Exhaled breath is a robust matrix of biomarkers divided between three fractions – gaseous breath, volatile breath, and breath condensate. Breath is collected non-invasively through bags (for gaseous ...breath), cold condensation chambers (breath condensate), and adsorbent traps (volatile breath). Due to the incredibly dilute nature of breath matrices, breath biomarker analysis requires precise analytical techniques, highly sensitive technology and often challenges the limit of detection of even the most advanced assays. Interest and advances in breath collection, analysis, and use have increased in recent years largely due to advances in analytical technology. Approved and validated breath tests are available as tools for researchers and clinicians. Novel development is ongoing. This article reviews the current applications for exhaled breath biomarkers.
The KEAP1–NRF2-mediated cytoprotective response plays a key role in cellular homoeostasis. Insufficient NRF2 signaling during chronic oxidative stress may be associated with the pathophysiology of ...several diseases with an inflammatory component, and pathway activation through direct modulation of the KEAP1–NRF2 protein–protein interaction is being increasingly explored as a potential therapeutic strategy. Nevertheless, the physicochemical nature of the KEAP1–NRF2 interface suggests that achieving high affinity for a cell-penetrant druglike inhibitor might be challenging. We recently reported the discovery of a highly potent tool compound which was used to probe the biology associated with directly disrupting the interaction of NRF2 with the KEAP1 Kelch domain. We now present a detailed account of the medicinal chemistry campaign leading to this molecule, which included exploration and optimization of protein–ligand interactions in three energetic “hot spots” identified by fragment screening. In particular, we also discuss how consideration of ligand conformational stabilization was important to its development and present evidence for preorganization of the lead compound which may contribute to its high affinity and cellular activity.
The Neotoma Paleoecology Database is a community-curated data resource that supports interdisciplinary global change research by enabling broad-scale studies of taxon and community diversity, ...distributions, and dynamics during the large environmental changes of the past. By consolidating many kinds of data into a common repository, Neotoma lowers costs of paleodata management, makes paleoecological data openly available, and offers a high-quality, curated resource. Neotoma’s distributed scientific governance model is flexible and scalable, with many open pathways for participation by new members, data contributors, stewards, and research communities. The Neotoma data model supports, or can be extended to support, any kind of paleoecological or paleoenvironmental data from sedimentary archives. Data additions to Neotoma are growing and now include >3.8 million observations, >17,000 datasets, and >9200 sites. Dataset types currently include fossil pollen, vertebrates, diatoms, ostracodes, macroinvertebrates, plant macrofossils, insects, testate amoebae, geochronological data, and the recently added organic biomarkers, stable isotopes, and specimen-level data. Multiple avenues exist to obtain Neotoma data, including the Explorer map-based interface, an application programming interface, the neotoma R package, and digital object identifiers. As the volume and variety of scientific data grow, community-curated data resources such as Neotoma have become foundational infrastructure for big data science.
•The authors propose Omega-Net: A novel convolutional neural network architecture for the detection, orientation, and segmentation of cardiac MR images.•Three modules comprise the network: a ...coarse-grained segmentation module, an attention module, and a fine-grained segmentation module.•The network is trained end-to-end from scratch using three-fold crossvalidation in 63 subjects (42 with hypertrophic cardiomyopathy, 21 healthy).•Performance of the Omega-Net is substantively improved compared with UNet alone.•In addition, to be comparable with other works, Omega-Net was retrained from scratch using five-fold cross-validation on the publicly available 2017 MICCAI Automated Cardiac Diagnosis Challenge (ACDC) dataset, achieving state-of-the-art performance in two of three segmentation classes.
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Pixelwise segmentation of the left ventricular (LV) myocardium and the four cardiac chambers in 2-D steady state free precession (SSFP) cine sequences is an essential preprocessing step for a wide range of analyses. Variability in contrast, appearance, orientation, and placement of the heart between patients, clinical views, scanners, and protocols makes fully automatic semantic segmentation a notoriously difficult problem. Here, we present Ω-Net (Omega-Net): A novel convolutional neural network (CNN) architecture for simultaneous localization, transformation into a canonical orientation, and semantic segmentation. First, an initial segmentation is performed on the input image; second, the features learned during this initial segmentation are used to predict the parameters needed to transform the input image into a canonical orientation; and third, a final segmentation is performed on the transformed image. In this work, Ω-Nets of varying depths were trained to detect five foreground classes in any of three clinical views (short axis, SA; four-chamber, 4C; two-chamber, 2C), without prior knowledge of the view being segmented. This constitutes a substantially more challenging problem compared with prior work. The architecture was trained using three-fold cross-validation on a cohort of patients with hypertrophic cardiomyopathy (HCM, N=42) and healthy control subjects (N=21). Network performance, as measured by weighted foreground intersection-over-union (IoU), was substantially improved for the best-performing Ω-Net compared with U-Net segmentation without localization or orientation (0.858 vs 0.834). In addition, to be comparable with other works, Ω-Net was retrained from scratch using five-fold cross-validation on the publicly available 2017 MICCAI Automated Cardiac Diagnosis Challenge (ACDC) dataset. The Ω-Net outperformed the state-of-the-art method in segmentation of the LV and RV bloodpools, and performed slightly worse in segmentation of the LV myocardium. We conclude that this architecture represents a substantive advancement over prior approaches, with implications for biomedical image segmentation more generally.
Osteoarthritis (OA) is the most common form of arthritis worldwide. Pain and reduced function are the main symptoms in this prevalent disease. There are currently no treatments for OA that modify ...disease progression; therefore analgesic drugs and joint replacement for larger joints are the standard of care. In light of several recent studies reporting the use of bisphosphonates for OA treatment, our work aimed to evaluate published literature to assess the effectiveness of bisphosphonates in OA treatment.
Literature databases were searched from inception to the 30th June 2012 for clinical trials of bisphosphonates to treat OA pain. Data was appraised and levels of evidence determined qualitatively using best evidence synthesis from the Cochrane Collaboration. The two largest studies were conducted with risedronate in the treatment of knee OA, for which meta-analyses were performed for pain and functional outcomes.
Our searches found 13/297 eligible studies, which included a total of 3832 participants. The trials recruited participants with OA of the hand (n=1), knee (n=8), knee and spine (n=3), or hip (n=1). Our meta-analysis of the two largest knee studies using risedronate 15 mg showed odds ratios favouring placebo interventions for the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain (1.73), WOMAC function (2.03), and WOMAC stiffness (1.82). However, 8 trials (61.5%) reported that bisphosphonates improve pain assessed by VAS scores and 2 (38.5%) reported significant improvement in WOMAC pain scores compared to control groups.
There is limited evidence that bisphosphonates are effective in the treatment of OA pain. Limitations of the studies we analysed included the differences in duration of bisphosphonate use, the dose and route of administration and the lack of long-term data on OA joint structure modification post-bisphosphonate therapy. Future more targeted studies are required to appreciate the value of bisphosphonates in treating osteoarthritis pain.
PROSPERO Register CRD42012002541.
To calculate the incidence of burning mouth syndrome (BMS) in Olmsted County, Minnesota, from 2000 through 2010.
By using the medical record linkage system of the Rochester Epidemiology Project, we ...identified newly diagnosed cases of BMS from January 1, 2000, through December 31, 2010. Diagnoses were confirmed through the presence of burning pain symptoms of the oral mucosa with normal oral examination findings and no associated clinical signs. Incidence was estimated using decennial census data for Olmsted County.
In total, 169 incident cases were identified, representing an annual age- and sex-adjusted incidence of BMS of 11.4 per 100,000 person-years. Age-adjusted incidence was significantly higher in women than in men (18.8 95% CI, 16.4-22.9 per 100,000 person-years vs 3.7 95% CI, 2.6-5.7 per 100,000 person-years; P<.001). Postmenopausal women aged 50 to 89 years had the highest incidence of the disease, with the maximal rate observed in women aged 70 to 79 years (70.3 per 100,000 person-years). After the age of 50 years, the incidence of BMS in men and women significantly increased across age groups (P=.02). Study participants residing in Olmsted County, Minnesota, were predominantly white, which is a study limitation. In addition, diagnostic criteria for identifying BMS in the present study may not apply for all situations because no diagnostic criteria are universally recognized for identifying BMS.
To our knowledge, this is the first population-based incidence study of BMS reported to date. The data reveal that BMS is an uncommon disease highly associated with female sex and advancing age.
Although more than thirty mammalian genomes have been sequenced to draft quality, very few of these include the Y chromosome. This has limited our understanding of the evolutionary dynamics of gene ...persistence and loss, our ability to identify conserved regulatory elements, as well our knowledge of the extent to which different types of selection act to maintain genes within this unique genomic environment. Here, we present the first MSY (male-specific region of the Y chromosome) sequences from two carnivores, the domestic dog and cat. By combining these with other available MSY data, our multiordinal comparison allows for the first accounting of levels of selection constraining the evolution of eutherian Y chromosomes. Despite gene gain and loss across the phylogeny, we show the eutherian ancestor retained a core set of 17 MSY genes, most being constrained by negative selection for nearly 100 million years. The X-degenerate and ampliconic gene classes are partitioned into distinct chromosomal domains in most mammals, but were radically restructured on the human lineage. We identified multiple conserved noncoding elements that potentially regulate eutherian MSY genes. The acquisition of novel ampliconic gene families was accompanied by signatures of positive selection and has differentially impacted the degeneration and expansion of MSY gene repertoires in different species.
Exhaled Breath Condensate: An Update Davis, Michael D; Montpetit, Alison J
Immunology and allergy clinics of North America,
11/2018, Letnik:
38, Številka:
4
Journal Article
Recenzirano
Exhaled breath condensate (EBC) is a promising source of biomarkers of lung disease. EBC research and utility has increased substantially over the past 2 decades. This review summarizes many of the ...factors regarding the composition of EBC, its collection, and analysis for the utility of both clinicians and researchers.
To assess the efficacy of pembrolizumab in patients with advanced relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS).
CITN-10 is a single-arm, multicenter phase II trial of 24 ...patients with advanced MF or SS. Patients were treated with pembrolizumab 2 mg/kg every 3 weeks for up to 24 months. The primary end point was overall response rate by consensus global response criteria.
Patients had advanced-stage disease (23 of 24 with stage IIB to IV MF/SS) and were heavily pretreated with a median of four prior systemic therapies. The overall response rate was 38% with two complete responses and seven partial responses. Of the nine responding patients, six had 90% or more improvement in skin disease by modified Severity Weighted Assessment Tool, and eight had ongoing responses at last follow-up. The median duration of response was not reached, with a median response follow-up time of 58 weeks. Immune-related adverse events led to treatment discontinuation in four patients. A transient worsening of erythroderma and pruritus occurred in 53% of patients with SS. This cutaneous flare reaction did not result in treatment discontinuation for any patient. The flare reaction correlated with high PD-1 expression on Sézary cells but did not associate with subsequent clinical responses or lack of response. Treatment responses did not correlate with expression of PD-L1, total mutation burden, or an interferon-γ gene expression signature.
Pembrolizumab demonstrated significant antitumor activity with durable responses and a favorable safety profile in patients with advanced MF/SS.
We have produced
-deficient rats by homologous recombination in embryonic stem cells. Consistent with the role of
in macrophage differentiation, there was a loss of peripheral blood monocytes, ...microglia in the brain, epidermal Langerhans cells, splenic marginal zone macrophages, bone-associated macrophages and osteoclasts, and peritoneal macrophages. Macrophages of splenic red pulp, liver, lung, and gut were less affected. The pleiotropic impacts of the loss of macrophages on development of multiple organ systems in rats were distinct from those reported in mice.
rats survived well into adulthood with postnatal growth retardation, distinct skeletal and bone marrow abnormalities, infertility, and loss of visceral adipose tissue. Gene expression analysis in spleen revealed selective loss of transcripts associated with the marginal zone and, in brain regions, the loss of known and candidate novel microglia-associated transcripts. Despite the complete absence of microglia, there was little overt phenotype in brain, aside from reduced myelination and increased expression of dopamine receptor-associated transcripts in striatum. The results highlight the redundant and nonredundant functions of CSF1R signaling and of macrophages in development, organogenesis, and homeostasis.
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