186 research outputs found
BRAF V600E mutations in urine and plasma cell-free DNA from patients with Erdheim-Chester disease.
Erdheim-Chester disease (ECD) is a rare histiocytosis with a high prevalence of BRAF V600E mutation (>50% of patients). Patients with BRAF-mutant ECD can respond to BRAF inhibitors. Unfortunately, the lack of adequate archival tissue often precludes BRAF testing. We hypothesized that cell-free DNA (cfDNA) from plasma or urine can offer an alternative source of biologic material for testing. We tested for BRAF V600E mutation in cfDNA from the plasma and urine of 6 ECD patients. In patients with available archival tissue, the result of BRAF mutation analysis was concordant with plasma and urine cfDNA results in all 3 patients (100% agreement, kappa 1.00). In all 6 patients, BRAF mutation analysis of plasma and urine cfDNA was concordant in 5 of 6 patients (83% agreement, kappa 0.67). Testing for BRAF V600E mutation in plasma and urine cfDNA should be further investigated as an alternative to archival tissue mutation analysis
Ultrasensitive plasma ctDNA <i>KRAS</i> assay for detection, prognosis, and assessment of therapeutic response in patients with unresectable pancreatic ductal adenocarcinoma
Gravity model in the Korean highway
We investigate the traffic flows of the Korean highway system, which contains
both public and private transportation information. We find that the traffic
flow T(ij) between city i and j forms a gravity model, the metaphor of physical
gravity as described in Newton's law of gravity, P(i)P(j)/r(ij)^2, where P(i)
represents the population of city i and r(ij) the distance between cities i and
j. It is also shown that the highway network has a heavy tail even though the
road network is a rather uniform and homogeneous one. Compared to the highway
network, air and public ground transportation establish inhomogeneous systems
and have power-law behaviors.Comment: 13 page
A universal model for mobility and migration patterns
Introduced in its contemporary form by George Kingsley Zipf in 1946, but with
roots that go back to the work of Gaspard Monge in the 18th century, the
gravity law is the prevailing framework to predict population movement, cargo
shipping volume, inter-city phone calls, as well as bilateral trade flows
between nations. Despite its widespread use, it relies on adjustable parameters
that vary from region to region and suffers from known analytic
inconsistencies. Here we introduce a stochastic process capturing local
mobility decisions that helps us analytically derive commuting and mobility
fluxes that require as input only information on the population distribution.
The resulting radiation model predicts mobility patterns in good agreement with
mobility and transport patterns observed in a wide range of phenomena, from
long-term migration patterns to communication volume between different regions.
Given its parameter-free nature, the model can be applied in areas where we
lack previous mobility measurements, significantly improving the predictive
accuracy of most of phenomena affected by mobility and transport processes.Comment: Main text and supplementary informatio
Spatial correlations in attribute communities
Community detection is an important tool for exploring and classifying the
properties of large complex networks and should be of great help for spatial
networks. Indeed, in addition to their location, nodes in spatial networks can
have attributes such as the language for individuals, or any other
socio-economical feature that we would like to identify in communities. We
discuss in this paper a crucial aspect which was not considered in previous
studies which is the possible existence of correlations between space and
attributes. Introducing a simple toy model in which both space and node
attributes are considered, we discuss the effect of space-attribute
correlations on the results of various community detection methods proposed for
spatial networks in this paper and in previous studies. When space is
irrelevant, our model is equivalent to the stochastic block model which has
been shown to display a detectability-non detectability transition. In the
regime where space dominates the link formation process, most methods can fail
to recover the communities, an effect which is particularly marked when
space-attributes correlations are strong. In this latter case, community
detection methods which remove the spatial component of the network can miss a
large part of the community structure and can lead to incorrect results.Comment: 10 pages and 7 figure
Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders
Background
Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families.
Methods
Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA).
Results
A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals.
Conclusions
This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts
Adult and Embryonic GAD Transcripts Are Spatiotemporally Regulated during Postnatal Development in the Rat Brain
GABA (gamma-aminobutyric acid), the main inhibitory neurotransmitter in the brain, is synthesized by glutamic acid decarboxylase (GAD). GAD exists in two adult isoforms, GAD65 and GAD67. During embryonic brain development at least two additional transcripts exist, I-80 and I-86, which are distinguished by insertions of 80 or 86 bp into GAD67 mRNA, respectively. Though it was described that embryonic GAD67 transcripts are not detectable during adulthood there are evidences suggesting re-expression under certain pathological conditions in the adult brain. In the present study we systematically analyzed for the first time the spatiotemporal distribution of different GADs with emphasis on embryonic GAD67 mRNAs in the postnatal brain using highly sensitive methods. hybridizations confirmed the occurrence of embryonic GAD67 transcripts in the olfactory bulb and furthermore detected their localization mainly in the subventricular zone and the rostral migratory stream.Embryonic GAD67 transcripts can hardly be detected in the adult brain, except for specific regions associated with neurogenesis and high synaptic plasticity. Therefore a functional role in processes like proliferation, migration or synaptogenesis is suggested
Performance and Diagnostic Accuracy of a Urine-Based Human Papillomavirus Assay in a Referral Population
Cancer Research UK Programme grant C569/A16891 provided funding to J.M.
Cuzick, supplemented by financial contributions and assay kits to J.M. Cuzick from Trovagene,
Qiagen, BD, Abbott, Genera, Hologic and Oncohealth
Prognostic utility of HOXB13 : IL17BR and molecular grade index in early-stage breast cancer patients from the Stockholm trial
Background: A dichotomous index combining two gene expression assays, HOXB13:IL17BR (H:I) and molecular grade index (MGI), was developed to assess risk of recurrence in breast cancer patients. The study objective was to demonstrate the prognostic utility of the combined index in early-stage breast cancer. Methods: In a blinded retrospective analysis of 588 ER-positive tamoxifen-treated and untreated breast cancer patients from the randomized prospective Stockholm trial, H:I and MGI were measured using real-time RT-PCR. Association with patient outcome was evaluated by Kaplan-Meier analysis and Cox proportional hazard regression. A continuous risk index was developed using Cox modeling. Results: The dichotomous H:I+MGI was significantly associated with distant recurrence and breast cancer death. The >50% of tamoxifen-treated patients categorized as low-risk had <3% 10-year distant recurrence risk. A continuous risk model (Breast Cancer Index (BCI)) was developed with the tamoxifen-treated group and the prognostic performance tested in the untreated group was 53% of patients categorized as low-risk with an 8.3% 10-year distant recurrence risk. Conclusion: Retrospective analysis of this randomized, prospective trial cohort validated the prognostic utility of H:I+MGI and was used to develop and test a continuous risk model that enables prediction of distant recurrence risk at the patient level.Original Publication:Piiha-Lotta Jerevall, Xiai-Jun Ma, Hongying Li, Ranelle Salunga, Nicole C. Kesty, Mark G. Erlander, Dennis Sgroi, Birgitta Holmlund, Lambert Skoog, Tommy Fornander, Bo Nordenskjöld and Olle Stål, Prognostic utility of HOXB13:IL17BR and Molecular Grade Index in early-stage breast cancer patients from the Stockholm trial, 2011, British Journal of Cancer, (104), 11, 1762-1769.http://dx.doi.org/10.1038/bjc.2011.145Copyright: Nature Publishing Grouphttp://npg.nature.com
Prognostic utility of the breast cancer index and comparison to Adjuvant! Online in a clinical case series of early breast cancer
Introduction\ud
Breast Cancer Index (BCI) combines two independent biomarkers, HOXB13:IL17BR (H:I) and the 5-gene molecular grade index (MGI), that assess estrogen-mediated signalling and tumor grade, respectively. BCI stratifies early-stage estrogen-receptor positive (ER+), lymph-node negative (LN-) breast cancer patients into three risk groups and provides a continuous assessment of individual risk of distant recurrence. Objectives of the current study were to validate BCI in a clinical case series and to compare the prognostic utility of BCI and Adjuvant!Online (AO).\ud
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Methods\ud
Tumor samples from 265 ER+LN- tamoxifen-treated patients were identified from a single academic institution's cancer research registry. The BCI assay was performed and scores were assigned based on a pre-determined risk model. Risk was assessed by BCI and AO and correlated to clinical outcomes in the patient cohort.\ud
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Results\ud
BCI was a significant predictor of outcome in a cohort of 265 ER+LN- patients (median age: 56-y; median follow-up: 10.3-y), treated with adjuvant tamoxifen alone or tamoxifen with chemotherapy (32%). BCI categorized 55%, 21%, and 24% of patients as low, intermediate and high-risk, respectively. The 10-year rates of distant recurrence were 6.6%, 12.1% and 31.9% and of breast cancer-specific mortality were 3.8%, 3.6% and 22.1% in low, intermediate, and high-risk groups, respectively. In a multivariate analysis including clinicopathological factors, BCI was a significant predictor of distant recurrence (HR for 5-unit increase = 5.32 [CI 2.18-13.01; P = 0.0002]) and breast cancer-specific mortality (HR for a 5-unit increase = 9.60 [CI 3.20-28.80; P < 0.0001]). AO was significantly associated with risk of recurrence. In a separate multivariate analysis, both BCI and AO were significantly predictive of outcome. In a time-dependent (10-y) ROC curve accuracy analysis of recurrence risk, the addition of BCI+AO increased predictive accuracy in all patients from 66% (AO only) to 76% (AO+BCI) and in tamoxifen-only treated patients from 65% to 81%.\ud
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Conclusions\ud
This study validates the prognostic performance of BCI in ER+LN- patients. In this characteristically low-risk cohort, BCI classified high versus low-risk groups with ~5-fold difference in 10-year risk of distant recurrence and breast cancer-specific death. BCI and AO are independent predictors with BCI having additive utility beyond standard of care parameters that are encompassed in AO
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