For many complex traits, gene regulation is likely to play a crucial mechanistic role. How the genetic architectures of complex traits vary between populations and subsequent effects on genetic ...prediction are not well understood, in part due to the historical paucity of GWAS in populations of non-European ancestry. We used data from the MESA (Multi-Ethnic Study of Atherosclerosis) cohort to characterize the genetic architecture of gene expression within and between diverse populations. Genotype and monocyte gene expression were available in individuals with African American (AFA, n = 233), Hispanic (HIS, n = 352), and European (CAU, n = 578) ancestry. We performed expression quantitative trait loci (eQTL) mapping in each population and show genetic correlation of gene expression depends on shared ancestry proportions. Using elastic net modeling with cross validation to optimize genotypic predictors of gene expression in each population, we show the genetic architecture of gene expression for most predictable genes is sparse. We found the best predicted gene in each population, TACSTD2 in AFA and CHURC1 in CAU and HIS, had similar prediction performance across populations with R2 > 0.8 in each population. However, we identified a subset of genes that are well-predicted in one population, but poorly predicted in another. We show these differences in predictive performance are due to allele frequency differences between populations. Using genotype weights trained in MESA to predict gene expression in independent populations showed that a training set with ancestry similar to the test set is better at predicting gene expression in test populations, demonstrating an urgent need for diverse population sampling in genomics. Our predictive models and performance statistics in diverse cohorts are made publicly available for use in transcriptome mapping methods at https://github.com/WheelerLab/DivPop.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Intracranial neoplasia is a common clinical condition in domestic companion animals, particularly in dogs. Application of advances in standard diagnostic and therapeutic modalities together with a ...broad interest in the development of novel translational therapeutic strategies in dogs has resulted in clinically relevant improvements in outcome for many canine patients. This review highlights the status of current diagnostic and therapeutic approaches to intracranial neoplasia and areas of novel treatment currently in development.
Purpose
To compare the shrinkage of denture bases fabricated by three methods: CAD/CAM, compression molding, and injection molding. The effect of arch form and palate depth was also tested.
Materials ...and Methods
Nine titanium casts, representing combinations of tapered, ovoid, and square arch forms and shallow, medium, and deep palate depths, were fabricated using electron beam melting (EBM) technology. For each base fabrication method, three poly(vinyl siloxane) impressions were made from each cast, 27 dentures for each method. Compression‐molded dentures were fabricated using Lucitone 199 poly methyl methacrylate (PMMA), and injection molded dentures with Ivobase's Hybrid Pink PMMA. For CAD/CAM, denture bases were designed and milled by Avadent using their Light PMMA. To quantify the space between the denture and the master cast, silicone duplicating material was placed in the intaglio of the dentures, the titanium master cast was seated under pressure, and the silicone was then trimmed and recovered. Three silicone measurements per denture were recorded, for a total of 243 measurements. Each silicone measurement was weighed and adjusted to the surface area of the respective arch, giving an average and standard deviation for each denture.
Results
Comparison of manufacturing methods showed a statistically significant difference (p = 0.0001). Using a ratio of the means, compression molding had on average 41% to 47% more space than injection molding and CAD/CAM. Comparison of arch/palate forms showed a statistically significant difference (p = 0.023), with shallow palate forms having more space with compression molding. The ovoid shallow form showed CAD/CAM and compression molding had more space than injection molding.
Conclusion
Overall, injection molding and CAD/CAM fabrication methods produced equally well‐fitting dentures, with both having a better fit than compression molding. Shallow palates appear to be more affected by shrinkage than medium or deep palates. Shallow ovoid arch forms appear to benefit from the use of injection molding compared to CAD/CAM and compression molding.
Clinical studies have evaluated the effect of conventional periodontal surgical therapy. In general, although some clinical gain in tissue support may be attained, these therapies do not support ...regeneration of the periodontal attachment. Even though the biological possibility of periodontal regeneration has been demonstrated, the clinical application of this intrinsic potential appears difficult to harness; thus also conceptually most intriguing candidate protocols face clinical challenges. In this review, we explore the bioclinical principles, condiciones sine quibus non, that unleash the innate potential of the periodontium to achieve clinically meaningful periodontal regeneration (i.e. space‐provision, wound stability and conditions for primary intention healing). Moreover, limiting factors and detrimental practices that may compromise clinical and biological outcomes are reviewed, as is tissue management in clinical settings.
Abstract Statement of problem The recent application of printing for the fabrication of dental restorations has not been compared and evaluated for margin discrepancy (margin fit) with restorations ...fabricated using milling and conventional hand-waxing techniques. Purpose The purpose of this in vitro study was to evaluate and compare margin discrepancy of complete gold crowns (CGCs) fabricated from printed, milled, and conventional hand-waxed patterns. Material and methods Thirty crown patterns were produced by each of 3 different methods: printed by ProJet DP 3000, milled by LAVA CNC 500, and hand waxed, then invested and cast into CGCs. Each crown was evaluated at 10 positions around the margin on the corresponding epoxy die under ×50 light microscopy to determine the mean and maximum margin discrepancy. Measurements were made using a micrometer positioning stage. The results were compared by ANOVA (α=.05). Results Milled and hand-waxed patterns were not statistically different from each other ( P >.05), while printed patterns produced significantly higher mean and maximum margin discrepancy than milled and hand-waxed patterns ( P <.05). Conclusions Relative to margin discrepancy, the LAVA CNC 500 milled and hand-waxed patterns were not significantly different from each other. The ProJet DP 3000 printed patterns were significantly different from LAVA CNC 500 milled and hand-waxed patterns, with an overall poorer result. Fabricating CGCs from printed patterns produced a significantly higher number of crowns with unacceptable margin discrepancy (>120 μm).
Thoracic radiotherapy decisions in patients with interstitial lung disease (ILD) are complex due to concerns about severe or even fatal radiation pneumonitis. This systematic review analysed the ...published evidence regarding the incidence of radiation pneumonitis and mortality after thoracic radiotherapy and investigated clinical and dosimetric predictors of radiation pneumonitis in lung cancer patients with ILD. A systematic search was carried out in PubMed, Medline, Embase and the Cochrane database for articles published between January 2000 and April 2021. Two authors independently screened eligible studies that met our predefined criteria. Studies were assessed for design and quality and a qualitative data synthesis was carried out. The search strategy resulted in 1750 articles. After two rounds of screening, 24 publications were included. The median overall incidence of grade ≥3 radiation pneumonitis was 19.7% (range 8–46%). The incidence was greater in conventional radical radiotherapy-treated patients (median 31.8%) compared with particle beam therapy- or stereotactic ablative radiotherapy-treated patients (median 12.5%). The median rate of grade 5 radiation pneumonitis was 11.9% (range 0–60%). The presence of ILD was an independent predictor of severe radiation pneumonitis. Severe radiation pneumonitis was more common in the presence of usual interstitial pneumonia (UIP) pattern or idiopathic pulmonary fibrosis (IPF) than non-UIP or non-IPF subtype. Several other clinical predictors were reported in the literature. V5, V10, V20 and mean lung dose were the most common dosimetric predictors for severe radiation pneumonitis, often with stricter dose constraints than conventionally used. Patients with lung cancer associated with ILD had a poorer overall survival compared with patients without ILD. In conclusion, patients with lung cancer associated with ILD have a poor prognosis. They are at high risk of severe and even fatal radiation pneumonitis. Careful patient selection is necessary, appropriate high-risk consenting and strict lung dose-volume constraints should be used, if these patients are to be treated with thoracic radiotherapy.
•Patients with lung cancer associated with ILD have a poor prognosis.•They are at increased risk of severe and even fatal radiation pneumonitis.•Patients must be counselled and appropriately consented regarding the increased risks when planning thoracic radiotherapy.•Careful patient selection & strict lung dose volume constraints should be chosen if treated with thoracic radiotherapy.
TNBC represents a heterogeneous subgroup of BC with poor prognosis and frequently resistant to CT.
The relationship between Bcl2 immunohistochemical protein expression and clinico-pathological ...outcomes was assessed in 736 TNBC-patients: 635 patients had early primary-TNBC (EP-TNBC) and 101 had primary locally advanced (PLA)-TNBC treated with neo-adjuvant- ATC-CT.
Negative Bcl2 (Bcl2-) was observed in 70% of EP-TNBC and was significantly associated with high proliferation, high levels of P-Cadherin, E-Cadherin and HER3 (P's < 0.01), while Bcl2+ was significantly associated with high levels of p27, MDM4 and SPAG5 (P < 0.01). After controlling for chemotherapy and other prognostic factors, Bcl2- was associated with 2-fold increased risk of death (P = 0.006) and recurrence (P = 0.0004). Furthermore, the prognosis of EP-TNBC/Bcl2- patients had improved both BC-specific survival (P = 0.002) and disease-free survival (P = 0.003), if they received adjuvant-ATC-CT. Moreover, Bcl2- expression was an independent predictor of pathological complete response of primary locally advanced triple negative breast cancer (PLA-TNBC) treated with neoadjuvant-ATC-CT (P = 0.008).
Adding Bcl2 to the panel of markers used in current clinical practice could provide both prognostic and predictive information in TNBC. TNBC/Bcl2- patients appear to benefit from ATC-CT, whereas Bcl2+ TNBC seems to be resistant to ATC-CT and may benefit from a trial of different type of chemotherapy with/without novel-targeted agents.
The excision of introns from pre-mRNA is an essential step in mRNA processing. We developed LeafCutter to study sample and population variation in intron splicing. LeafCutter identifies variable ...splicing events from short-read RNA-seq data and finds events of high complexity. Our approach obviates the need for transcript annotations and circumvents the challenges in estimating relative isoform or exon usage in complex splicing events. LeafCutter can be used both to detect differential splicing between sample groups and to map splicing quantitative trait loci (sQTLs). Compared with contemporary methods, our approach identified 1.4-2.1 times more sQTLs, many of which helped us ascribe molecular effects to disease-associated variants. Transcriptome-wide associations between LeafCutter intron quantifications and 40 complex traits increased the number of associated disease genes at a 5% false discovery rate by an average of 2.1-fold compared with that detected through the use of gene expression levels alone. LeafCutter is fast, scalable, easy to use, and available online.
Primary and secondary nervous system involvement occurs in 4% and 5%–12%, respectively, of all canine non-Hodgkin lymphomas. The recent new classification of canine malignant lymphomas, based on the ...human World Health Organization classification, has been endorsed with international acceptance. This histological and immunocytochemical classification provides a unique opportunity to study the histologic anatomic distribution patterns in the central and peripheral nervous system of these defined lymphoma subtypes. In this study, we studied a cohort of 37 dogs with lymphoma, which at necropsy had either primary (n = 1, 2.7%) or secondary (n = 36; 97.3%) neural involvement. These T- (n = 16; 43.2%) or B-cell (n = 21; 56.8%) lymphomas were further classified into 12 lymphoma subtypes, with predominant subtypes including peripheral T-cell lymphoma (PTCL) or diffuse large B-cell lymphoma (DLBCL), respectively. This systematic study identified 6 different anatomically based histologically defined patterns of lymphoma infiltration in the nervous system of dogs. Different and distinct combinations of anatomical patterns correlated with specific lymphoma subtypes. Lymphoma infiltration within the meningeal, perivascular, and periventricular compartments were characteristic of DLBCL, whereas peripheral nerve involvement was a frequent feature of PTCL. Similarly cell counts above 64 cells/μL in cerebrospinal samples correlated best with marked meningeal and periventricular lymphoma infiltration histologically. Prospective studies are needed in order to confirm the hypothesis that these combinations of histological neuroanatomic patterns reflect targeting of receptors specific for the lymphoma subtypes at these various sites.
Mechanical and neurophysiological anisotropies mediate three-dimensional responses of the heart of ITALIC! Homarus americanus Although hearts ITALIC! in vivoare loaded multi-axially by pressure, ...studies of invertebrate cardiac function typically use uniaxial tests. To generate whole-heart length-tension curves, stretch pyramids at constant lengthening and shortening rates were imposed uniaxially and biaxially along longitudinal and transverse axes of the beating whole heart. To determine whether neuropeptides that are known to modulate cardiac activity in ITALIC! H. americanusaffect the active or passive components of these length-tension curves, we also performed these tests in the presence of SGRNFLRFamide (SGRN) and GYSNRNYLRFamide (GYS). In uniaxial and biaxial tests, both passive and active forces increased with stretch along both measurement axes. The increase in passive forces was anisotropic, with greater increases along the longitudinal axis. Passive forces showed hysteresis and active forces were higher during lengthening than shortening phases of the stretch pyramid. Active forces at a given length were increased by both neuropeptides. To exert these effects, neuropeptides might have acted indirectly on the muscle via their effects on the cardiac ganglion, directly on the neuromuscular junction, or directly on the muscles. Because increases in response to stretch were also seen in stimulated motor nerve-muscle preparations, at least some of the effects of the peptides are likely peripheral. Taken together, these findings suggest that flexibility in rhythmic cardiac contractions results from the amplified effects of neuropeptides interacting with the length-tension characteristics of the heart.
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