46 research outputs found
Chemical genetics approach to restoring p27Kip1 reveals novel compounds with antiproliferative activity in prostate cancer cells
<p>Abstract</p> <p>Background</p> <p>The cyclin-dependent kinase (CDK) inhibitor p27<sup>Kip1 </sup>is downregulated in a majority of human cancers due to ectopic proteolysis by the ubiquitin-proteasome pathway. The expression of p27 is subject to multiple mechanisms of control involving several transcription factors, kinase pathways and at least three different ubiquitin ligases (SCF<sup>SKP2</sup>, KPC, Pirh2), which regulate p27 transcription, translation, protein stability and subcellular localization. Using a chemical genetics approach, we have asked whether this control network can be modulated by small molecules such that p27 protein expression is restored in cancer cells.</p> <p>Results</p> <p>We developed a cell-based assay for measuring the levels of endogenous nuclear p27 in a high throughput screening format employing LNCaP prostate cancer cells engineered to overexpress SKP2. The assay platform was optimized to Z' factors of 0.48 - 0.6 and piloted by screening a total of 7368 chemical compounds. During the course of this work, we discovered two small molecules of previously unknown biological activity, SMIP001 and SMIP004, which increase the nuclear level of p27 at low micromolar concentrations. SMIPs (small molecule inhibitors of p27 depletion) also upregulate p21<sup>Cip1</sup>, inhibit cellular CDK2 activity, induce G1 delay, inhibit colony formation in soft agar and exhibit preferential cytotoxicity in LNCaP cells relative to normal human fibroblasts. Unlike SMIP001, SMIP004 was found to downregulate SKP2 and to stabilize p27, although neither SMIP is a proteasome inhibitor. Whereas the screening endpoint - nuclear p27 - was robustly modulated by the compounds, SMIP-mediated cell cycle arrest and apoptosis were not strictly dependent on p27 and p21 - a finding that is explained by parallel inhibitory effects of SMIPs on positive cell cycle regulators, including cyclins E and A, and CDK4.</p> <p>Conclusions</p> <p>Our data provide proof-of-principle that the screening platform we developed, using endogenous nuclear p27 as an endpoint, presents an effective means of identifying bioactive molecules with cancer selective antiproliferative activity. This approach, when applied to larger and more diverse sets of compounds with refined drug-like properties, bears the potential of revealing both unknown cellular pathways globally impinging on p27 and novel leads for chemotherapeutics targeting a prominent molecular defect of human cancers.</p
DNA multigene characterization of Fasciola hepatica and Lymnaea neotropica and its fascioliasis transmission capacity in Uruguay, with historical correlation, human report review and infection risk analysis
Fascioliasis is a highly pathogenic zoonotic disease emerging in recent decades, in part due to the effects of climate and global changes. South America is the continent presenting more numerous human fascioliasis endemic areas and the highest Fasciola hepatica infection prevalences and intensities known in humans. These serious public health scenarios appear mainly linked to altitude areas in Andean countries, whereas lowland areas of non-Andean countries, such as Uruguay, only show sporadic human cases or outbreaks. To understand this difference, we characterized F. hepatica from cattle and horses and lymnaeids of Uruguay by sequencing of ribosomal DNA ITS-2 and ITS-1 spacers and mitochondrial DNA cox1, nad1 and 16S genes. Results indicate that vectors belong to Lymnaea neotropica instead of to Lymnaea viator, as always reported from Uruguay. Our correlation of fasciolid and lymnaeid haplotypes with historical data on the introduction and spread of livestock species into Uruguay allow to understand the molecular diversity detected. We study the life cycle and transmission features of F. hepatica by L. neotropica of Uruguay under standardized experimental conditions to enable a comparison with the transmission capacity of F. hepatica by Galba truncatula at very high altitude in Bolivia. Results demonstrate that although L. neotropica is a highly efficient vector in the lowlands, its transmission capacity is markedly lower than that of G. truncatula in the highlands. On this baseline, we review the human fascioliasis cases reported in Uruguay and analyze the present and future risk of human infection in front of future climate change estimations
The type specimens of sucking lice (anoplura) deposited in the entomological collection of Instituto Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
Large-scale unit commitment under uncertainty: an updated literature survey
The Unit Commitment problem in energy management aims at finding the optimal production schedule of a set of generation units, while meeting various system-wide constraints. It has always been a large-scale, non-convex, difficult problem, especially in view of the fact that, due to operational requirements, it has to be solved in an unreasonably small time for its size. Recently, growing renewable energy shares have strongly increased the level of uncertainty in the system, making the (ideal) Unit Commitment model a large-scale, non-convex and uncertain (stochastic, robust, chance-constrained) program. We provide a survey of the literature on methods for the Uncertain Unit Commitment problem, in all its variants. We start with a review of the main contributions on solution methods for the deterministic versions of the problem, focussing on those based on mathematical programming techniques that are more relevant for the uncertain versions of the problem. We then present and categorize the approaches to the latter, while providing entry points to the relevant literature on optimization under uncertainty. This is an updated version of the paper "Large-scale Unit Commitment under uncertainty: a literature survey" that appeared in 4OR 13(2), 115--171 (2015); this version has over 170 more citations, most of which appeared in the last three years, proving how fast the literature on uncertain Unit Commitment evolves, and therefore the interest in this subject
The first study of molecular prevalence and species characterization of Cryptosporidium in free-range chicken (Gallus gallus domesticus) from Brazil
Global variation in anastomosis and end colostomy formation following left-sided colorectal resection
Background
End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection.
Methods
This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model.
Results
In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6路9 per cent) from low-HDI, 254 (15路5 per cent) from middle-HDI and 1268 (77路6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57路5, 40路9 and 35路4 per cent; P < 0路001) and subsequent use of end colostomy (52路2, 24路8 and 18路9 per cent; P < 0路001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3路20, 95 per cent c.i. 1路35 to 7路57; P = 0路008) after risk adjustment for malignant disease (OR 2路34, 1路65 to 3路32; P < 0路001), emergency surgery (OR 4路08, 2路73 to 6路10; P < 0路001), time to operation at least 48 h (OR 1路99, 1路28 to 3路09; P = 0路002) and disease perforation (OR 4路00, 2路81 to 5路69; P < 0路001).
Conclusion
Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone
Highly Pathogenic and Multidrug Resistant Avian Pathogenic Escherichia Coli in Free-Range Chickens from Brazil
ABSTRACT Avian pathogenic Escherichiacoli (APEC) virulence mechanism has been continuously studied and it is believed to be multifactorial and because of this, this work aimed to characterize potentially APEC strains isolated from free-range hens. Isolates were submitted to PCR for the detection of virulence genes, which were of high prevalence. In vivo inoculation of day-old chicks revealed that 49 of these strains were of high and intermediate pathogenicity. In addition, isolates were submitted to antimicrobials susceptibility test with the majority of the strains presenting multiresistance. Phylogenetic analysis showed a greater presence of potentially APEC isolates in-group B2. In addition, high heterogeneity was detected among the isolates byXbaI enzyme. Fifteen serogroups were identified, being the O8 the most frequent. These results strengthen the fact that a combination of diverse factors are associated with the pathogenicity APEC strains, as well as to highlight its importance to public health and that free-range hens can act as a reservoirs of potentially zoonoticbacteria
Shiga Toxigenic and Atypical Enteropathogenic Escherichia coli in the Feces and Carcasses of Slaughtered Pigs
Coordena莽茫o de Aperfei莽oamento de Pessoal de N铆vel Superior (CAPES)Funda莽茫o de Amparo 脿 Pesquisa do Estado de S茫o Paulo (FAPESP)Escherichia coli is a pathogen of major importance in swine and public health. To determine the prevalence of Shiga toxigenic E. coli (STEC) and enteropathogenic E. coli (EPEC), samples were collected from the feces and carcasses of swines. In total, 441 samples were collected in four samplings, of which 141 samples tested positive for either the stx1, stx2, and/or eae genes. From the positive samples, one STEC and 15 atypical EPEC (aEPEC) isolates were obtained, and all originated from the same sampling. In addition to eae, lpfA(O157/OI-141), ehxA, toxB, and lpfA(O113) were present in the aEPEC isolates. The only stx2-containing isolate carried stx2e and belonged to serotype O103:HNT. Resistance to four or more antimicrobials was found in almost half of the isolates, and some isolates shared the same fingerprint patterns by enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR). The presence of certain virulence genes and the high level of resistance to antimicrobials, as well as the possible fecal contamination of carcasses showed that some of the isolates are of public health concern.o TEXTO COMPLETO DESTE ARTIGO, ESTAR脕 DISPON脥VEL 脌 PARTIR DE AGOSTO DE 2015.91211191125Coordena莽茫o de Aperfei莽oamento de Pessoal de N铆vel Superior (CAPES)Funda莽茫o de Amparo 脿 Pesquisa do Estado de S茫o Paulo (FAPESP)Coordena莽茫o de Aperfei莽oamento de Pessoal de N铆vel Superior (CAPES)Funda莽茫o de Amparo 脿 Pesquisa do Estado de S茫o Paulo (FAPESP)FAPESP [2008/00417-0