2,732 research outputs found
The Sirenic Links between Diabetes, Obesity, and Bladder Cancer
There is considerable evidence of a positive association between the incidence of type 2 diabetes mellitus (T2DM) and obesity with bladder cancer (BCa), with the link between T2DM and obesity having already been established. There also appear to be potential associations between Pleckstrin homology domain containing S1 (PLEKHS1) and the Insulin-like Growth Factor (IGF) axis. Seven literature searches were carried out to investigate the backgrounds of these potential links. PLEKHS1 is a candidate biomarker in BCa, with mutations that are easily detectable in urine and increased expression seemingly associated with worse disease states. PLEKHS1 has also been implicated as a potential mediator for the onset of T2DM in people with obesity. The substantial evidence of the involvement of IGF in BCa, the role of the IGF axis in obesity and T2DM, and the global prevalence of T2DM and obesity suggest there is scope for investigating the links between these components. Preliminary findings on the relationship between PLEKHS1 and the IGF axis signal possible associations with BCa progression. This indicates that PLEKHS1 plays a role in the pathogenesis of BCa that may be mediated by members of the IGF axis. Further detailed research is needed to establish the relationship between PLEKHS1 and the IGF axis in BCa and determine how these phenomena overlap with T2DM and obesity
SELDI-TOF-MS determination of hepcidin in clinical samples using stable isotope labelled hepcidin as an internal standard
<p>Abstract</p> <p>Background</p> <p>Hepcidin is a 25-residue peptide hormone crucial to iron homeostasis. It is essential to measure the concentration of hepcidin in cells, tissues and body fluids to understand its mechanisms and roles in physiology and pathophysiology. With a mass of 2791 Da hepcidin is readily detectable by mass spectrometry and LC-ESI, MALDI and SELDI have been used to estimate systemic hepcidin concentrations by analysing serum or urine. However, peak heights in mass spectra may not always reflect concentrations in samples due to competition during binding steps and variations in ionisation efficiency. Thus the purpose of this study was to develop a robust assay for measuring hepcidin using a stable isotope labelled hepcidin spiking approach in conjunction with SELDI-TOF-MS.</p> <p>Results</p> <p>We synthesised and re-folded hepcidin labelled with <sup>13</sup>C/<sup>15</sup>N phenylalanine at position 9 to generate an internal standard for mass spectrometry experiments. This labelled hepcidin is 10 Daltons heavier than the endogenous peptides and does not overlap with the isotopic envelope of the endogenous hepcidin or other common peaks in human serum or urine mass spectra and can be distinguished in low resolution mass spectrometers. We report the validation of adding labelled hepcidin into serum followed by SELDI analysis to generate an improved assay for hepcidin.</p> <p>Conclusion</p> <p>We demonstrate that without utilising a spiking approach the hepcidin peak height in SELDI spectra gives a good indication of hepcidin concentration. However, a stable isotope labelled hepcidin spiking approach provides a more robust assay, measures the absolute concentration of hepcidin and should facilitate inter-laboratory hepcidin comparisons.</p
Prognostic DNA Methylation Biomarkers in High-risk Non–muscle-invasive Bladder Cancer:A Systematic Review to Identify Loci for Prospective Validation
Context: High-risk non–muscle-invasive bladder cancer (HR-NMIBC) represents over 30% of all incident urothelial bladder cancers (BCs); patients are at risk of progression, and 20–30% will die from BC within 5 yr. Current guidelines recommend induction and maintenance of intravesical bacillus Calmette-Guérin (BCG) or upfront radical cystectomy for highest-risk disease, treatments with markedly different morbidity, mortality, and patient burden. There are no validated biomarkers to facilitate such treatment decisions. Alterations in DNA methylation are commonplace in BC; hence, measurable changes in DNA methylation represent an opportunity for the discovery of such biomarkers.Objective: To systematically assess the evidence regarding DNA methylation markers as prognosticators for HR-NMIBC.Evidence acquisition: Standard systematic review methods were employed with searches undertaken in MEDLINE, EMBASE, and PubMed up to January 2019. Studies that included patients with HR-NMIBC and investigated the utility of DNA methylation biomarkers as prognostic tools were included.Evidence synthesis: Of 63 prognostic biomarker studies identified, 21 met the protocol-driven inclusion criteria and were directly relevant to HR-NMIBC patient outcomes: tumour recurrence (TR), tumour progression (TP), disease-specific survival (DSS), and overall survival (OS). These studies described 140 methylation markers; of these, the most promising were cadherin-13 (CDH13; hazard ratios [HRs]: 5.1 for TR, 6.6 for TP, 3.8–8.0 for OS), protocadherins (PCDHs; HRs: 4.7 for TR, 2.5 for TP, 3.0–4.8 for OS), Runt domain transcription factor 3 (RUNX3; HR: 5.1 for TP), Homeobox 9 (HOXA9; HR: 1.9 for TR), Islet-1 (ISL1; HRs: 1.7 for TR, 3.3 for TP), and PAX6 (HR: 2.2 for TR).Conclusions: This systematic review identifies a number of potentially useful prognostic methylation markers for HR-NMIBC. These loci (CDH13, PCDHs, RUNX3, HOXA9, ISL1, and PAX6) should be validated in prospective studies in order to translate benefit to patients.Patient summary: Early bladder cancer represents a more complex spectrum of disease than can be assessed by conventional methods Emerging studies on molecular markers will improve our understanding of this disease, and may enable more precise and personalised treatment.</p
Prognostic DNA Methylation Biomarkers in High-risk Non–muscle-invasive Bladder Cancer:A Systematic Review to Identify Loci for Prospective Validation
Context: High-risk non–muscle-invasive bladder cancer (HR-NMIBC) represents over 30% of all incident urothelial bladder cancers (BCs); patients are at risk of progression, and 20–30% will die from BC within 5 yr. Current guidelines recommend induction and maintenance of intravesical bacillus Calmette-Guérin (BCG) or upfront radical cystectomy for highest-risk disease, treatments with markedly different morbidity, mortality, and patient burden. There are no validated biomarkers to facilitate such treatment decisions. Alterations in DNA methylation are commonplace in BC; hence, measurable changes in DNA methylation represent an opportunity for the discovery of such biomarkers.Objective: To systematically assess the evidence regarding DNA methylation markers as prognosticators for HR-NMIBC.Evidence acquisition: Standard systematic review methods were employed with searches undertaken in MEDLINE, EMBASE, and PubMed up to January 2019. Studies that included patients with HR-NMIBC and investigated the utility of DNA methylation biomarkers as prognostic tools were included.Evidence synthesis: Of 63 prognostic biomarker studies identified, 21 met the protocol-driven inclusion criteria and were directly relevant to HR-NMIBC patient outcomes: tumour recurrence (TR), tumour progression (TP), disease-specific survival (DSS), and overall survival (OS). These studies described 140 methylation markers; of these, the most promising were cadherin-13 (CDH13; hazard ratios [HRs]: 5.1 for TR, 6.6 for TP, 3.8–8.0 for OS), protocadherins (PCDHs; HRs: 4.7 for TR, 2.5 for TP, 3.0–4.8 for OS), Runt domain transcription factor 3 (RUNX3; HR: 5.1 for TP), Homeobox 9 (HOXA9; HR: 1.9 for TR), Islet-1 (ISL1; HRs: 1.7 for TR, 3.3 for TP), and PAX6 (HR: 2.2 for TR).Conclusions: This systematic review identifies a number of potentially useful prognostic methylation markers for HR-NMIBC. These loci (CDH13, PCDHs, RUNX3, HOXA9, ISL1, and PAX6) should be validated in prospective studies in order to translate benefit to patients.Patient summary: Early bladder cancer represents a more complex spectrum of disease than can be assessed by conventional methods Emerging studies on molecular markers will improve our understanding of this disease, and may enable more precise and personalised treatment.</p
Metabolomic Evidence for a Field Effect in Histologically Normal and Metaplastic Tissues in Patients with Esophageal Adenocarcinoma
Patients with Barrett's esophagus (BO) are at increased risk of developing esophageal adenocarcinoma (EAC). Most Barrett's patients, however, do not develop EAC, and there is a need for markers that can identify those most at risk. This study aimed to see if a metabolic signature associated with the development of EAC existed. For this, tissue extracts from patients with EAC, BO, and normal esophagus were analyzed using 1H nuclear magnetic resonance. Where possible, adjacent histologically normal tissues were sampled in those with EAC and BO. The study included 46 patients with EAC, 7 patients with BO, and 68 controls who underwent endoscopy for dyspeptic symptoms with normal appearances. Within the cancer cohort, 9 patients had nonneoplastic Barrett's adjacent to the cancer suitable for biopsy. It was possible to distinguish between histologically normal, BO, and EAC tissue in EAC patients [area under the receiver operator curve (AUROC) 1.00, 0.86, and 0.91] and between histologically benign BO in the presence and absence of EAC (AUROC 0.79). In both these cases, sample numbers limited the power of the models. Comparison of histologically normal tissue proximal to EAC versus that from controls (AUROC 1.00) suggests a strong field effect which may develop prior to overt EAC and hence be useful for identifying patients at high risk of developing EAC. Excellent sensitivity and specificity were found for this model to distinguish histologically normal squamous esophageal mucosa in EAC patients and healthy controls, with 8 metabolites being very significantly altered. This may have potential diagnostic value if a molecular signature can detect tissue from which neoplasms subsequently arise
Scattering statistics of rock outcrops: Model-data comparisons and Bayesian inference using mixture distributions
The probability density function of the acoustic field amplitude scattered by
the seafloor was measured in a rocky environment off the coast of Norway using
a synthetic aperture sonar system, and is reported here in terms of the
probability of false alarm. Interpretation of the measurements focused on
finding appropriate class of statistical models (single versus two-component
mixture models), and on appropriate models within these two classes. It was
found that two-component mixture models performed better than single models.
The two mixture models that performed the best (and had a basis in the physics
of scattering) were a mixture between two K distributions, and a mixture
between a Rayleigh and generalized Pareto distribution. Bayes' theorem was used
to estimate the probability density function of the mixture model parameters.
It was found that the K-K mixture exhibits significant correlation between its
parameters. The mixture between the Rayleigh and generalized Pareto
distributions also had significant parameter correlation, but also contained
multiple modes. We conclude that the mixture between two K distributions is the
most applicable to this dataset.Comment: 15 pages, 7 figures, Accepted to the Journal of the Acoustical
Society of Americ
Electron Beam-Treated Enzymatically Mineralized Gelatin Hydrogels for Bone Tissue Engineering
Biological hydrogels are highly promising materials for bone tissue engineering (BTE) due to their high biocompatibility and biomimetic characteristics. However, for advanced and customized BTE, precise tools for material stabilization and tuning material properties are desired while optimal mineralisation must be ensured. Therefore, reagent-free crosslinking techniques such as high energy electron beam treatment promise effective material modifications without formation of cytotoxic by-products. In the case of the hydrogel gelatin, electron beam crosslinking further induces thermal stability enabling biomedical application at physiological temperatures. In the case of enzymatic mineralisation, induced by Alkaline Phosphatase (ALP) and mediated by Calcium Glycerophosphate (CaGP), it is necessary to investigate if electron beam treatment before mineralisation has an influence on the enzymatic activity and thus affects the mineralisation process. The presented study investigates electron beam-treated gelatin hydrogels with previously incorporated ALP and successive mineralisation via incubation in a medium containing CaGP. It could be shown that electron beam treatment optimally maintains enzymatic activity of ALP which allows mineralisation. Furthermore, the precise tuning of material properties such as increasing compressive modulus is possible. This study characterizes the mineralised hydrogels in terms of mineral formation and demonstrates the formation of CaP in dependence of ALP concentration and electron dose. Furthermore, investigations of uniaxial compression stability indicate increased compression moduli for mineralised electron beam-treated gelatin hydrogels. In summary, electron beam-treated mineralized gelatin hydrogels reveal good cytocompatibility for MG-63 osteoblast like cells indicating a high potential for BTE applications
Trends in Decline of Antiretroviral Resistance among ARV-Experienced Patients in the HIV Outpatient Study: 1999–2008
Background. Little is known about temporal trends in frequencies of clinically relevant ARV resistance mutations in HIV strains from U.S. patients undergoing genotypic testing (GT) in routine HIV care. Methods. We analyzed cumulative frequency of HIV resistance among patients in the HIV Outpatient Study (HOPS) who, during 1999–2008 and while prescribed antiretrovirals, underwent GT with plasma HIV RNA >1,000 copies/mL. Exposure ≥4 months to each of three major antiretroviral classes (NRTI, NNRTI and PI) was defined as triple-class exposure (TCE). Results. 906 patients contributed 1,570 GT results. The annual frequency of any major resistance mutations decreased during 1999–2008 (88% to 79%, P = 0.05). Resistance to PIs decreased among PI-exposed patients (71% to 46%, P = 0.010) as exposure to ritonavir-boosted PIs increased (6% to 81%, P < 0.001). Non-significant declines were observed in resistance to NRTIs among NRTI-exposed (82% to 67%), and triple-class-resistance among TCE patients (66% to 41%), but not to NNRTIs among NNRTI-exposed. Conclusions. HIV resistance was common but declined in HIV isolates from subgroups of ARV-experienced HOPS patients during 1999–2008. Resistance to PIs among PI-exposed patients decreased, possibly due to increased representation of patients whose only PI exposures were to boosted PIs
Community structure and function of high-temperature chlorophototrophic microbial mats inhabiting diverse geothermal environments
Six phototrophic microbial mat communities from different geothermal springs (YNP) were studied using metagenome sequencing and geochemical analyses. The primary goals of this work were to determine differences in community composition of high-temperature phototrophic mats distributed across the Yellowstone geothermal ecosystem, and to identify metabolic attributes of predominant organisms present in these communities that may correlate with environmental attributes important in niche differentiation. Random shotgun metagenome sequences from six phototrophic communities (average~ 53 Mbp/site) were subjected to multiple taxonomic, phylogenetic and functional analyses. All methods, including G+C content distribution, MEGAN analyses and oligonucleotide frequency-based clustering, provided strong support for the dominant community members present in each site. Cyanobacteria were only observed in non-sulfidic sites; de novo assemblies were obtained for Synechococcus-like populations at Chocolate Pots (CP_7) and Fischerella-like populations at White Creek (WC_6). Chloroflexi-like sequences (esp. Roseiflexus and/or Chloroflexus spp.) were observed in all six samples and contained genes involved in bacteriochlorophyll biosynthesis and the 3-hydroxypropionate carbon fixation pathway. Other major sequence assemblies were obtained for a Chlorobiales population from CP_7 (proposed family Thermochlorobacteriaceae), and an anoxygenic, sulfur-oxidizing Thermochromatium-like (Gamma-proteobacteria) population from Bath Lake Vista Annex (BLVA_20). Additional sequence coverage is necessary to establish more complete assemblies of other novel bacteria in these sites (e.g., Bacteroidetes and Firmicutes); however, current assemblies suggested that several of these organisms play important roles in heterotrophic and fermentative metabolisms. Definitive linkages were established between several of the dominant phylotypes present in these habitats and important functional processes such a
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