3-2.6]) (between-group difference, 2.2 [95% CI, 2.1-2.4]; P<.001). Conclusions and RelevanceIn this preliminary analysis of an ongoing trial, an intervention that encouraged an energy-reduced Mediterranean diet and physical activity, compared with advice to follow an energy-unrestricted Mediterranean diet, resulted in a significantly greater increase in diet adherence after 12 months. Further evaluation of long-term cardiovascular effects is needed. Trial Registrationisrctn.com Identifier: ISRCTN89898870 This preliminary exploratory analysis of the ongoing PREDIMED-Plus randomized trial reports dietary adherence among Spanish community-dwelling participants with metabolic syndrome randomized to an energy-reduced Mediterranean diet, physical activity, and behavioral support vs an energy-unrestricted Mediterranean diet alone

Integrative development of a short screening questionnaire of highly processed food consumption (sQ-HPF)

Background: Recent lifestyle changes include increased consumption of highly processed foods (HPF), which has been associated with an increased risk of non-communicable diseases (NCDs). However, nutritional information relies on the estimation of HPF consumption from food-frequency questionnaires (FFQ) that are not explicitly developed for this purpose. We aimed to develop a short screening questionnaire of HPF consumption (sQ-HPF) that integrates criteria from the existing food classification systems. Methods: Data from 4400 participants (48.1% female and 51.9% male, 64.9 +/- 4.9 years) of the Spanish PREDIMED-Plus (PREvention with MEDiterranean DIet) trial were used for this analysis. Items from the FFQ were classified according to four main food processing-based classification systems (NOVA, IARC, IFIC and UNC). Participants were classified into tertiles of HPF consumption according to each system. Using binomial logistic regression, food groups associated with agreement in the highest tertile for at least two classification systems were chosen as items for the questionnaire. ROC analysis was used to determine cut-off points for the frequency of consumption of each item, from which a score was calculated. Internal consistency of the questionnaire was assessed through exploratory factor analysis (EFA) and Cronbach's analysis, and agreement with the four classifications was assessed with weighted kappa coefficients. Results: Regression analysis identified 14 food groups (items) associated with high HPF consumption for at least two classification systems. EFA showed that items were representative contributors of a single underlying factor, the HPF dietary pattern (factor loadings around 0.2). We constructed a questionnaire asking about the frequency of consumption of those items. The threshold frequency of consumption was selected using ROC analysis. Comparison of the four classification systems and the sQ-HPF showed a fair to high agreement. Significant changes in lifestyle characteristics were detected across tertiles of the sQ-HPF score. Longitudinal changes in HPF consumption were also detected by the sQ-HPF, concordantly with existing classification systems. Conclusions: We developed a practical tool to measure HPF consumption, the sQ-HPF. This may be a valuable instrument to study its relationship with NCDs