The generation of new lymphatic vessels through lymphangiogenesis and the remodelling of existing lymphatics are thought to be important steps in cancer metastasis. The past decade has been exciting ...in terms of research into the molecular and cellular biology of lymphatic vessels in cancer, and it has been shown that the molecular control of tumour lymphangiogenesis has similarities to that of tumour angiogenesis. Nevertheless, there are significant mechanistic differences between these biological processes. We are now developing a greater understanding of the specific roles of distinct lymphatic vessel subtypes in cancer, and this provides opportunities to improve diagnostic and therapeutic approaches that aim to restrict the progression of cancer.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
In vitro models of the developing brain such as three-dimensional brain organoids offer an unprecedented opportunity to study aspects of human brain development and disease. However, the cells ...generated within organoids and the extent to which they recapitulate the regional complexity, cellular diversity and circuit functionality of the brain remain undefined. Here we analyse gene expression in over 80,000 individual cells isolated from 31 human brain organoids. We find that organoids can generate a broad diversity of cells, which are related to endogenous classes, including cells from the cerebral cortex and the retina. Organoids could be developed over extended periods (more than 9 months), allowing for the establishment of relatively mature features, including the formation of dendritic spines and spontaneously active neuronal networks. Finally, neuronal activity within organoids could be controlled using light stimulation of photosensitive cells, which may offer a way to probe the functionality of human neuronal circuits using physiological sensory stimuli.
Lymphatic metastasis is facilitated by lymphangiogenic growth factors VEGF-C and VEGF-D that are secreted by some primary tumors. We identified regulation of PGDH, the key enzyme in prostaglandin ...catabolism, in endothelial cells of collecting lymphatics, as a key molecular change during VEGF-D-driven tumor spread. The VEGF-D-dependent regulation of the prostaglandin pathway was supported by the finding that collecting lymphatic vessel dilation and subsequent metastasis were affected by nonsteroidal anti-inflammatory drugs (NSAIDs), known inhibitors of prostaglandin synthesis. Our data suggest a control point for cancer metastasis within the collecting lymphatic endothelium, which links VEGF-D/VEGFR-2/VEGFR-3 and the prostaglandin pathways. Collecting lymphatics therefore play an active and important role in metastasis and may provide a therapeutic target to restrict tumor spread.
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► Collecting lymphatics undergo critical morphological changes during metastasis ► Isolated and characterized collecting lymphatic endothelial cells (cLECs) ► VEGF-D regulation of prostaglandins in cLECs facilitates metastasis ► NSAIDs as potential antimetastatic therapies for VEGF-D-driven spread
The soil transmitted helminths are a group of parasitic worms responsible for extensive morbidity in many of the world's most economically depressed locations. With growing emphasis on disease ...mapping and eradication, the availability of accurate and cost-effective diagnostic measures is of paramount importance to global control and elimination efforts. While real-time PCR-based molecular detection assays have shown great promise, to date, these assays have utilized sub-optimal targets. By performing next-generation sequencing-based repeat analyses, we have identified high copy-number, non-coding DNA sequences from a series of soil transmitted pathogens. We have used these repetitive DNA elements as targets in the development of novel, multi-parallel, PCR-based diagnostic assays.
Utilizing next-generation sequencing and the Galaxy-based RepeatExplorer web server, we performed repeat DNA analysis on five species of soil transmitted helminths (Necator americanus, Ancylostoma duodenale, Trichuris trichiura, Ascaris lumbricoides, and Strongyloides stercoralis). Employing high copy-number, non-coding repeat DNA sequences as targets, novel real-time PCR assays were designed, and assays were tested against established molecular detection methods. Each assay provided consistent detection of genomic DNA at quantities of 2 fg or less, demonstrated species-specificity, and showed an improved limit of detection over the existing, proven PCR-based assay.
The utilization of next-generation sequencing-based repeat DNA analysis methodologies for the identification of molecular diagnostic targets has the ability to improve assay species-specificity and limits of detection. By exploiting such high copy-number repeat sequences, the assays described here will facilitate soil transmitted helminth diagnostic efforts. We recommend similar analyses when designing PCR-based diagnostic tests for the detection of other eukaryotic pathogens.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Using the power of gravitational lensing magnification by massive galaxy clusters, the Hubble Frontier Fields provide deep views of six patches of the high-redshift Universe. The combination of deep ...Hubble imaging and exceptional lensing strength has revealed the greatest numbers of multiply-imaged galaxies available to constrain models of cluster mass distributions. However, even with O(100) images per cluster, the uncertainties associated with the reconstructions are not negligible. The goal of this paper is to show the diversity of model magnification predictions. We examine seven and nine mass models of Abell 2744 and MACS J0416, respectively, submitted to the Mikulski Archive for Space Telescopes for public distribution in 2015 September. The dispersion between model predictions increases from 30 per cent at common low magnifications (... ~ 2) to 70 per cent at rare high magnifications (... ~ 40). MACS J0416 exhibits smaller dispersions than Abell 2744 for 2 < ... < 10. We show that magnification maps based on different lens inversion techniques typically differ from each other by more than their quoted statistical errors. This suggests that some models underestimate the true uncertainties, which are primarily due to various lensing degeneracies. Though the exact mass sheet degeneracy is broken, its generalized counterpart is not broken at least in Abell 2744. Other local degeneracies are also present in both clusters. Our comparison of models is complementary to the comparison of reconstructions of known synthetic mass distributions. By focusing on observed clusters, we can identify those that are best constrained, and therefore provide the clearest view of the distant Universe. (ProQuest: ... denotes formulae/symbols omitted.)
Splicing varies across brain regions, but the single-cell resolution of regional variation is unclear. We present a single-cell investigation of differential isoform expression (DIE) between brain ...regions using single-cell long-read sequencing in mouse hippocampus and prefrontal cortex in 45 cell types at postnatal day 7 ( www.isoformAtlas.com ). Isoform tests for DIE show better performance than exon tests. We detect hundreds of DIE events traceable to cell types, often corresponding to functionally distinct protein isoforms. Mostly, one cell type is responsible for brain-region specific DIE. However, for fewer genes, multiple cell types influence DIE. Thus, regional identity can, although rarely, override cell-type specificity. Cell types indigenous to one anatomic structure display distinctive DIE, e.g. the choroid plexus epithelium manifests distinct transcription-start-site usage. Spatial transcriptomics and long-read sequencing yield a spatially resolved splicing map. Our methods quantify isoform expression with cell-type and spatial resolution and it contributes to further our understanding of how the brain integrates molecular and cellular complexity.
Current ablation therapy for atrial fibrillation is suboptimal, and long-term response is challenging to predict. Clinical trials identify bedside properties that provide only modest prediction of ...long-term response in populations, while patient-specific models in small cohorts primarily explain acute response to ablation. We aimed to predict long-term atrial fibrillation recurrence after ablation in large cohorts, by using machine learning to complement biophysical simulations by encoding more interindividual variability.
Patient-specific models were constructed for 100 atrial fibrillation patients (43 paroxysmal, 41 persistent, and 16 long-standing persistent), undergoing first ablation. Patients were followed for 1 year using ambulatory ECG monitoring. Each patient-specific biophysical model combined differing fibrosis patterns, fiber orientation maps, electrical properties, and ablation patterns to capture uncertainty in atrial properties and to test the ability of the tissue to sustain fibrillation. These simulation stress tests of different model variants were postprocessed to calculate atrial fibrillation simulation metrics. Machine learning classifiers were trained to predict atrial fibrillation recurrence using features from the patient history, imaging, and atrial fibrillation simulation metrics.
We performed 1100 atrial fibrillation ablation simulations across 100 patient-specific models. Models based on simulation stress tests alone showed a maximum accuracy of 0.63 for predicting long-term fibrillation recurrence. Classifiers trained to history, imaging, and simulation stress tests (average 10-fold cross-validation area under the curve, 0.85±0.09; recall, 0.80±0.13; precision, 0.74±0.13) outperformed those trained to history and imaging (area under the curve, 0.66±0.17) or history alone (area under the curve, 0.61±0.14).
A novel computational pipeline accurately predicted long-term atrial fibrillation recurrence in individual patients by combining outcome data with patient-specific acute simulation response. This technique could help to personalize selection for atrial fibrillation ablation.
For more than a decade, early treatment of sepsis has been driven by algorithms. In this study conducted predominantly in Australia and New Zealand, the use of algorithm-based treatment was not ...superior to usual care.
Severe sepsis has a reported annual incidence in adults of up to 300 cases per 100,000 population.
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Despite decreasing mortality from sepsis in recent years,
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the risk of death remains high.
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The fundamental principles for the management of sepsis include early recognition, control of the source of infection, appropriate and timely administration of antimicrobial drugs, and resuscitation with intravenous fluids and vasoactive drugs.
Patients presenting to the emergency department account for a large proportion of patients with severe sepsis.
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Reported in-hospital mortality ranges in this subgroup from 20 to 50%.
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In 2001, a proof-of-concept, randomized trial . . .
This clinical report updates and replaces a 2008 clinical report from the American Academy of Pediatrics, which addressed the roles of maternal and early infant diet on the prevention of atopic ...disease, including atopic dermatitis, asthma, and food allergy. As with the previous report, the available data still limit the ability to draw firm conclusions about various aspects of atopy prevention through early dietary interventions. Current evidence does not support a role for maternal dietary restrictions during pregnancy or lactation. Although there is evidence that exclusive breastfeeding for 3 to 4 months decreases the incidence of eczema in the first 2 years of life, there are no short- or long-term advantages for exclusive breastfeeding beyond 3 to 4 months for prevention of atopic disease. The evidence now suggests that any duration of breastfeeding ≥3 to 4 months is protective against wheezing in the first 2 years of life, and some evidence suggests that longer duration of any breastfeeding protects against asthma even after 5 years of age. No conclusions can be made about the role of breastfeeding in either preventing or delaying the onset of specific food allergies. There is a lack of evidence that partially or extensively hydrolyzed formula prevents atopic disease. There is no evidence that delaying the introduction of allergenic foods, including peanuts, eggs, and fish, beyond 4 to 6 months prevents atopic disease. There is now evidence that early introduction of peanuts may prevent peanut allergy.
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