Massively parallel sequencing technologies hold incredible promise for the study of DNA sequence variation, particularly the identification of variants affecting human disease. The unprecedented ...throughput and relatively short read lengths of Roche/454, Illumina/Solexa, and other platforms have spurred development of a new generation of sequence alignment algorithms. Yet detection of sequence variants based on short read alignments remains challenging, and most currently available tools are limited to a single platform or aligner type. We present VarScan, an open source tool for variant detection that is compatible with several short read aligners. We demonstrate VarScan's ability to detect SNPs and indels with high sensitivity and specificity, in both Roche/454 sequencing of individuals and deep Illumina/Solexa sequencing of pooled samples. Availability and Implementation: Source code and documentation freely available at http://genome.wustl.edu/tools/cancer-genomics implemented as a Perl package and supported on Linux/UNIX, MS Windows and Mac OSX. Contact: dkoboldt@genome.wustl.edu Supplementary information: Supplementary data are available at Bioinformatics online.
Whole-genome sequencing of samples from seven subjects with secondary acute myeloid leukemia identified somatic mutations. These data, together with genotype analysis of the antecedent ...myelodysplastic syndromes (MDS), revealed the clonal evolution of MDS and secondary AML.
The myelodysplastic syndromes, a heterogeneous group of diseases characterized by ineffective hematopoiesis, are the most common cause of acquired bone marrow failure in adults.
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Secondary acute myeloid leukemia (AML) develops in approximately one third of persons with myelodysplastic syndromes.
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Clinical discrimination between the myelodysplastic syndromes and secondary AML currently rests predominantly on cytomorphologic analysis, since patients with myelodysplastic syndromes have dysplastic hematopoiesis and a myeloblast count of less than 20%, whereas those with a myeloblast count of 20% or more have AML. Although considerable overlap exists between the spectrum of cytogenetic and molecular lesions seen in the two disorders, there . . .
Predictive modeling with electronic health record (EHR) data is anticipated to drive personalized medicine and improve healthcare quality. Constructing predictive statistical models typically ...requires extraction of curated predictor variables from normalized EHR data, a labor-intensive process that discards the vast majority of information in each patient's record. We propose a representation of patients' entire raw EHR records based on the Fast Healthcare Interoperability Resources (FHIR) format. We demonstrate that deep learning methods using this representation are capable of accurately predicting multiple medical events from multiple centers without site-specific data harmonization. We validated our approach using de-identified EHR data from two US academic medical centers with 216,221 adult patients hospitalized for at least 24 h. In the sequential format we propose, this volume of EHR data unrolled into a total of 46,864,534,945 data points, including clinical notes. Deep learning models achieved high accuracy for tasks such as predicting: in-hospital mortality (area under the receiver operator curve AUROC across sites 0.93-0.94), 30-day unplanned readmission (AUROC 0.75-0.76), prolonged length of stay (AUROC 0.85-0.86), and all of a patient's final discharge diagnoses (frequency-weighted AUROC 0.90). These models outperformed traditional, clinically-used predictive models in all cases. We believe that this approach can be used to create accurate and scalable predictions for a variety of clinical scenarios. In a case study of a particular prediction, we demonstrate that neural networks can be used to identify relevant information from the patient's chart.
There is a need for in vivo diagnostic imaging probes that can noninvasively measure tumor-infiltrating CD8+ leukocytes. Such imaging probes could be used to predict early response to cancer ...immunotherapy, help select effective single or combination immunotherapies, and facilitate the development of new immunotherapies or immunotherapy combinations. This study was designed to optimize conditions for performing CD8 PET imaging with 89Zr-Df-IAB22M2C and determine whether CD8 PET imaging could provide a safe and effective noninvasive method of visualizing the whole-body biodistribution of CD8+ leukocytes. Methods: We conducted a phase 1 first-in-humans PET imaging study using an anti-CD8 radiolabeled minibody, 89Zr-Df-IAB22M2C, to detect whole-body and tumor CD8+ leukocyte distribution in patients with metastatic solid tumors. Patients received 111 MBq of 89Zr-Df-IAB22M2C followed by serial PET scanning over 5–7 d. A 2-stage design included a dose-escalation phase and a dose-expansion phase. Biodistribution, radiation dosimetry, and semiquantitative evaluation of 89Zr-Df-IAB22M2C uptake were performed in all patients. Results: Fifteen subjects with metastatic melanoma, non–small cell lung cancer, and hepatocellular carcinoma were enrolled. No drug-related adverse events or abnormal laboratory results were noted except for a transient increase in antidrug antibodies in 1 subject. 89Zr-Df-IAB22M2C accumulated in tumors and CD8-rich tissues (e.g., spleen, bone marrow, nodes), with maximum uptake at 24–48 h after injection and low background activity in CD8-poor tissues (e.g., muscle and lung). Radiotracer uptake in tumors was noted in 10 of 15 subjects, including 7 of 8 subjects on immunotherapy, 1 of 2 subjects on targeted therapy, and 2 of 5 treatment-naïve subjects. In 3 patients with advanced melanoma or hepatocellular carcinoma on immunotherapy, posttreatment CD8 PET/CT scans demonstrated increased 89Zr-Df-IAB22M2C uptake in tumor lesions, which correlated with response. Conclusion: CD8 PET imaging with 89Zr-Df-IAB22M2C is safe and has the potential to visualize the whole-body biodistribution of CD8+ leukocytes in tumors and reference tissues, and may predict early response to immunotherapy.
How species with similar repertoires of protein-coding genes differ so markedly at the phenotypic level is poorly understood. By comparing organ transcriptomes from vertebrate species spanning ∼350 ...million years of evolution, we observed significant differences in alternative splicing complexity between vertebrate lineages, with the highest complexity in primates. Within 6 million years, the splicing profiles of physiologically equivalent organs diverged such that they are more strongly related to the identity of a species than they are to organ type. Most vertebrate species-specific splicing patterns are cis-directed. However, a subset of pronounced splicing changes are predicted to remodel protein interactions involving trans-acting regulators. These events likely further contributed to the diversification of splicing and other transcriptomic changes that underlie phenotypic differences among vertebrate species.
Aggressive cancers often have activating mutations in growth-controlling oncogenes and inactivating mutations in tumor-suppressor genes. In neuroblastoma, amplification of the MYCN oncogene and ...inactivation of the ATRX tumor-suppressor gene correlate with high-risk disease and poor prognosis. Here we show that ATRX mutations and MYCN amplification are mutually exclusive across all ages and stages in neuroblastoma. Using human cell lines and mouse models, we found that elevated MYCN expression and ATRX mutations are incompatible. Elevated MYCN levels promote metabolic reprogramming, mitochondrial dysfunction, reactive-oxygen species generation, and DNA-replicative stress. The combination of replicative stress caused by defects in the ATRX-histone chaperone complex, and that induced by MYCN-mediated metabolic reprogramming, leads to synthetic lethality. Therefore, ATRX and MYCN represent an unusual example, where inactivation of a tumor-suppressor gene and activation of an oncogene are incompatible. This synthetic lethality may eventually be exploited to improve outcomes for patients with high-risk neuroblastoma.
The red fox Vulpes vulpes is one of the world’s most widespread carnivores. A key to its success has been its broad, opportunistic diet. The fox was introduced to Australia about 150 years ago, and ...within 30 years of its introduction was already recognised as a threat to livestock and native wildlife.
We reviewed 85 fox diet studies (totalling 31693 samples) from throughout the species’ geographic range within Australia. Mammals were a major component of fox diet, being present in 70 ± 19% of samples across n = 160 locations. Invertebrates (38 ± 26% n = 130) and plant material (26 ± 25% n = 123) were also both staple foods and often the dominant food category recorded. Birds (13 ± 11% n = 137) and reptiles (10 ± 15% n = 132) were also commonly reported, while frogs were scarcely represented (1.6 ± 3.6% n = 111) in fox diet studies.
Biogeographical differences reveal factors that likely determine prey availability. Diet composition varied with ecosystem, level of vegetation clearing and condition, and climate zone.
Sample type (i.e. stomach versus scat samples) also significantly influenced reporting of diet composition. Livestock and frogs were underrepresented in records based on analysis of scats, whereas small mammals (native rodents, dasyurid marsupials, and bats) were more likely to be recorded in studies of scats than in studies of stomach contents.
Diet varied seasonally, reflecting activity patterns of prey species and food availability. This synthesis also captures temporal shifts in fox diet over 70 years (1951–2020), as foxes have switched to consuming more native species in the wake of successful broadscale biological control of the invasive European rabbit Oryctolagus cuniculus.
Diet analyses, such as those summarised in this review, capture the evidence required to motivate for greater control of foxes in Australia. This synthesis also highlights the importance of integrated pest species management to meet biodiversity conservation outcomes.
Since its introduction to Australia about 150 years ago, the red fox has become established across all but the northern tropical climates. Foxes are opportunistic carnivores taking a broad range of food items, from the smallest insects through to large mammal species. Fox populations have been established and supplemented by the spread of other introduced species (black bars in this figure) – especially the invasive European rabbit Oryctolagus cuniculus, house mouse Mus musculus, and livestock. Subsequent predation by foxes on native wildlife has devastated local wildlife populations, contributing to the extinction and extirpation of Australian native species. This review of 85 studies and about 31700 samples reveals biogeographical differences that capture the range of factors determining prey availability. This synthesis also identifies temporal shifts in fox diet over 70 years (1951–2020), as foxes have switched to consuming more native species in the wake of successful rabbit biocontrol. These changes highlight the importance of holistic management of invasive and introduced species for biodiversity conservation.
The pathogenesis of Alzheimer's disease (AD) is a critical unsolved question; and although recent studies have demonstrated a strong association between altered brain immune responses and disease ...progression, the mechanistic cause of neuronal dysfunction and death is unknown. We have previously described the unique CVN-AD mouse model of AD, in which immune-mediated nitric oxide is lowered to mimic human levels, resulting in a mouse model that demonstrates the cardinal features of AD, including amyloid deposition, hyperphosphorylated and aggregated tau, behavioral changes, and age-dependent hippocampal neuronal loss. Using this mouse model, we studied longitudinal changes in brain immunity in relation to neuronal loss and, contrary to the predominant view that AD pathology is driven by proinflammatory factors, we find that the pathology in CVN-AD mice is driven by local immune suppression. Areas of hippocampal neuronal death are associated with the presence of immunosuppressive CD11c(+) microglia and extracellular arginase, resulting in arginine catabolism and reduced levels of total brain arginine. Pharmacologic disruption of the arginine utilization pathway by an inhibitor of arginase and ornithine decarboxylase protected the mice from AD-like pathology and significantly decreased CD11c expression. Our findings strongly implicate local immune-mediated amino acid catabolism as a novel and potentially critical mechanism mediating the age-dependent and regional loss of neurons in humans with AD.
The axial skeleton of extinct saurischian dinosaurs (i.e., theropods, sauropodomorphs), like living birds, was pneumatized by epithelial outpocketings of the respiratory system. Pneumatic signatures ...in the vertebral column of fossil saurischians include complex branching chambers within the bone (internal pneumaticity) and large chambers visible externally that are bounded by neural arch laminae (external pneumaticity). Although general aspects of internal pneumaticity are synapomorphic for saurischian subgroups, the individual internal pneumatic spaces cannot be homologized across species or even along the vertebral column, due to their variability and absence of topographical landmarks. External pneumatic structures, in contrast, are defined by ready topological landmarks (vertebral laminae), but no consistent nomenclatural system exists. This deficiency has fostered confusion and limited their use as character data in phylogenetic analysis.
We present a simple system for naming external neural arch fossae that parallels the one developed for the vertebral laminae that bound them. The nomenclatural system identifies fossae by pointing to reference landmarks (e.g., neural spine, centrum, costal articulations, zygapophyses). We standardize the naming process by creating tripartite names from "primary landmarks," which form the zygodiapophyseal table, "secondary landmarks," which orient with respect to that table, and "tertiary landmarks," which further delineate a given fossa.
The proposed nomenclatural system for lamina-bounded fossae adds clarity to descriptions of complex vertebrae and allows these structures to be sourced as character data for phylogenetic analyses. These anatomical terms denote potentially homologous pneumatic structures within Saurischia, but they could be applied to any vertebrate with vertebral laminae that enclose spaces, regardless of their developmental origin or phylogenetic distribution.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective:
To characterize cognitive and behavioral features, physical findings, and brain atrophy patterns in pathology‐proven corticobasal degeneration (CBD) and corticobasal syndrome (CBS) with ...known histopathology.
Methods:
We reviewed clinical and magnetic resonance imaging data in all patients evaluated at our center with either an autopsy diagnosis of CBD (n = 18) or clinical CBS at first presentation with known histopathology (n = 40). Atrophy patterns were compared using voxel‐based morphometry.
Results:
CBD was associated with 4 clinical syndromes: progressive nonfluent aphasia (n = 5), behavioral variant frontotemporal dementia (n = 5), executive‐motor (n = 7), and posterior cortical atrophy (n = 1). Behavioral or cognitive problems were the initial symptoms in 15 of 18 patients; less than half exhibited early motor findings. Compared to controls, CBD patients showed atrophy in dorsal prefrontal and perirolandic cortex, striatum, and brainstem (p < 0.001 uncorrected). The most common pathologic substrates for clinical CBS were CBD (35%), Alzheimer disease (AD, 23%), progressive supranuclear palsy (13%), and frontotemporal lobar degeneration (FTLD) with TDP inclusions (13%). CBS was associated with perirolandic atrophy irrespective of underlying pathology. In CBS due to FTLD (tau or TDP), atrophy extended into prefrontal cortex, striatum, and brainstem, whereas in CBS due to AD, atrophy extended into temporoparietal cortex and precuneus (p < 0.001 uncorrected).
Interpretation:
Frontal lobe involvement is characteristic of CBD, and in many patients frontal, not parietal or basal ganglia, symptoms dominate early stage disease. CBS is driven by medial perirolandic dysfunction, but this anatomy is not specific to a single underlying histopathology. Antemortem prediction of CBD will remain challenging until clinical features of CBD are redefined, and sensitive, specific biomarkers are identified. ANN NEUROL 2011;
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