1.
Synthetic Peptides Mimic gp75 from Paracoccidioides brasiliensis in the Diagnosis of Paracoccidioidomycosis.
Source
Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo-Escola Paulista de Medicina, Disciplina de Imunologia, Rua Botucatu, 862, 4º andar, São Paulo, 04023-900, Brazil.
Abstract
Paracoccidioidomycosis (PCM) is a systemic granulomatous disease, endemic in Latin America, caused by the thermal dimorphic fungus Paracoccidioides brasiliensis. Although some fungal antigens have already been characterized and used for serological diagnosis, cross-reactions have been frequently observed. Thus, the examination of fungal forms in clinical specimens or isolation of P. brasiliensis by culture is still the most frequent method for the diagnosis of this mycosis. In this study, a random peptide phage display library was used to select mimotopes of P. brasiliensis, which were employed as antigens in an indirect enzyme-linked immunosorbent assay. The protective monoclonal antibody against experimental PCM (anti-gp75) was used as molecular target to screen a phage display library. That approach led to a synthetic peptide named P2, which was synthesized and tested against PCM patients' sera to check whether it was recognized. There was significant recognition of P2 by sera of untreated PCM patients when compared with normal human sera. Sera from treated PCM group, patients with other mycosis or co-infected with HIV had much lower recognition of P2 than untreated patient group. The test showed a sensitivity of 100 and 94.59% of specificity in relation to human sera control. These data indicate a potential use of P2 as diagnostic tool in PCM. Its application for serological diagnosis of PCM may contribute to the development and standardization of simpler, faster and highly reproducible immunodiagnostic tests at low cost.
- PMID:
- 22249604
- [PubMed - as supplied by publisher]
Structural basis of high-affinity nuclear localization signal interactions with importin-α
Source
School of Chemistry and Molecular Biosciences Australian Infectious Diseases Research Centre Australian Research Council Centre of Excellence for Integrative Legume Research, The University of Queensland, Brisbane, QLD 4072, Australia School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW 2650, Australia Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Abstract
Classical nuclear localization signals (cNLSs), comprising one (monopartite cNLSs) or two clusters of basic residues connected by a 10-12 residue linker (bipartite cNLSs), are recognised by the nuclear import factor importin-α. The cNLSs bind along a concave groove on importin-α, however, specificity determinants of cNLSs remain poorly understood. We present a structural and interaction analysis study of importin-α binding to both designed and naturally-occurring high-affinity cNLS-like sequences; the peptide inhibitors Bimax1 and Bimax2, and cNLS peptides of cap-binding protein 80. Our data suggest that cNLSs and cNLS-like sequences can achieve high affinity through maximising interactions at the importin-α minor site, and by taking advantage of multiple linker-region interactions. Our study defines an extended set of binding cavities on the importin-α surface, and also expands on recent observations that longer linker sequences are allowed, and that long-range electrostatic complementarity can contribute to cNLS-binding affinity. Altogether, our study explains the molecular and structural basis of the results of a number of recent studies including systematic mutagenesis and peptide library approaches, and provides an improved level of understanding on the specificity determinants of a cNLS. Our results have implications for identifying cNLSs in novel proteins.
© 2012 John Wiley & Sons A/S.
- PMID:
- 22248489
- [PubMed - as supplied by publisher]
Combinatorial Peptide Ligand Libraries For The Analysis Of Low-Expression Proteins. Validation For Normal Urine And Definition Of A First Protein Map.
Source
Laboratory of Pathophysiology of Uremia, G. Gaslini Children Hospithal, Genoa, Italy.
Abstract
In this review, we report the evolution on experimental conditions for the analysis of normal urine based on combinatorialpeptide ligand libraries (CPLL) treatment and successive 2-DE and 2-DE/MS analysis. The main topics are: 1- definition of the urine sample requirements, 2- optimization of the urine/ligand ratio, 3- essay conditions, 4- en bloc elution. Overall, normal urine protein composition as studied by 2-DE includes over 2600 spots. Relevant data on inter-and intra-essay reproducibility obtained by the analysis of different normal urines repeated several times are also here presented. We found a 73% reproducibility upon analysis of the same sample and 68% correspondence of protein composition among different normal urine samples. Based on the above results, we are completing the characterization with LC- MS of 249 spots. The composition of normal urine proteins after CPLLs is finally shown with the indication of those spots which are currently under identification. This map will be completed in a near future; in the meantime this would represent the basic reference sample for newly-developed studies on human diseases.
Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Template-Assisted and Self-Activating Clicked Peptide as a Synthetic Mimic of the SH2 Domain.
Abstract
A new synthetic strategy for obtaining artificial receptors that selectively regulate and/or control specific protein/protein interactions was developed based on the template-assisted and the self-activating click reaction applied to a combinatorial library. Synthetic mimics of the Grb2-SH2 domain, examined as a model case, selectively bound to a target signaling protein to induce cytotoxicity and inhibit tumor growth in vivo.
Hybrid compounds: from simple combinations to nanomachines.
Source
Department of Neuropathology, Heinrich Heine University Dsseldorf, Dsseldorf, Germany.
Abstract
The combination of two different and independently acting compounds into one covalently linked hybrid compound can convey synergy from the effects of both independently acting moieties to the new composite compound, leading to a pharmacological potency greater than the sum of each individual moiety's potencies. Here, we review a variety of such hybrid compounds, which can consist of various functional parts, molecular recognition or subcellular targeting moieties, or combinations thereof, acting either simultaneously or sequentially. Such moieties within a hybrid compound can consist of a variety of substance classes, including small organic molecules, polypeptides or nucleic acids identified either via rational molecular design or selection from libraries. Precedent for hybrid compounds comes from naturally occurring proteins and small molecules, such as botulinum toxin and bleomycin, which are secreted by micro-organisms. We review the high degree of suitability of hybrid compounds for the treatment of multifactorial diseases by simultaneously hitting several targets along an identified disease pathway. Examples are hybrid compounds against Alzheimer's disease, against the cancer-relevant phosphoinisitide-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and epidermal growth factor signaling cascade, or in antimalarial therapy via simultaneous hitting of different mechanisms of hemozoin formation. Molecular recognition by peptides or aptamers (recognition-specific RNA or peptidesequences) can be combined with the transport of small molecule β-sheet breakers or toxins, or targeting to ubiquitin-dependent proteolysis. The vision of molecular nanomachines is currently realized in sequentially acting modular nanotransporters, consisting of four modules including a target, a membrane and nuclear translocation sequence, as well as a drug attachment domain. Through the rational combination of existing drugs and the synergy of their effects, a rapid amplification of their potency may be achieved, greatly accelerating drug development. A further enhancement of simultaneous multitarget action is enabled through the design of multifunctional hybrid drugs with sequential effects that make these hybrid molecules resemble intelligent nanomachines.
Study on CCR5 analogs and affinity peptides.
Source
Biopharmaceutical Centre, State Key Laboratory of Biocontrol, College of Life Sciences, Sun Yat-Sen University, Guangdong 510275, China.
Abstract
The G protein-coupled receptor of human chemokine receptor 5 (CCR5) is a key target in the human immunodeficiency virus (HIV) infection process due to its major involvement in binding to the HIV type 1 (HIV-1) envelope glycoprotein gp120 and facilitating virus entry into the cells. The identification of naturally occurring CCR5 mutations (especially CCR5 delta-32) has allowed us to address the CCR5 molecule as a promising target to prevent or resist HIV infection in vivo. To obtain high-affinity peptides that can be used to block CCR5, CCR5 analogs with high conformational similarity are required. In this study, two recombinant proteins named CCR5 N-Linker-E2 and CCR5 mN-E1-E2 containing the fragments of the CCR5 N-terminal, the first extracellular loop or the second extracellular loop are cloned from a full-length human CCR5 cDNA. The recombinant human CCR5 analogs with self-cleavage activity of the intein Mxe or Ssp in the vector pTwinI were then produced with a high-yield expression and purification system in Escherichia coli. Experiments of extracellular epitope-activity identification (such as immunoprecipitation and indirective/competitive enzyme-linked immunosorbent assay) confirmed the close similarity between the epitope activity of the CCR5 analogs and that of the natural CCR5, suggesting the applicability of the recombinant CCR5 analogs as antagonists of the chemokine ligands. Subsequent screening of high-affinity peptides from the phage random-peptides library acquired nine polypeptides, which could be used as CCR5 peptide antagonists. The CCR5 analogs and affinity peptides elucidated in this paper provide us with a basis for further study of the mechanism of inhibition of HIV-1 infection.
- PMID:
- 22238429
- [PubMed - as supplied by publisher]
Screening serum biomarker of knee osteoarthritis using a phage display technique.
Abstract
OBJECTIVES:
To screen serum biomarker of knee osteoarthritis (OA) using a phage random peptide library.
DESIGN AND METHODS:
A phage random peptide library of random peptide 12-mers was screened with purified immunoglobulin G (IgG) from sera of knee OA patients. Patients with knee rheumatoid arthritis (RA), hip OA, non-erosive hand OA or erosive hand OA, and healthy volunteers were used as controls.
RESULTS:
A phage clone with inserted peptide TGLESGHGPGDS (named KOA1) showed 90% positive reaction rate with the knee OA patients, significantly higher than that with the knee RA patients (27.8%), the non-erosive hand OA patients (34.3%), the erosive hand OA patients (31.3%) and the healthy controls (12.0%), but not the hip OA patients (82.5%).
CONCLUSIONS:
The novel knee OA mimic peptide KOA1 identified with a random phage display peptide library and sera from knee OA patients could be a potential serum biomarker for knee OA.
Copyright © 2011. Published by Elsevier Inc.
Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials.
Source
Diabetes Research Division, Department of Internal Medicine F, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark.
Abstract
OBJECTIVE:
To determine whether treatment with agonists of glucagon-like peptide-1 receptor (GLP-1R) result in weight loss in overweight or obese patients with or without type 2 diabetes mellitus.
DESIGN:
Systematic review with meta-analyses.
DATA SOURCES:
Electronic searches (Cochrane Library, Medline, Embase, and Web of Science) and manual searches (up to May 2011). Review methods Randomised controlled trials of adult participants with a body mass index of 25 or higher; with or without type 2 diabetes mellitus; and who received exenatide twice daily, exenatide once weekly, or liraglutide once daily at clinically relevant doses for at least 20 weeks. Control interventions assessed were placebo, oral antidiabetic drugs, or insulin.
DATA EXTRACTION:
Three authors independently extracted data. We used random effects models for the primary meta-analyses. We also did subgroup, sensitivity, regression, and sequential analyses to evaluate sources of intertrial heterogeneity, bias, and the robustness of results after adjusting for multiple testing and random errors.
RESULTS:
25 trials were included in the analysis. GLP-1R agonist groups achieved a greater weight loss than control groups (weighted mean difference -2.9 kg, 95% confidence interval -3.6 to -2.2; 21 trials, 6411 participants). We found evidence of intertrial heterogeneity, but no evidence of bias or small study effects in regression analyses. The results were confirmed in sequential analyses. We recorded weight loss in the GLP-1R agonist groups for patients without diabetes (-3.2 kg, -4.3 to -2.1; three trials) as well as patients with diabetes (-2.8 kg, -3.4 to -2.3; 18 trials). In the overall analysis, GLP-1R agonists had beneficial effects on systolic and diastolic blood pressure, plasma concentrations of cholesterol, and glycaemic control, but did not have a significant effect on plasma concentrations of liver enzymes. GLP-1R agonists were associated with nausea, diarrhoea, and vomiting, but not with hypoglycaemia.
CONCLUSIONS:
The present review provides evidence that treatment with GLP-1R agonists leads to weight loss in overweight or obese patients with or without type 2 diabetes mellitus.
Identification of naturally processed hepatitis C virus-derived major histocompatibility complex class I ligands.
Source
Department of Medicine II, University of Freiburg, Freiburg, Germany.
Abstract
Fine mapping of human cytotoxic T lymphocyte (CTL) responses against hepatitis C virus (HCV) is based on external loading of target cells with synthetic peptides which are either derived from prediction algorithms or from overlappingpeptide libraries. These strategies do not address putative host and viral mechanisms which may alter processing as well as presentation of CTL epitopes. Therefore, the aim of this proof-of-concept study was to identify naturally processed HCV-derived major histocompatibility complex (MHC) class I ligands. To this end, continuous human cell lines were engineered to inducibly express HCV proteins and to constitutively express high levels of functional HLA-A2. These cell lines were recognized in an HLA-A2-restricted manner by HCV-specific CTLs. Ligands eluted from HLA-A2 molecules isolated from large-scale cultures of these cell lines were separated by high performance liquid chromatography and further analyzed by electrospray ionization quadrupole time of flight mass spectrometry (MS)/tandem MS. These analyses allowed the identification of two HLA-A2-restricted epitopes derived from HCV nonstructural proteins (NS) 3 and 5B (NS3(1406-1415) and NS5B(2594-2602)). In conclusion, we describe a general strategy that may be useful to investigate HCV pathogenesis and may contribute to the development of preventive and therapeutic vaccines in the future.
Development of molecular techniques for imaging and treatment of tumors.
Source
Department of Nuclear Medicine. University Hospital of Heidelberg, Heidelberg, Germany: 2 Clinical Cooperation Unit Nuclear Medicine, DKFZ and University of Heidelberg, Heidelberg, Germany: 3 Department of Radiopharmaceutical Chemistry, DKFZ Heidelberg, Heidelberg, Germany - uwe.haberkorn@med.uni-heidelberg.de.
Abstract
With the advances in molecular biology and biochemistry new imaging and treatment modalities based on the biological properties of tissues have been developed. In oncology, the major progress has been achieved using peptide and antibody targeting vectors. Besides the identification of new target structures, progress in molecular biology also made new techniques for the development of new biomolecules. This relies on the identification of lead compounds and on the screening of various derivatives of these compounds one at a time. The principle of high-troughput methods for the identification of novel high affinity binders is to generate a vast library of possible variants of the molecule of interest and screen the population for the few variants that show the property of interest. The attracting feature of the concept arises from the huge number of candidate molecules that can be used for further evaluation. After the characterization of the structure-function relationships for the lead compounds found in this process further improvement by rational design of analogs can be performed.
Ginger Rogers? No, Ginger Ale and its invisible proteome.
Abstract
The trace proteome of a Ginger drink, stated to be produced with a ginger root extract, has been investigated via capture with combinatorial peptide ligand libraries (ProteoMiner). Although in traces, we could confirm the presence of five grape proteins and one apple protein, but not even the faintest trace of any ginger root proteins. The first two findings are correct, as the producer stated that this beverage had been reinforced with 12% grape juice and 6% apple juice, but the absence of even traces of ginger proteins does not permit the classification of this beverage as a ginger extract on a proteomics scale. However, organoleptic tasting has confirmed the presence of a ginger extract, due to its piquant and tongue-biting taste. Nevertheless, any ginger root extract must be considered as a minor component as compared to the presence of grape and apple juice. At the light of these findings, it is hoped that the competent authorities will in the future make compulsory the proper labelling also of beverages so that all amounts of compounds utilized will be clearly stated in the label, including the presumptive main component.
Copyright © 2011. Published by Elsevier B.V.
Peptide discovery using bacterial display and flow cytometry.
Abstract
Peptides are increasingly used as therapeutic and diagnostic agents. The combination of bacterial cell-surface displaypeptide libraries with magnetic- and fluorescence-activated cell sorting technologies provides an efficient and highly effective methodology to identify and engineer peptides for a growing number of molecular recognition applications. Here, detailed protocols for both the generation and screening of bacterial display peptide libraries are presented. The methods described enable the discovery and evolutionary optimization of protein-binding peptides, cell-specific peptides, and enzyme substrates for diverse biotechnology applications.
Copyright © 2012 Elsevier Inc. All rights reserved.
- PMID:
- 22230566
- [PubMed - in process]
Identification and molecular characterization of three new K(+)-channel specific toxins from the Chinese scorpion Mesobuthus martensii Karsch revealing intronic number polymorphism and alternative splicing in duplicated genes.
Source
Department of Biological Science and Technology, School of Environmental Studies & State Key Laboratory of Biogeology and Environmental Geology, China University of Geosciences (Wuhan), Wuhan 430074, China.
Abstract
K(+)-channel specific toxins from scorpions are powerful probes used in the structural and functional characterization of different subfamilies of K(+)-channels which are thought to be the most diverse ion channels. However, only a limited number of K(+)-channels toxins have been identified from scorpions so far; moreover, little is known about the mechanisms for the generation of a combinatorial peptide library in a venom gland of a scorpion. Here, we identified and characterized three new K(+)-channels toxin-like peptides from the scorpion Mesobuthus martensii Karsch, which were referred to as BmKcug1, BmKcug2 and BmKcugx, respectively. BmKcug1 and BmKcug2 are two new members of α-KTx1 subfamily, and have been classified as α-KTx1.14 and α-KTx1.15, respectively. BmKcugx represents a new subfamily of K(+)-channel specific toxins which was classified into α-KTx22. BmKcugx was thus classified as α-KTx22.1. Genomic analysis demonstrated that BmKcugx gene has two exons interrupted by an intron inserted in the signal peptide encoding region, whereas BmKcug1a (a close homologue of BmKcug1)/BmKcug2 gene was interrupted by two introns, located within the 5'UTR of the gene and in the signal peptide encoding region, respectively. Transcriptomic analysis for the venom glands of M. martensii Karsch indicated that the abundances of the transcripts of BmKcug1a and BmKcug2 are much higher than that of BmKcugx; it suggests that the intron in 5'UTR could markedly increase the expression level of the K(+)-channel toxins. Alignment of the genomic sequences of BmKcug1a and BmKcug2 revealed that an alternative splicing event occurred at the intron 1-exon 2 junction in the 5'UTR of BmKcug2 transcript.
Copyright © 2012. Published by Elsevier Inc.
A novel mouse CD133 binding-peptide screened by phage display inhibits cancer cell motility in vitro.
Source
Department of Pathology and Key Laboratory of Molecule Tumor Pathology of Guangdong Province, Southern Medical University, Guangzhou, 510515, Guangdong, China, Sunjinmin198206@163.com.
Abstract
Increased expression of CD133 (Prominin-1), an important cancer stem cell-associated marker, has been observed in the cancer stem cells of a variety of human and mouse cancers. However, no natural ligand of CD133 has yet been identified and little is known about its function. In the present study, LS-7 (amino acid sequence: LQNAPRS), a specific binding peptide targeting mouse CD133, was screened and identified for the first time by phage-displayed peptide librarytechnology. The in vitro and in vivo affinity and specificity of LS-7 were determined, and MTT, adhesion, and migration assays were performed to evaluate the effects of LS-7 on the biological behaviors of cancer cells. To determine which signaling pathways are affected by LS-7, HMGB1, S-100A4, CXCR7, uPAR, AMFR, STAT3, and c-Met gene and protein expression were evaluated by RT-PCR and Western blot. Flow cytometry and immunofluorescence assays showed specific, high-affinity binding of the peptide to mCD133 in vitro. Confocal microscopy confirmed the co-localization of LS-7 positive cells and CD133-positive cells. Migration and wound-healing assays showed that LS-7 significantly inhibited the migration of colon and breast cancer cells in a concentration-dependent manner. In vivo experiments also confirmed the high specificity and affinity of LS-7 to mCD133. RT-PCR and Western blot showed that the expressions of only c-Met and STAT3 decreased obviously in colon and breast cancer cells exposed to LS-7. These findings may provide a novel tool for anti-motility and anti-metastasis strategies in cancer research and cancer stem cell therapy.
Ultra-sensitive electrochemical immunosensor using analyte peptidomimetics selected from phage display peptide libraries.
Source
Departamento de Química, Facultad de Ciencias Exactas, Físico-Químicas y Naturales, Universidad Nacional de Río Cuarto, Agencia Postal N 3, 5800 Río Cuarto, Argentina.
Abstract
Immunosensors for small analytes have been a great addition to the analytical toolbox due to their high sensitivity and extended analytical range. In these systems the analyte is detected when it competes for binding to the detecting antibody with a tracer compound. In this work we introduce the use of phage particles bearing peptides that mimic the target analyte as surrogates for conventional tracers. As a proof of concept, we developed a magneto-electrochemical immunosensor (EI) for the herbicide molinate and compare its performance with conventional formats. Using the same anti-molinate antibody and phage particles bearing a molinate peptidomimetic, the EI performed with an IC(50) of 0.15ngmL(-1) (linear range from 4.4×10(-3) to 10ngmL(-1)). Compared to the conventional ELISA, the EI was faster (minutes), performed with a much wider linear range, and the detection limit that was 2500-fold lower. The EI produced consistent measurements and could be successfully used to assay river water samples with excellent recoveries. By using the same EI with a conventional tracer, we found that an important contribution to the gain in sensitivity is due to the filamentous structure of the phage (9×1000nm) which works as a multienzymatic tracer, amplifying the competitive reaction. Since phage-borne peptidomimetics can be selected from phage display libraries in a straightforward systematic manner and their production is simple and inexpensive, they can contribute to facilitate the development of ultrasensitive biosensors.
Copyright © 2011 Elsevier B.V. All rights reserved.
Characterization of potential elastase inhibitor-peptides regulated by a molecular switch for wound dressings applications.
Source
Center of Chemistry, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal.
Abstract
Elastase plays an important role in wound healing process, degrading damaged tissue and allowing complete tissue recovery. The levels of human neutrophil elastase (HNE) are usually controlled by endogenous inhibitors. However, in the presence of high levels of elastase, like the ones present in chronic wounds, the inhibitors cannot overcome this overproduction and the enzyme starts to degrade the surrounding healthy tissue. In this work we report the development of a molecular switch to control the elastase activity in the exudate of non-healing chronic wounds. A peptide library was generated and screened in a microarray format for protein kinase-mediated phosphorylation. Two peptides were identified as casein kinase Iδ (CKI) substrates: KRCCPDTCGIKCL and its analogous peptide KRMMPDTMGIKML, with cysteine residues replaced by methionine residues. These peptides were studied in solution, both in the phosphorylated and non-phosphorylated forms as potential inhibitors for elastase. The obtained results show that the reversible process of phosphorylation/dephosphorylation results in differential inhibitory activity of the peptides. Thus the reversible process of phosphorylation/dephosphorylation can be used as a kind of molecular switch to control elastase activity. Degradation studies reveal that both the inhibitor-peptides and CKI are degraded by elastase. These results envisage the safe utilisation of these inhibitor-peptides together with CKI in the formulation of wound dressings.
Copyright © 2011 Elsevier Inc. All rights reserved.
A comprehensive library of blocked dipeptides reveals intrinsic backbone conformational propensities of unfolded proteins.
Source
Department of Chemistry, Korea University, Seoul 136-701, Korea.
Abstract
Despite prolonged scientific efforts to elucidate the intrinsic peptide backbone preferences of amino-acids based on understanding of intermolecular forces, many open questions remain, particularly concerning neighboring peptideinteraction effects on the backbone conformational distribution of short peptides and unfolded proteins. Here, we show that spectroscopic studies of a complete library of 400 dipeptides reveal that, irrespective of side-chain properties, the backbone conformation distribution is narrow and they adopt polyproline II and β-strand, indicating the importance of backbone peptide solvation and electronic effects. By directly comparing the dipeptide circular dichroism and NMR results with those of unfolded proteins, the comprehensive dipeptides form a complete set of structural motifs of unfolded proteins. We thus anticipate that the present dipeptide library with spectroscopic data can serve as a useful database for understanding the nature of unfolded protein structures and for further refinements of molecular mechanical parameters. Proteins 2011; © 2011 Wiley Periodicals, Inc.
Copyright © 2011 Wiley Periodicals, Inc.
Current advances in peptide and small molecule microarray technologies.
Source
Department of Biological Science, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore.
Abstract
Microarrays offer a compact solution for massively parallel screening. In recent years, microarrays have branched away from the exclusive pursuit of small molecule 'hits' in target centric screens, towards the sophisticated dissection of disease biology and comparative profiling of cellular states. This has led to innovative and instructive ways in which the platform may be deployed, providing new-found methods with which to harness the throughput achievable. Library design and diversity continues to drive success with peptide and small molecule microarrays. Newer synthesis and immobilization strategies extend the already wide repertoire of fabrication methods available. Herein we describe the latest advances in the small molecule and peptide microarray arena, which herald even more exciting breakthroughs in the coming decade.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Radionuclide Therapy in Neuroendocrine Tumours: A Systematic Review.
Source
Department of Nuclear Medicine, Hamilton Health Sciences & St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada.
Abstract
The purpose of this systematic review was to investigate the effects of therapeutic radiopharmaceuticals in patients with different types of advanced neuroendocrine tumour (NETs). A literature search was carried out in MEDLINE and EMBASE from January 1998 to November 2010. The Cochrane Library (to Issue 10, 2010) and the Standards and Guidelines Evidence Inventory of Cancer Guidelines, including over 1100 English-language cancer guidelines from January 2003 to June 2010, were also checked. No existing systematic reviews or clinical practice guidelines based on a systematic review or randomised controlled trials focusing on this topic were found. Twenty-four fully published articles were abstracted and summarised: 16 articles focused on five peptide receptor radionuclide therapy ((111)In-DTPAOC, (90)Y-DOTALAN, (90)Y-DOTATOC, (90)Y-DOTATATE, and (177)Lu-DOTATATE) and eight focused on (131)I-MIBG treatment. Limited evidence from a historical comparison of studies in one centre supported that (177)Lu-DOTATATE might be associated with greater clinical outcomes compared with (90)Y-DOTATOC or (111)In-DTPAOC. The severe toxicities for (177)Lu-DOTATATE included hepatic insufficiency in 0.6%, myelodysplastic syndrome in 0.8% and renal insufficiency in 0.4% of patients in this study. Insufficient evidence suggested efficacy of (131)I-MIBG in adult NET patients, but the overall tumour response rate from (131)I-MIBG was 27-75% for malignant neuroblastoma, paraganglioma or pheochromocytoma. Haematological toxicities were the main severe side-effects after (131)I-MIBG and 4% of patients developed secondary malignancies in one study. To date, peptide receptor radionuclide therapy seems to be an acceptable option and is relatively safe in adult advanced NET patients with receptor uptake positive on scintigraphy, but patients' renal function must be monitored. (131)I-MIBG may be effective for malignant neuroblastoma, paraganglioma or pheochromocytoma, but its side-effects need to be considered. No strong evidence exists to support that one therapeutic radiopharmaceutical is more effective than others. Well-designed and good-quality randomised controlled trials are required on this research topic.
Copyright © 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Pepitome: evaluating improved spectral library search for identification complementarity and quality assessment.
Abstract
Spectral libraries have emerged as a viable alternative to protein sequence databases for peptide identification. Theselibraries contain previously detected peptide sequences and their corresponding tandem mass spectra (MS/MS). Search engines can then identify peptides by comparing experimental MS/MS scans to those in the library. Many of these algorithms employ the dot product score for measuring the quality of a spectrum-spectrum match (SSM). This scoring system does not offer a clear statistical interpretation and ignores fragment ion m/z discrepancies in the scoring. We developed a new spectral library search engine, Pepitome, which employs statistical systems for scoring SSMs. Pepitome outperformed the leading library search tool, SpectraST, when analyzing data sets acquired on three different mass spectrometry platforms. We characterized the reliability of spectral library searches by confirming shotgun proteomics identifications through RNA-Seq data. Applying spectral library and database searches on the same sample revealed their complementary nature. Pepitome identifications enabled the automation of quality analysis and quality control (QA/QC) for shotgun proteomics data acquisition pipelines.
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