Identification of a biomarker panel for colorectal cancer diagnosis

<p>Abstract</p> <p>Background</p> <p>Malignancies arising in the large bowel cause the second largest number of deaths from cancer in the Western World. Despite progresses made during the last decades, colorectal cancer remains one of the most frequent and deadly neoplasias in the western countries.</p> <p>Methods</p> <p>A genomic study of human colorectal cancer has been carried out on a total of 31 tumoral samples, corresponding to different stages of the disease, and 33 non-tumoral samples. The study was carried out by hybridisation of the tumour samples against a reference pool of non-tumoral samples using Agilent Human 1A 60-mer oligo microarrays. The results obtained were validated by qRT-PCR. In the subsequent bioinformatics analysis, gene networks by means of Bayesian classifiers, variable selection and bootstrap resampling were built. The consensus among all the induced models produced a hierarchy of dependences and, thus, of variables.</p> <p>Results</p> <p>After an exhaustive process of pre-processing to ensure data quality--lost values imputation, probes quality, data smoothing and intraclass variability filtering--the final dataset comprised a total of 8, 104 probes. Next, a supervised classification approach and data analysis was carried out to obtain the most relevant genes. Two of them are directly involved in cancer progression and in particular in colorectal cancer. Finally, a supervised classifier was induced to classify new unseen samples.</p> <p>Conclusions</p> <p>We have developed a tentative model for the diagnosis of colorectal cancer based on a biomarker panel. Our results indicate that the gene profile described herein can discriminate between non-cancerous and cancerous samples with 94.45% accuracy using different supervised classifiers (AUC values in the range of 0.997 and 0.955).</p

Orientation and dynamics of transmembrane peptides: the power of simple models

In this review we discuss recent insights obtained from well-characterized model systems into the factors that determine the orientation and tilt angles of transmembrane peptides in lipid bilayers. We will compare tilt angles of synthetic peptides with those of natural peptides and proteins, and we will discuss how tilt can be modulated by hydrophobic mismatch between the thickness of the bilayer and the length of the membrane spanning part of the peptide or protein. In particular, we will focus on results obtained on tryptophan-flanked model peptides (WALP peptides) as a case study to illustrate possible consequences of hydrophobic mismatch in molecular detail and to highlight the importance of peptide dynamics for the experimental determination of tilt angles. We will conclude with discussing some future prospects and challenges concerning the use of simple peptide/lipid model systems as a tool to understand membrane structure and function

Claudins in lung diseases

Tight junctions are the most apically localized part of the epithelial junctional complex. They regulate the permeability and polarity of cell layers and create compartments in cell membranes. Claudins are structural molecules of tight junctions. There are 27 claudins known, and expression of different claudins is responsible for changes in the electrolyte and solute permeability in cells layers. Studies have shown that claudins and tight junctions also protect multicellular organisms from infections and that some infectious agents may use claudins as targets to invade and weaken the host's defense. In neoplastic diseases, claudin expression may be up- or downregulated. Since their expression is associated with specific tumor types or with specific locations of tumors to a certain degree, they can, in a restricted sense, also be used as tumor markers. However, the regulation of claudin expression is complex involving growth factors and integrins, protein kinases, proto-oncogens and transcription factors. In this review, the significance of claudins is discussed in lung disease and development

Influence of pyridine versus piperidine ligands on the chemical, DNA binding and cytotoxic properties of light activated trans,trans,trans-[Pt(N3)2(OH)2(NH3)(L)]

The photocytotoxicity and photobiochemical properties of the new complex trans, trans, trans-[Pt(N3)2(OH)2(NH3)(piperidine)] (5) are compared with its analogue containing the less basic and less lipophilic ligand pyridine (4). The log P (n-octanol/water) values were of -1.16 and -1.84 for the piperidine and pyridine complexes, respectively, confirmed that piperidine increases the hydrophobicity of the complex. DFT and TDDFT calculations indicate that 5 has accessible singlet and triplet states which can promote ligand dissociation when populated by both UVA and visible white light. When activated by UVA or white light, both compounds showed similar cytotoxic potencies in various human cancer cell lines although their selectivity was different. The time needed to reach similar antiproliferative activity was noticeably decreased by introducing the piperidine ligand. Neither compound showed cross-resistance in three oxoplatin-resistant cell lines. Furthermore, both compounds showed similar anticlonogenic activity when activated by UVA radiation. Interactions of the light-activated complexes with DNA showed similar kinetics and levels of DNA platination and similar levels of DNA interstrand cross-linking (ca. 5 %). Also the ability to unwind double stranded DNA where comparable for the piperidine analogue (24°, respectively), while the piperidine complex showed higher potency in changing the conformation of DNA, as measured in an ethidium bromide binding assay. These results indicate that the nature of the heterocyclic nitrogen ligand can have subtle influences on both the phototoxicity and photobiochemistry of this class of photochemotherapeutic agents

Photocontrolled DNA binding of a receptor-targeted organometallic ruthenium(II) complex

A photoactivated ruthenium(II) arene complex has been conjugated to two receptor-binding peptides, a dicarba analogue of octreotide and the Arg-Gly-Asp (RGD) tripeptide. These peptides can act as “tumor-targeting devices” since their receptors are overexpressed on the membranes of tumor cells. Both ruthenium–peptide conjugates are stable in aqueous solution in the dark, but upon irradiation with visible light, the pyridyl-derivatized peptides were selectively photodissociated from the ruthenium complex, as inferred by UV–vis and NMR spectroscopy. Importantly, the reactive aqua species generated from the conjugates, [(η6-p-cym)Ru(bpm)(H2O)]2+, reacted with the model DNA nucleobase 9-ethylguanine as well as with guanines of two DNA sequences, 5′dCATGGCT and 5′dAGCCATG. Interestingly, when irradiation was performed in the presence of the oligonucleotides, a new ruthenium adduct involving both guanines was formed as a consequence of the photodriven loss of p-cymene from the two monofunctional adducts. The release of the arene ligand and the formation of a ruthenated product with a multidentate binding mode might have important implications for the biological activity of such photoactivated ruthenium(II) arene complexes. Finally, photoreactions with the peptide–oligonucleotide hybrid, Phac-His-Gly-Met-linker-p5′dCATGGCT, also led to arene release and to guanine adducts, including a GG chelate. The lack of interaction with the peptide fragment confirms the preference of such organometallic ruthenium(II) complexes for guanine over other potential biological ligands, such as histidine or methionine amino acids

Microbial profile and antibiotic susceptibility of culture-positive bacterial endophthalmitis

Purpose To assess the distribution of microorganisms isolated from patients with bacterial endophthalmitis and their antimicrobial susceptibility.Methods Retrospective analysis of medical and microbiological records of patients with suspected diagnosis of endophthalmitis. the following information was assessed: number of presumed and culture-positive endophthalmitis cases, source of infection, microbiological result (aqueous and/or vitreous culture and Gram staining), microbial characterization and distribution, and antimicrobial susceptibility.Results A total of 107 (46%) of 231 patients with bacterial endophthalmitis showed positive results by gram stain or culture. of these, 97 (42%) patients were positive for culture only. Most of them (62%) were secondary to a surgical procedure (postoperative), 12% were posttraumatic and 26% were secondary to an unknown source or the data were unavailable. A total of 100 microorganisms were isolated (38 aqueous and 67 vitreous samples) from the 97 culture-positive cases (91% were gram-positive and 9% were gram-negative). Coagulase-negative Staphylococcus (CoNS) (48%) were the most frequently isolated, followed by Stretococcus viridans (18%), and Staphylococcus aureus (13%). the antimicrobial susceptibility for CoNS was as follows: amikacin-91.6%, cephalothin-97.9%, ceftriaxone-50%, ciprofloxacin-62.5%, chloramphenicol-91.8%, gatifloxacin-79.5%, gentamicin-72.9%, moxifloxacin-89.5%, ofloxacin-70.8%, oxacillin-58.3%, penicillin-33.3%, tobramycin-85.4%, and vancomycin-100%.Conclusion Gram-positive bacteria were the major causes of infectious endophthalmitis in this large series, usually following surgery. CoNS was the most common isolate. of interest, susceptibility to oxacillin and fourth-generation quinolones was lower than previously published. Eye (2011) 25, 382-388; doi:10.1038/eye.2010.236; published online 18 February 2011Universidade Federal de São Paulo, Dept Ophthalmol, São Paulo, BrazilUniversidade Federal de São Paulo, Special Lab Clin Microbiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Ophthalmol, São Paulo, BrazilUniversidade Federal de São Paulo, Special Lab Clin Microbiol, São Paulo, BrazilWeb of Scienc

Approaching imperial narratives one sense at a time: views and sounds at an Inka settlement in northwest Argentina

Throughout history, empires have deployed a vast array of strategies to promote their worldview and to control the colonized. Amongst non-violent ones, hosting public ceremonies to show off an empire’s capabilities and to enact and reinforce new desired relations and identities, seemed to be especially effective. This article presents new data and interpretations on how the Inkas employed ritual architecture to manipulate the somatic experiences of the colonized. Specifically, we analyze the public space of an Inka settlement located in the North Calchaquí Valley (Argentina) in order to show how the Inkas used architecture and spatial design to impose certain sensorial modalities and to manage their sequential stimulus and intensity. In an attempt to overcome a reigning visual paradigm among this line of inquiry, we present an analysis that combines visual and acoustical data collected on site, with three-dimensional modeling of terrain, architecture, and sound propagation. Results indicate that through a careful layout design that involved the management of visual and acoustic permeability, the Inkas not only organized groups and practices, but also created different experiences for different people.Fil: Ferrari, Alejandro Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Leibowicz, Ivan Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Multidisciplinario de Historia y Ciencias Humanas; ArgentinaFil: Acuto, Felix Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Multidisciplinario de Historia y Ciencias Humanas; Argentin