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The aim of this study is to evaluate adsorption kinetics and isotherms of synthetic orange dye onto organoclay prepared from commercial sodium bentonite (Fluidgel called) from aqueous solutions. The effects of pH, contact time, initial dye concentrations, dosage clay and temperature were investigated experimentally. Commercial sodium bentonite was modified by using quaternary ammonium cations (hexadecyltrimethylammonium bromide) as a modifying agent. The characterization of commercial Fluidgel and modified clay (organophifilic Fluidgel) was accomplished by using XRD, TGA, BET and SEM/EDX techniques. The optimum pH value for the adsorption experiments was found to be next of 6 (pH not adjusted) and all the experiments were carried out at this pH value. The pseudo-first-order kinetic model agrees very well with the experimental results. Equilibrium data were also fitted to the Freundlich isotherm model in the studied temperature range for low initial concentrations of synthetic orange. The results indicate that organoclay is a suitable adsorbent for the adsorption of dyes.

This study aimed to evaluate the adsorption of toluene in two forms of sodium smectite national clays called Fluidgel and produced in northeastern Brazil: commercial and chemically modified with quaternary ammonium salt (hexadecyltrimethylammonium bromide) by the process of organophilization. The commercial Fluidgel and organoclay were characterized by a physical-chemical study evaluating their adsorptive properties and quality from the process of organophilization on the morphology and chemical composition, in relation to their affinity for volatile organic compounds in processes such as BTX adsorption. Toluene adsorption onto clays, commercial and organoclay, with particle diameter of 0.55 mm was carried out in batch system at room temperature with constant stirring. The adsorption study was conducted at initial toluene concentration of 100 ppm, 10 g of clay per liter of effluent and at initial pH of about 6. For kinetic data fitting, pseudo-first-order, pseudo-second-order and intraparticle diffusion models were applied. The results obtained with the characterization analyses showed the efficiency of organophilization process. The adsorption kinetics process showed that the kinetic model of pseudo- second-order was the best fit to experimental data. The adsorption study presented a percentage removal of toluene from about 96 % to equilibrium time of 180 min.

In view of the need to obtain genetically superior eucalyptus clones that promote productivity coupled with quality, we used multivariate statistical techniques for the selection and evaluation of Eucalyptus spp. clones for wood production. The experiments were carried out in three environments in the districts of Eldorado do Sul, Butiá and São Gabriel. A clone of the commercial species Eucalyptus saligna was used as a common control in all trials. A total of 84 eucalyptus clones were used belonging to the breeding program in Rio Grande do Sul, Brazil, in a randomized block design, with 20 replicates and one plant per plot, spacing 3.50 x 2.14 m. Silvicultural practices were performed according to the particularities required by each environment. The clones were evaluated at 36 months for diameter at breast height, total height, total individual volume with bark and survival of clones. The datawere submitted to a joint analysis of variance, and the significance was interpreted by the F test at 5% probability. Interaction tests were performed and then multivariate models were used. Selection of clones from their values of genetic divergence and heterogeneity in relation to the others can be used to increase variability in breeding populations. Improvement strategies such as Intrapopulation Recurrent Selection can be "fed" from selections made based on these parameters, but also focusing on increasing productivity and improving wood technology. There wasa great difference in behavior of the clones for each environment, demonstrating the influence of genotype x environment interactions, which can be evaluated later in amplified clonal tests or in the observation plantings of these clones; these will serve for the future indication of genotypes for commercial plantations. [ABSTRACT FROM AUTHOR]

Mercury is a highly hazardous water contaminant; both organic and inorganic forms are cumulatively and extremely toxic. In this context, this study describes the application of TiO2 -based systems modified with 5, 8, 10 and 15 wt% Fe using the impregnation method for the photocatalytic reduction of Hg2+. Characterization of TiO2 and synthesized materials was performed by using Brunauer, Emmett and Taller area, pore diameter and pore volume, scanning electron microscopy, point zero charge, X-ray diffraction (XRD), Fourier transform infrared spectroscopy, photoacoustic and Mössbauer spectroscopy. The photocatalytic reduction of Hg2+ was performed in batch stirred tank reactor and compound parabolic collector solar photoreactor, in the presence of catalysts, under four different reaction conditions. The process of heterogeneous photocatalysis was studied in the treatment of synthetic wastewater containing mercury chloride (HgCl2 ) in different reaction conditions. In particular, the influence of oxygen and formic acid was analyzed. The results showed that an addition of 8% to the iron weight improved the performance of the photocatalytic titania in the reduction of Hg2+ (artificial radiation). In the presence of this catalyst, and reaction medium containing only mercuric chloride in an aqueous solution containing oxygen, Hg2+ was 100% reduced, after 3 h of reaction. However, under solar radiation, the reduction of Hg2+ obtained was 67%. [ABSTRACT FROM AUTHOR]

Several studies have focused on the removal and recovery of precious metal ions from industrial wastewater due to their environmental and economic importance. Adsorption on bentonite clays has been shown to possess a high removal potential for several metal ions. We herein investigated the dynamic adsorption of silver using a fixed-bed column and a calcined bentonite clay called Verde-lodo as an adsorbent. A fluid dynamic study was performed to evaluate the adsorption system's metal-ion removal capacity (qu and qt), the mass transfer zone and the percentage of total removal according to different effluent's flow. Adsorption-desorption cycles were carried out using nitric acid as an eluent to evaluate the useful lifetime of the column. The breakthrough curves were fitted to the Bohart-Adams model (quasichemical). Moreover, the zeta potential was analyzed to explain the difference between the removal capacity obtained for the static and dynamic systems. [ABSTRACT FROM AUTHOR]

Abstract: Several benzofuran derivatives linked to a 3-indoletetrahydropyridine through an alkyl chain were prepared and evaluated for serotonin transporter and 5-HT1A receptor affinities. Their design, synthesis and structure–activity relationships are described. [Copyright &y& Elsevier]

Le forum départemental d'échange d'informations en pathologies infectieuses « INFMED » par messagerie électronique a été créé en 2008 afin d'améliorer la circulation de l'information parmi les médecins du département. Une première analyse de l'activité du forum en 2015 a montré une activité croissante, une satisfaction globale des utilisateurs, avec comme avantage souligné, entre autres, le renforcement du lien entre les professionnels. L'objectif de notre étude était d'analyser l'activité du forum depuis l'épidémie de SARS-CoV-2 pour en évaluer son impact dans la gestion de la crise sanitaire. Les statistiques descriptives d'activité du forum ont été réalisées à partir de l'outil d'inscription Infmed. En complément, une enquête a été faite pendant la semaine 24 auprès des utilisateurs, via un questionnaire en ligne. L'analyse du nombre de messages échangés permet de constater une augmentation progressive depuis la création du forum avec successivement en 2010, 2015 et 2019 165, 678 et 1077 messages par an. Sur le 1er premier semestre 2020, 1858 messages ont été échangés, avec 2 pics d'activité : le 17 mars, jour du confinement, et le 11 mai, jour du déconfinement. Le nombre d'abonnés est passé de 288 en février 2020 à 510 en mai 2020, avec une nette prédominance de médecins généralistes (79 %) travaillant dans le département (84,9 %). Cinquante-sept pour cent des abonnés ont répondu au questionnaire. Trente-cinq pour cent se sont inscrits dans le contexte de crise sanitaire. La qualité des informations échangées était jugée à 8/10 (IQR : 8–9) en médiane, versus 6/10 (IQR : 5–7) pour les informations reçues via d'autres sources. L'aide à la prise en charge des patients en période épidémique a été cotée à 9/10 (IQR : 8–10) en médiane par les utilisateurs, favorisée par la rapidité des informations transmises et la réactivité des réponses aux questions posées. Les échanges ont renforcé le lien avec les infectiologues pour 89 % des participants, avec les pédiatres pour 56,3 %, et avec l'ARS pour 45 % d'entre eux. Soixante-deux pour cent ont jugé le forum utile pour le renforcement du lien ville–hôpital, noté à 8/10 (IQR : 7–9) en médiane au cours de la crise sanitaire. La grande majorité des utilisateurs (98,6 %) pense rester active dans la vie du forum après la fin de l'épidémie de COVID-19. Cet outil d'échange à l'échelle départementale entre des professionnels de compétences complémentaires a répondu aux attentes des différents acteurs du système de santé pour l'amélioration des pratiques et l'implication de chacun dans la gestion d'une crise sanitaire. Les discussions sur les recommandations des agences de santé et des sociétés savantes ont favorisé l'application de celles-ci en tenant compte des situations locales, permettant ainsi de consolider le lien ville–hôpital. [ABSTRACT FROM AUTHOR]

Individual well-being is generally thought of from the perspective of the risk factors which might compromise it. Assuming that positive dimensions of well-being are also worth considering, VanderWeele and Wȩziak-Białowolska et al. developed and tested the Flourish Index (FI) and the Secure Flourish Index (SFI). These 10- and 12-item questionnaires, respectively, measure 5 and 6 dimensions of human flourishing. This article presents the translation of these indexes into French (as FI–F and SFI–F) and the assessment of their psychometric properties on a sample of 2,376 French-speaking respondents. The validity and reliability indicators used by Wȩziak-Białowolska et al. were calculated for our French indexes and found to be very close to theirs. Item groupings were confirmed using correlation and factor analyses. The hierarchical structure of both French indexes matched the English indexes' second-order and bi-factor model analyses. Reliability and construct validity were good. The brief time required to complete the FI–F or SFI–F and their excellent psychometric properties make them very promising tools for research on the general well-being of Francophone populations. [ABSTRACT FROM AUTHOR]

Let A be a finite commutative ring with identity. A subset H of the A-module An is called an R-short covering of An if every element of this module can be written as a sum of a multiple of an element in H and an A-linear combination with at most R canonical vectors. Let c(A,n,R) be the minimum cardinality of an R-short covering of An. In this work, the numbers c(A,n,0)c(A,n,0) are computed when A is a direct product of chain rings (extending previous results by Yildiz et al.) and when A is a finite local ring such that D(A)²={0}, where D(A) denotes the set of all zero divisors of A. In order to obtain these results, we develop a method based on action of group, the min-max principle and pairwise weakly linearly independent sets (a concept introduced in this article). A structural connection between classical covering and short covering is described too. Thus a combination of previous results is applied to improve known bounds on short coverings for several values. [ABSTRACT FROM AUTHOR]

La leptospirose est responsable chaque année de près de 60 000 décès dans le monde. La transmission a le plus souvent lieu par contact indirect avec de l'eau ou un sol contaminé par l'urine d'un animal infecté. En France, la majorité des cas surviennent dans les départements d'outre-mer. Par ailleurs, dans les zones tempérées, la leptospirose est rapportée après certains loisirs aquatiques ; de ce fait, l'augmentation de la pratique des sports d'eaux vives en métropole, notamment le canyoning , pourrait conduire à une augmentation du nombre de cas. Nous avons donc cherché à connaître dans quelle mesure les cas de leptospirose survenus entre 2010 et 2018 dans 2 départements alpins étaient liés au canyoning. Nous avons mené une étude rétrospective portant sur tous les cas de leptospirose hospitalisés entre le 1er janvier 2010 et le 31 décembre 2018 dans les 2 hôpitaux référents de 2 départements alpins. Les patients étaient inclus lorsque la sérologie ou la PCR leptospirose dans le sang, les urines ou le LCR était positive, ou lorsque le tableau était très évocateur, même en l'absence de confirmation biologique. Nous avons recueilli des données concernant les symptômes de la maladie, sa gravité, les modes de contamination présumés, ainsi que des paramètres biologiques. Cinquante-quatre cas de leptospirose ont été inclus, dont deux sans confirmation biologique. Seize patients (29 %) ont été admis en services de soins continus ou de réanimation ; l'un d'eux est décédé. Dix-sept (31 %) patients présentaient une atteinte rénale sévère (clairance de la créatinine inférieure à 30 mL/minute ou nécessité de dialyse) ; 21 (38 %) avaient des transaminases à plus de 3 fois la normale et 25 (46 %) une cholestase ictérique. Vingt-huit (52 %) patients rapportaient un contact avec de l'eau douce avant l'apparition des symptômes, et 11 (20,4 %) d'entre eux avaient pratiqué du canyoning. Dix de ces 11 cas liés au canyoning étaient survenus dans l'un des deux départements. Notre série conforte l'hypothèse que le canyoning est un mode émergent d'acquisition de la leptospirose dans nos départements alpins. Il n'y a à notre connaissance pas de publication rapportant ce lien entre leptospirose et pratique du canyoning en France métropolitaine. La connaissance de ce lien entre leptospirose et canyoning a permis de mettre en place certaines mesures de prévention dans la région. Un arrêté municipal a ainsi interdit depuis mai 2018 la pratique d'activités de loisirs aquatiques dans un canyon où 6 cas de leptospirose étaient survenus parmi 20 jeunes hommes ayant participé à une journée de canyoning. Par ailleurs, les pratiquants du canyoning devraient être informés du risque de leptospirose, qui peut être limité par le port de combinaison en néoprène et la vaccination, et de la nécessité d'une consultation rapide en cas d'apparition de symptômes évocateurs de cette infection potentiellement grave. [ABSTRACT FROM AUTHOR]

Background: As early as 1995, the Institute of Medicine suggested that nurses were inadequately prepared for and educated about climate change and its health consequences. The aim of this systematic review is to identify the most reliable, robust, and valid instruments for measuring nurses' knowledge and awareness of climate change and climate-associated diseases., Methods: Included studies were appraised using the Mixed-Methods Appraisal Tool and the Appraisal tool for Cross-Sectional Studies. The psychometrics and clinimetrics of the instruments were evaluated using the COSMIN Risk of Bias checklist and the COSMIN methodology for assessing content validity., Results: Medline, PubMed, Embase, CINAHL Ebesco, Cochrane Library Wiley, Web of Science Core Collection, Trip Database, JBI OVID SP, GreenFILE EBSCO, Google Scholar, ProQuest Dissertations and Theses Global, and DART-EU were consulted. The 14 studies retained identified eight different instruments evaluating attitudes, perceptions, environmental awareness, environmental sensitivity, environmental attitudes, behaviours, motivation, concern, optimism, and experience. This review is reported according to the PRISMA guidelines., Conclusions: The New Ecological Paradigm Scale (NEPS) and the Climate, Health, and Nursing Tool (CHANT) are the most reliable, robust, and valid instruments for measuring nurses' knowledge and awareness of climate change and climate-associated diseases.

Background: Climate change is a health emergency. Each year, it is estimated to cost more than 230 million years of life expectancy, with 4-9 million premature deaths associated with air pollution, and 9 million excess deaths due to non-optimal temperatures, representing 7% more temperature-related deaths since 2015 and 66% more since 2000., Objective: Identify and evaluate the reliability, fidelity, and validity of instruments measuring nurses' knowledge and awareness of climate change and climate-associated diseases., Methods: A systematic literature review will retrieve and assess studies examining instruments measuring nurses' knowledge and awareness of climate change and climate-associated diseases. Using predefined search terms for nurses, climate change, literacy and scales or tools, we will search for published articles recorded in the following electronic databases, with no language or date restrictions, from their inception until 31 October 2023: Medline Ovid SP (from 1946), PubMed (NOT Medline[sb], from 1996), Embase.com (from 1947), CINAHL Ebesco (from 1937), the Cochrane Library Wiley (from 1992), Web of Science Core Collection (from 1900), the Trip Database (from 1997), JBI OVID SP (from 1998), and the GreenFILE EBSCO. We will also hand-search relevant articles' bibliographies and search for unpublished studies using Google Scholar, ProQuest Dissertations and Theses Global, and DART-EUrope.eu. This will be completed by exploring the gray literature in OpenGrey and the Grey Literature Report, from inception until 31 October 2023, in collaboration with a librarian. Twelve bibliographic databases will be searched for publications up to 31 October 2023. The papers selected will be assessed for their quality., Results: The electronic database searches were completed in May 2023. Retrieved articles are being screened, and the study will be completed by October 2023. After removing duplicates, our search strategy has retrieved 3449 references., Conclusions: This systematic review will provide specific knowledge about instruments to measure nurses' knowledge, awareness, motivation, attitudes, behaviors, beliefs, skills, and competencies regarding climate change and climate-associated diseases.

Current data and scientific predictions about the consequences of climate change are accurate in suggesting disaster. Since 2019, climate change has become a threat to human health, and major consequences on health and health systems are already observed. Climate change is a central concern for the nursing discipline, even though nursing theorists' understanding of the environment has led to problematic gaps that impact the current context. Today, nursing discipline is facing new challenges. Nurses are strategically placed to respond to the impacts of climate change through their practice, research, and training in developing, implementing, and sustaining innovation towards climate change mitigation and adaptation. It is urgent for them to adapt their practice to this reality to become agents of change.

KRAS G12C is one of the most common mutations detected in non-small cell lung cancer (NSCLC) patients, and it is a marker of poor prognosis. The first FDA-approved KRAS G12C inhibitors, sotorasib and adagrasib, have been an enormous breakthrough for patients with KRAS G12C mutant NSCLC; however, resistance to therapy is emerging. The transcriptional coactivators YAP1/TAZ and the family of transcription factors TEAD1-4 are the downstream effectors of the Hippo pathway and regulate essential cellular processes such as cell proliferation and cell survival. YAP1/TAZ-TEAD activity has further been implicated as a mechanism of resistance to targeted therapies. Here, we investigate the effect of combining TEAD inhibitors with KRAS G12C inhibitors in KRAS G12C mutant NSCLC tumor models. We show that TEAD inhibitors, while being inactive as single agents in KRAS G12C -driven NSCLC cells, enhance KRAS G12C inhibitor-mediated anti-tumor efficacy in vitro and in vivo. Mechanistically, the dual inhibition of KRAS G12C and TEAD results in the downregulation of MYC and E2F signatures and in the alteration of the G2/M checkpoint, converging in an increase in G1 and a decrease in G2/M cell cycle phases. Our data suggest that the co-inhibition of KRAS G12C and TEAD leads to a specific dual cell cycle arrest in KRAS G12C NSCLC cells.

Background: Using evidence-based practice (EBP) improves the implementation of safe, high-quality healthcare for patients, reduces avoidable costs, and plays a crucial role in bridging knowledge-action gaps and reducing health inequities. EBP combines the best available evidence in the relevant literature with patient preferences and values and healthcare professionals' (HCPs) expertise., Methods: Systematic searches of ten bibliographic databases, unpublished works, and the Grey Literature Report sought studies published up to 30 September 2022., Results: The 15 studies retained involved 2712 nurses. Three types of effective educational interventions were identified: (1) multifaceted educational strategies incorporating mentoring and tutoring; (2) single educational strategies, often delivered online; and (3) multifaceted educational strategies using the five steps of EBP. Eleven primary outcomes (EBP beliefs, EBP self-efficacy, perceived EBP implementation, EBP competencies, EBP knowledge, EBP skills, EBP attitudes, EBP behaviors, EBP desire, EBP practice, and perceptions of organizational culture and readiness) were assessed using 13 qualitative and quantitative instruments., Conclusions: Ensuring the successful implementation of EBP requires effective educational strategies. Computer-based learning seems the most cost-effective and efficient strategy, when considering caregivers' characteristics, the clinical field, and educational interventions across the pre-, peri-, and post-implementation processes.

Malignant pleural mesothelioma, a tumor arising from the membrane covering the lungs and the inner side of the ribs, is a cancer in which genetic alterations of genes encoding proteins that act on or are part of the Hippo-YAP1 signaling pathway are frequent. Dysfunctional Hippo signaling may result in aberrant activation of the transcriptional coactivator protein YAP1, which binds to and activates transcription factors of the TEAD family. Recent studies have associated elevated YAP1 protein activity with a poor prognosis of malignant mesothelioma and its resistance to current therapies, but its role in tumor maintenance is unclear. In this study, we investigate the dependence of malignant mesothelioma on YAP1 signaling to maintain fully established tumors in vivo. We show that downregulation of YAP1 in a dysfunctional Hippo genetic background results in the inhibition of YAP1/TEAD-dependent gene expression, the induction of apoptosis, and the inhibition of tumor cell growth in vitro. The conditional downregulation of YAP1 in established tumor xenografts leads to the inhibition of YAP1-dependent gene transcription and eventually tumor regression. This effect is only seen in the YAP1-activated MSTO-211H mesothelioma xenograft model, but not in the Hippo-independent HCT116 colon cancer xenograft model. Our data demonstrate that, in the context of a Hippo pathway mutated background, YAP1 activity alone is enough to maintain the growth of established tumors in vivo, thus validating the concept of inhibiting the activated YAP1-TEAD complex for the treatment of malignant pleural mesothelioma patients., (© 2022. The Author(s).)

The parasitism by Trichomonas vaginalis is complex and in part is mediated by cytoadherence accomplished via five surface proteins named adhesins and a glycoconjugate called lipophosphoglycan (TvLPG). In this study, we evaluated the ability of T. vaginalis isolates to adhere to cells, plastic (polystyrene microplates), intrauterine device (IUD), and vaginal ring. Of 32 T. vaginalis isolates, 4 (12.5%) were strong adherent. The T. vaginalis isolates TV-LACM6 and TV-LACM14 (strong polystyrene-adherent) were also able to adhere to IUD and vaginal ring. Following chemical treatments, results demonstrated that the T. vaginalis components, lipophosphoglycan, cytoskeletal proteins, and surface molecules, were involved in both adherence to polystyrene and cytoadherence. The gene expression level from four adhesion proteins was highest in trophozoites adhered to cells than trophozoites adhered to the abiotic surface (polystyrene microplate). Our data indicate the major involvement of TvLPG in adherence to polystyrene, and that adhesins are important for cytoadherence. Furthermore, to our knowledge, this is the first report showing the T. vaginalis adherence to contraceptive devices, reaffirming its importance as pathogen among women in reproductive age.

It is unclear whether immunosuppression is a risk factor for herpes encephalitis. Herein, we describe a rare case of herpes simplex virus type 2 encephalitis in a patient treated with low-dose methotrexate for HLA-B27-associated spondyloarthritis. The patient was successfully treated with acyclovir but presented sequelae of encephalitis. Here we discuss the possible role of low-dose methotrexate therapy as a risk factor of neurological herpes reactivation and severe disease. The host-related and viral risk factors are also addressed.

Trichomonas vaginalis is the aethiologic agent of trichomoniasis, the most common non-viral sexually transmitted disease in the world. The purinergic signaling pathway is mediated by extracellular nucleotides and nucleosides that are involved in many biological effects as neurotransmission, immunomodulation and inflammation. Extracellular nucleotides can be hydrolyzed by a family of enzymes known as ectonucleotidases including the ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) family which hydrolyses nucleosides triphosphate and diphosphate as preferential substrates and ecto-5'-nucleotidase which catalyzes the conversion of monophosphates into nucleosides. In T. vaginalis the E-NTPDase and ecto-5'-nucleotidase activities upon adenine nucleotides have already been characterized in intact trophozoites but little is known concerning guanine nucleotides and nucleoside. These enzymes may exert a crucial role on nucleoside generation, providing the purine sources for the synthesis de novo of these essential nutrients, sustaining parasite growth and survival. In this study, we investigated the hydrolysis profile of guanine-related nucleotides and nucleoside in intact trophozoites from long-term-grown and fresh clinical isolates of T. vaginalis. Knowing that guanine nucleotides are also substrates for T. vaginalis ectoenzymes, we evaluated the profile of nucleotides consumption and guanosine uptake in trophozoites submitted to a serum limitation condition. Results show that guanine nucleotides (GTP, GDP, GMP) were substrates for T. vaginalis ectonucleotidases, with expected kinetic parameters for this enzyme family. Different T. vaginalis isolates (two from the ATCC and nine fresh clinical isolates) presented a heterogeneous hydrolysis profile. The serum culture condition increased E-NTPDase and ecto-5'-nucleotidase activities with high consumption of extracellular GTP generating enhanced GDP, GMP and guanosine levels as demonstrated by HPLC, with final accumulation of the nucleoside. The transcript levels of the five TvNTPDases gene sequences were analyzed by qRT-PCR and the highest gene expressions were found for TvNTPDase 2 and 4. The extracellular guanosine uptake was observed as (13C)GTP nucleotide into parasite DNA and it was lower than that observed for adenosine, labeled as (13C)ATP. These findings indicate the T. vaginalis preference for adenosine uptake and the accumulation of guanosine in the extracellular milieu, corroborating with HPLC data. Our data demonstrate, for the first time, the cascade of guanine nucleotides in T. vaginalis and open possibilities on the study of guanine-related purines other than the classical intracellular activity of G proteins for signal transduction., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Trichomonas vaginalis is a protozoan that parasitizes the human urogenital tract causing trichomoniasis, the most common non-viral sexually transmitted disease. The parasite has unique genomic characteristics such as a large genome size and expanded gene families. Ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) is an enzyme responsible for hydrolyzing nucleoside tri- and diphosphates and has already been biochemically characterized in T. vaginalis. Considering the important role of this enzyme in the production of extracellular adenosine for parasite uptake, we evaluated the gene expression of five putative NTPDases in T. vaginalis. We showed that all five putative TvNTPDase genes (TvNTPDase1-5) were expressed by both fresh clinical and long-term grown isolates. The amino acid alignment predicted the presence of the five crucial apyrase conserved regions, transmembrane domains, signal peptides, phosphorylation and catalytic sites. Moreover, a phylogenetic analysis showed that TvNTPDase sequences make up a clade with NTPDases intracellularly located. Biochemical NTPDase activity (ATP and ADP hydrolysis) is responsive to the serum-restrictive conditions and the gene expression of TvNTPDases was mostly increased, mainly TvNTPDase2 and TvNTPDase4, although there was not a clear pattern of expression among them. In summary, the present report demonstrates the gene expression patterns of predicted NTPDases in T. vaginalis., (© FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Trichomonas vaginalis is the etiologic agent of trichomonosis, the most common non-viral sexually transmitted disease worldwide. This infection is associated with several health consequences, including cervical and prostate cancers and HIV acquisition. Gene expression analysis has been facilitated because of available genome sequences and large-scale transcriptomes in T. vaginalis, particularly using quantitative real-time polymerase chain reaction (qRT-PCR), one of the most used methods for molecular studies. Reference genes for normalization are crucial to ensure the accuracy of this method. However, to the best of our knowledge, a systematic validation of reference genes has not been performed for T. vaginalis. In this study, the transcripts of nine candidate reference genes were quantified using qRT-PCR under different cultivation conditions, and the stability of these genes was compared using the geNorm and NormFinder algorithms. The most stable reference genes were α-tubulin, actin and DNATopII, and, conversely, the widely used T. vaginalis reference genes GAPDH and β-tubulin were less stable. The PFOR gene was used to validate the reliability of the use of these candidate reference genes. As expected, the PFOR gene was upregulated when the trophozoites were cultivated with ferrous ammonium sulfate when the DNATopII, α-tubulin and actin genes were used as normalizing gene. By contrast, the PFOR gene was downregulated when the GAPDH gene was used as an internal control, leading to misinterpretation of the data. These results provide an important starting point for reference gene selection and gene expression analysis with qRT-PCR studies of T. vaginalis.

Trichomonas vaginalis is the etiological agent of trichomoniasis, the most common non-viral sexually transmitted disease (STD) in world, with 276.4 million new cases each year. T. vaginalis can be naturally infected with Mycoplasma hominis and Trichomonasvirus species. This study aimed to evaluate the prevalence of T. vaginalis infected with four distinct T. vaginalis viruses (TVVs) and M. hominis among isolates from patients in Porto Alegre city, South Brazil. An additional goal of this study was to investigate whether there is association between metronidazole resistance and the presence of M. hominis during TVV infection. The RNA expression level of the pyruvate ferredoxin oxidoreductase (PFOR) gene was also evaluated among metronidazole-resistant and metronidazole-sensitive T. vaginalis isolates. A total of 530 urine samples were evaluated, and 5.7% samples were positive for T. vaginalis infection. Among them, 4.51% were isolated from female patients and 1.12% were from male patients. Remarkably, the prevalence rates of M. hominis and TVV-positive T. vaginalis isolates were 56.7% and 90%, respectively. Most of the T. vaginalis isolates were metronidazole-sensitive (86.7%), and only four isolates (13.3%) were resistant. There is no statistically significant association between infection by M. hominis and infection by TVVs. Our results refute the hypothesis that the presence of the M. hominis and TVVs is enough to confer metronidazole resistance to T. vaginalis isolates. Additionally, the role of PFOR RNA expression levels in metronidazole resistance as the main mechanism of resistance to metronidazole could not be established. This study is the first report of the T. vaginalis infection by M. hominis and TVVs in a large collection of isolates from South Brazil., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Blocking the oncoprotein murine double minute 2 (MDM2)-p53 protein-protein interaction has long been considered to offer a broad cancer therapeutic strategy, despite the potential risks of selecting tumors harboring p53 mutations that escape MDM2 control. In this study, we report a novel small-molecule inhibitor of the MDM2-p53 interaction, SAR405838 (MI-77301), that has been advanced into phase I clinical trials. SAR405838 binds to MDM2 with K(i) = 0.88 nmol/L and has high specificity over other proteins. A cocrystal structure of the SAR405838:MDM2 complex shows that, in addition to mimicking three key p53 amino acid residues, the inhibitor captures additional interactions not observed in the p53-MDM2 complex and induces refolding of the short, unstructured MDM2 N-terminal region to achieve its high affinity. SAR405838 effectively activates wild-type p53 in vitro and in xenograft tumor tissue of leukemia and solid tumors, leading to p53-dependent cell-cycle arrest and/or apoptosis. At well-tolerated dose schedules, SAR405838 achieves either durable tumor regression or complete tumor growth inhibition in mouse xenograft models of SJSA-1 osteosarcoma, RS4;11 acute leukemia, LNCaP prostate cancer, and HCT-116 colon cancer. Remarkably, a single oral dose of SAR405838 is sufficient to achieve complete tumor regression in the SJSA-1 model. Mechanistically, robust transcriptional upregulation of PUMA induced by SAR405838 results in strong apoptosis in tumor tissue, leading to complete tumor regression. Our findings provide a preclinical basis upon which to evaluate SAR405838 as a therapeutic agent in patients whose tumors retain wild-type p53., (©2014 American Association for Cancer Research.)

Introduction: The purpose of the present study was (1) to test the accuracy of a small-volume cone-beam computed tomographic (CBCT) device in detecting horizontal root fractures (HRFs) in teeth with and without an intracanal metallic post (IMP) and (2) to investigate the use of 2 different acquisition protocols of a CBCT device for HRF diagnosis., Methods: Forty endodontically treated teeth with and without an IMP were examined using PreXion 3D CBCT scanner (Terarecon, San Mateo, CA) with a 5-cm high and 5-cm diameter cylinder at 0.10-mm voxel reconstruction. Two observers analyzed the samples to determine the presence and location of HRFs., Results: Sensitivity values ranged from 0.40-0.80. The most favorable results were found for the samples with no IMP observed using the protocol of a higher number of x-ray projections (0.70-0.80). Accuracy in the groups with an IMP ranged from 75%-90% in the 1024 x-ray projection protocol (HI-HI group) versus 70%-85% for the same samples examined in the 512 x-ray projection protocol (HI-STD group). Intraobserver agreement ranged from relevant to perfect concordance for both protocols (HI-HI = Kappa: 0.60-1.00 and HI-STD = Kappa: 0.55-0.89). Interobserver agreement ranged from moderate to perfect concordance for both protocols (HI-HI = Kappa: 0.79-0.89 and HI-STD = Kappa: 0.42-0.76)., Conclusions: Even though there are statistically significant differences for the protocol with the higher number of x-ray projections, we found high accuracy, sensitivity, sensibility, and intra- and interobserver agreement in detecting HRFs for both Prexion 3D protocols., (Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

In Brazil, the first genetically modified (GM) crop was released in 1998, and it is estimated that 84, 78, and 50% of crop areas containing soybean, corn, and cotton, respectively, were transgenic in 2012. This intense and rapid adoption rate confirms that the choice to use technology has been the main factor in developing national agriculture. Thus, this review focuses on understanding these dynamics in the context of farmers, trade relations, and legislation. To accomplish this goal, a survey was conducted using the database of the National Cultivar Registry and the National Service for Plant Variety Protection of the Ministry of Agriculture, Livestock and Supply [Ministério da Agricultura, Pecuária e Abastecimento (MAPA)] between 1998 and October 13, 2013. To date, 36 events have been released: five for soybeans, 18 for corn, 12 for cotton, and one for beans. From these events, 1395 cultivars have been developed and registered: 582 for soybean, 783 for corn and 30 for cotton. Monsanto owns 73.05% of the technologies used to develop these cultivars, while the Dow AgroScience - DuPont partnership and Syngenta have 16.34 and 4.37% ownership, respectively. Thus, the provision of transgenic seeds by these companies is an oligopoly supported by legislation. Moreover, there has been a rapid replacement of conventional crops by GM crops, whose technologies belong almost exclusively to four multinational companies, with the major ownership by Monsanto. These results reflect a warning to the government of the increased dependence on multinational corporations for key agricultural commodities.

Trichomonas vaginalis is the causative agent of trichomonosis, the most common non-viral sexually transmitted disease. Infection with this protozoan may have serious consequences, especially for women. Currently, 5-nitroimidazole drugs are the treatment of choice for trichomonosis, but the emergence of resistance has limited the effectiveness of this therapy. In this context, this study aimed to evaluate the anti-T. vaginalis activity of marine-associated fungi found in the South Brazilian Coast. A total of 42 marine-associated fungal species (126 filtrate samples) isolated from 39 different marine organisms, mainly sponges, were selected to be screened against T. vaginalis. Of these, two filtrate samples from Hypocrea lixii F02 and Penicillium citrinum F40 showed significant growth-inhibitory activity (up to 100%) against ATCC 30236 and fresh clinical isolates, including a metronidazole-resistant isolate. Minimum inhibitory concentration (MIC) values of H. lixii F02 and P. citrinum F40 samples for all isolates tested, including the metronidazole-resistant isolate, were 2.5 mg/mL. The kinetic growth curve showed that the filtrate samples were able to reduce the density of parasites to zero within 24 h of incubation, which was confirmed by microscopy. Both fungal filtrate samples exhibited no hemolytic activity, and the P. citrinum F40 filtrate sample showed low cytotoxicity against Vero cells. These data suggest that marine-associated fungi from the South Brazilian Coast may produce potential candidates for further investigation and possible use in the treatment of metronidazole-resistant trichomonosis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Trichomonosis, caused by the flagellate protozoan Trichomonas vaginalis, is the most common non-viral sexually transmitted disease worldwide. Actually, the infection treatment is based on 5-nitroimidazole drugs. However, an emergent number of resistant isolates makes important the search for new therapeutic arsenal. In this sense, the investigation of plants and their metabolites is an interesting approach. In the present study, the anti-T. vaginalis activity of 44 aqueous extracts from 23 Caatinga plants used in folk medicine was evaluated. After screening 44 aqueous extracts from 23 distinct plants against two isolates from ATCC and four fresh clinical isolates, only the Polygala decumbens root extract was effective in reducing significantly the trophozoite viability. The MIC value against all isolates tested, including the metronidazole resistant, was 1.56 mg/mL. The kinetic growth assays showed that the extract was able to completely abolish the parasite density in the first hours of incubation, confirmed by microscopy. In summary, this study describes the first report on the activity of P. decumbens from Caatinga against T. vaginalis, being directly related to the popular knowledge and use.

Purpose: The aim of this study was to show preclinical efficacy and clinical development potential of PKI-587, a dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor., Experimental Design: In vitro class 1 PI3K enzyme and human tumor cell growth inhibition assays and in vivo five tumor xenograft models were used to show efficacy., Results: In vitro, PKI-587 potently inhibited class I PI3Ks (IC(50) vs. PI3K-α = 0.4 nmol/L), PI3K-α mutants, and mTOR. PKI-587 inhibited growth of 50 diverse human tumor cell lines at IC(50) values of less than 100 nmol/L. PKI-587 suppressed phosphorylation of PI3K/mTOR effectors (e.g., Akt), and induced apoptosis in human tumor cell lines with elevated PI3K/mTOR signaling. MDA-MB-361 [breast; HER2(+), PIK3CA mutant (E545K)] was particularly sensitive to this effect, with cleaved PARP, an apoptosis marker, induced by 30 nmol/L PKI-587 at 4 hours. In vivo, PKI-587 inhibited tumor growth in breast (MDA-MB-361, BT474), colon (HCT116), lung (H1975), and glioma (U87MG) xenograft models. In MDA-MB-361 tumors, PKI-587 (25 mg/kg, single dose i.v.) suppressed Akt phosphorylation [at threonine(T)308 and serine(S)473] for up to 36 hours, with cleaved PARP (cPARP) evident up to 18 hours. PKI-587 at 25 mg/kg (once weekly) shrank large (∼1,000 mm(3)) MDA-MB-361 tumors and suppressed tumor regrowth. Tumor regression correlated with suppression of phosphorylated Akt in the MDA-MB-361 model. PKI-587 also caused regression in other tumor models, and efficacy was enhanced when given in combination with PD0325901 (MEK 1/2 inhibitor), irinotecan (topoisomerase I inhibitor), or HKI-272 (neratinib, HER2 inhibitor)., Conclusion: Significant antitumor efficacy and a favorable pharmacokinetic/safety profile justified phase 1 clinical evaluation of PKI-587., (©2011 AACR.)

A series of mono-morpholino 1,3,5-triazine derivatives (8a-8q) bearing a 3-oxa-8-azabicyclo[3.2.1]octane were prepared and evaluated for PI3-kinase/mTOR activity. Replacement of one of the bis-morpholines in lead compound 1 (PKI-587) with 3-oxa-8-azabicyclo[3.2.1]octane and reduction of the molecular weight yielded 8m (PKI-179), an orally efficacious dual PI3-kinase/mTOR inhibitor. The in vitro activity, in vivo efficacy, and PK properties of 8m are discussed., (Copyright © 2010. Published by Elsevier Ltd.)

PKI-402 is a selective, reversible, ATP-competitive, equipotent inhibitor of class I phosphatidylinositol 3-kinases (PI3K), including PI3K-alpha mutants, and mammalian target of rapamycin (mTOR; IC(50) versus PI3K-alpha = 2 nmol/L). PKI-402 inhibited growth of human tumor cell lines derived from breast, brain (glioma), pancreas, and non-small cell lung cancer tissue and suppressed phosphorylation of PI3K and mTOR effector proteins (e.g., Akt at T308) at concentrations that matched those that inhibited cell growth. In MDA-MB-361 [breast: Her2(+) and PIK3CA mutant (E545K)], 30 nmol/L PKI-402 induced cleaved poly(ADP-ribose) polymerase (PARP), a marker for apoptosis. In vivo, PKI-402 inhibited tumor growth in MDA-MB-361, glioma (U87MG), and lung (A549) xenograft models. In MDA-MB-361, PKI-402 at 100 mg/kg (daily for 5 days, one round) reduced initial tumor volume of 260 mm(3) to 129 mm(3) and prevented tumor regrowth for 70 days. In MDA-MB-361 tumors, PKI-402 (100 mg/kg, single dose) suppressed Akt phosphorylation (at T308) and induced cleaved PARP. Suppression of phosphorylated Akt (p-Akt) was complete at 8 hours and still evident at 24 hours. Cleaved PARP was evident at 8 and 24 hours. In normal tissue (heart and lung), PKI-402 (100 mg/kg) had minimal effect on p-Akt, with no detectable cleaved PARP. Preferential accumulation of PKI-402 in tumor tissue was observed. Complete, sustained suppression of Akt phosphorylation may cause tumor regression in MDA-MB-361 and other xenograft models. We are testing whether dual PI3K/mTOR inhibitors can durably suppress p-Akt, induce cleaved PARP, and cause tumor regression in a diverse set of human tumor xenograft models. Mol Cancer Ther; 9(4); 976-84. (c)2010 AACR.

The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure-activity relationships and the in vitro and in vivo activity of analogues in this series are described.

The synthesis and stereochemical determination of 1-(4-(4-((1R,5R,6R)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea (2), an active metabolite of the potent PI3 kinase inhibitor PKI-179 (1), is described. Stereospecific hydroboration of the double bond of 2,5-dihydro-1H-pyrrole 8 gave the 2,3-trans alcohol 9 exclusively. The configuration of the 3-hydroxyl group in 9 was inverted by an oxidation and stereoselective reduction sequence to give the corresponding 2,3-cis isomer 23. Both exo (21) and endo (27) isomers of the metabolite 2 were prepared via a practical synthetic route from 9 and 23, respectively, and the stereochemistry of 2 was determined to be endo. The endo isomer (27) was separated into two enantiomers 28 and 29 by chiral HPLC. Compound 2 was found to be enantiomerically pure and identical to the enantiomer 28. The absolute stereochemistry of the enantiomer 28 was determined by Mosher's method, thus establishing the stereochemistry of the active metabolite 2.

We are introducing a novel series of 2,4-diaminoquinazolines as beta-catenin/Tcf4 inhibitors which were identified by ligand-based design. Here we elucidate the SAR of this series and explain how we were able to improve key molecular properties such as solubility and cLogP leading to compound 9. Analogue 9 exhibited better biological activity and improved physical and pharmacological properties relative to the HTS hit 49. Furthermore, 9 demonstrated good cell growth inhibition against several human colorectal cancer lines such as LoVo and HT29. In addition, treatment with compound 9 led to gene expression changes that overlapped significantly with the transcriptional profile resulting from the pathway inhibition by siRNA knockdown of beta-catenin or Tcf4. Subsequently, 9 was tested for efficacy in a beta-catenin/RKE-mouse xenograft, where it led to more then 50% decrease in tumor volume.

This article describes the syntheses and SAR of a series of imidazolopyrimidine derivatives, which are evaluated as inhibitors of PI3-Kinase (PI3K) and mTOR. These compounds were found to be ATP competitive with good tumor cell growth inhibition, and suppression of pathway specific biomakers such as phosphorylation of Akt at T308., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Botryosphaeran (EPS(FRU)), an exopolysaccharide of the beta-(1-->3,1-->6)-d-glucan type with 31% branching at C-6, is produced by the fungus Botryosphaeria rhodina MAMB-05 when grown on fructose as carbon source. Botryosphaeran was derivatized by sulfonation to induce anticoagulant activity. The effectiveness of the sulfonation reaction by chlorosulfonic acid in pyridine was monitored by the degree of substitution and FT-IR analysis of the sulfonated EPS(FRU) (once sulfonated, EPS(FRUSULF); and re-sulfonated, EPS(FRURESULF)). Activated partial thromboplastin time (APTT) and thrombin time (TT) tests of EPS(FRURESULF) indicated significant in vitro anticoagulant activity that was dose-dependent. EPS(FRU) did not inhibit any of the coagulation tests.

The synthesis and SAR of a series of 2,4-diamino-quinazoline derivatives as beta-catenin/Tcf-4 inhibitors are described. This series was developed by modifying the initial lead 1, which was identified by screening of our compound library and found to inhibit the beta-catenin/Tcf-4 pathway. Replacement of the biphenyl moiety in compound 1 with the N-phenylpiperidine-4-carboxamide chain as in 2, resulted in a number of new analogues, which are potent inhibitors of the beta-catenin/Tcf-4 pathway. Compound such as 16k exhibited good cellular potency, solubility, metabolic stability and oral bioavailability.