Extracellular vesicles (EVs) are highly abundant in human biofluids, containing a repertoire of macromolecules and biomarkers representative of the tissue of origin. EVs released by tumours can ...communicate key signals both locally and to distant sites to promote growth and survival or impact invasive and metastatic progression. Microscale flow cytometry of circulating EVs is an emerging technology that is a promising alternative to biopsy for disease diagnosis. However, biofluid‐derived EVs are highly heterogeneous in size and composition, making their analysis complex. To address this, we developed a machine learning approach combined with EV microscale cytometry using tissue‐ and disease‐specific biomarkers to generate predictive models. We demonstrate the utility of this novel extracellular vesicle machine learning analysis platform (EVMAP) to predict disease from patient samples by developing a blood test to identify high‐grade prostate cancer and validate its performance in a prospective 215 patient cohort. Models generated using the EVMAP approach significantly improved the prediction of high‐risk prostate cancer, highlighting the clinical utility of this diagnostic platform for improved cancer prediction from a blood test.
We developed the extracellular vesicle machine learning analysis platform (EVMAP) to improve the prediction of diseases such as cancer. The platform combines extracellular vesicle analysis using microscale cytometry with a machine learning approach to generate predictive models. In this work, we utilized EVMAP to generate a blood test to predict high‐grade prostate cancer in men that was significantly more accurate than the prostate‐specific antigen test. This platform could be applied to many different diseases.
Core Ideas
Association analyses of cold‐tolerance traits of white clover revealed 17 quantitative loci
Genomic tetraploid parameterization allowed description of population
Genomic tetraploid ...parameterization improved QTL detection in this polyploidy species
WSCdr found to be important physiological mechanism conferring cold tolerance
Four candidate genes discovered for WSCdr
Significant phenotypic variation explained by markers found associated with traits
MAS for some tolerance traits now seems possible
White clover (Trifolium repens L.) is the most important grazing perennial forage legume in temperate climates. However, its limited capacity to survive and restore growth after low temperatures during winter constrains the productivity and wide adoption of the crop. Despite the importance of cold tolerance for white clover cultivar development, the genetic basis of this trait remains largely unknown. Hence, in this study, we performed the first genome‐wide association study (GWAS) analyses in white clover to identify quantitative trait loci (QTL) for cold‐tolerance‐related traits. Seeds from 192 divergent genotypes from six populations in the Patagonia region of South America were collected and seed‐derived plants were further clonally propagated. Clonal trials were established in three locations representing temperature gradient associated with elevation. Given the allotetraploid nature of the white clover genome, distinct genetic models (diploid and tetraploid) were tested. Only the tetraploid parameterization was able to detect the 53 loci associated with cold‐tolerance traits. Out of the 53 single nucleotide polymorphism (SNP) trait associations, 17 controlled more than one trait or were stable across multiple sites. This work represents the first report of QTL for cold‐tolerance‐related traits, providing insights into its genetic basis and candidate genomic regions for further functional validation studies.
Background
There is an unmet clinical need for minimally invasive diagnostic tests to improve the detection of grade group (GG) ≥3 prostate cancer relative to prostate antigen‐specific risk ...calculators. We determined the accuracy of the blood‐based extracellular vesicle (EV) biomarker assay (EV Fingerprint test) at the point of a prostate biopsy decision to predict GG ≥3 from GG ≤2 and avoid unnecessary biopsies.
Methods
This study analyzed 415 men referred to urology clinics and scheduled for a prostate biopsy, were recruited to the APCaRI 01 prospective cohort study. The EV machine learning analysis platform was used to generate predictive EV models from microflow data. Logistic regression was then used to analyze the combined EV models and patient clinical data and generate the patients' risk score for GG ≥3 prostate cancer.
Results
The EV‐Fingerprint test was evaluated using the area under the curve (AUC) in discrimination of GG ≥3 from GG ≤2 and benign disease on initial biopsy. EV‐Fingerprint identified GG ≥3 cancer patients with high accuracy (0.81 AUC) at 95% sensitivity and 97% negative predictive value. Using a 7.85% probability cutoff, 95% of men with GG ≥3 would have been recommended a biopsy while avoiding 144 unnecessary biopsies (35%) and missing four GG ≥3 cancers (5%). Conversely, a 5% cutoff would have avoided 31 unnecessary biopsies (7%), missing no GG ≥3 cancers (0%).
Conclusions
EV‐Fingerprint accurately predicted GG ≥3 prostate cancer and would have significantly reduced unnecessary prostate biopsies.
We developed an accurate diagnostic blood test for grade group (GG) ≥3 prostate cancer that comprises the generation of a microflow cytometry dataset of three prostate cancer extracellular vesicle (EV) biomarkers, analysis with a novel machine learning algorithm to generate predictive EV models, and logistic regression analysis of these models with patient clinical data to calculate the risk score for the probability of GG ≥3 prostate cancer.
The identification of population bottlenecks is critical in conservation because populations that have experienced significant reductions in abundance are subject to a variety of genetic and ...demographic processes that can hasten extinction. Genetic bottleneck tests constitute an appealing and popular approach for determining if a population decline has occurred because they only require sampling at a single point in time, yet reflect demographic history over multiple generations. However, a review of the published literature indicates that, as typically applied, microsatellite‐based bottleneck tests often do not detect bottlenecks in vertebrate populations known to have experienced declines. This observation was supported by simulations that revealed that bottleneck tests can have limited statistical power to detect bottlenecks largely as a result of limited sample sizes typically used in published studies. Moreover, commonly assumed values for mutation model parameters do not appear to encompass variation in microsatellite evolution observed in vertebrates and, on average, the proportion of multi‐step mutations is underestimated by a factor of approximately two. As a result, bottleneck tests can have a higher probability of ‘detecting’ bottlenecks in stable populations than expected based on the nominal significance level. We provide recommendations that could add rigor to inferences drawn from future bottleneck tests and highlight new directions for the characterization of demographic history.
Inflammatory bowel disease (IBD) is a chronic disease connected to the immune system, with a predilection for the gastrointestinal tract. However, a large proportion of the patients have ...extraintestinal manifestations (EIM), and the ocular system is affected in some patients. The clinical presentation of ocular pathology is broad, ranging from asymptomatic cases to blindness, leading to high morbidity. Ocular complications can be primary and, in general, are associated with episodes of acute flare-ups that subside with immunological management of the digestive disease. Secondary complications arise from the primary ones and as adverse effects of immunological treatment. In addition, on many occasions, the ocular manifestation may appear prior to the presentation of digestive symptoms. The presence of a multidisciplinary team that includes a gastroenterologist and an ophthalmologist is important in order to achieve early diagnosis of ocular complications, thereby preventing, treating, and avoiding unfavorable and irreversible long-term ocular sequelae.
PurposeThe Alberta Prostate Cancer Research Initiative (APCaRI) Registry and Biorepository was established in 2014 by the APCaRI to facilitate the collection of clinical and patient-reported data, ...biospecimen, to measure prostate cancer outcomes and to support the development and clinical translation of innovative technologies to better diagnose and predict outcomes for patients with prostate cancer.ParticipantsMen suspected with prostate cancer and referred to Urology centres in Alberta were enrolled in the APCaRI 01 study, while men with a prior prostate cancer diagnosis participated in the APCaRI 03 study from 1 July 2014 to 30 June 2019. The APCaRI Registry and Biorepository links biospecimens and data from a wide representation of patients drawn from an Alberta population of more than 4 million.Findings to dateFrom 1 July 2014 to 30 June 2019, total APCaRI 01 and 03 study recruitment was 3754 men; 142 (4%) of these men withdrew in full, 65 men (2%) withdrew biospecimens and 123 men (3%) died of any cause. Over this same time, 8677 patient-reported outcome measure (PROM) surveys and 7368 biospecimens were collected and are available from the registry and biorepository, respectively. The data entry error rate was 0.8% and 0.95% for critical and non-critical values, respectively, and 1.8% for patient-reported surveys.Future plansThe APCaRI Registry and Biorepository will collect longitudinal data and PROM surveys until 2024, patient outcomes up to 25 years after recruitment and biospecimen storage for up to 25 years. The APCaRI cohorts will continue to provide data and samples to researchers conducting retrospective studies. The richness of the data and biospecimens will complement many different research questions, ultimately to improve the quality of care for men with prostate cancer.
Normal physiology relies on the organization of transmembrane proteins by molecular scaffolds, such as tetraspanins. Oncogenesis frequently involves changes in their organization or expression. The ...tetraspanin CD151 is thought to contribute to cancer progression through direct interaction with the laminin-binding integrins α3β1 and α6β1. However, this interaction cannot explain the ability of CD151 to control migration in the absence of these integrins or on non-laminin substrates. We demonstrate that CD151 can regulate tumor cell migration without direct integrin binding and that integrin-free CD151 (CD151(free)) correlates clinically with tumor progression and metastasis. Clustering CD151(free) through its integrin-binding domain promotes accumulation in areas of cell-cell contact, leading to enhanced adhesion and inhibition of tumor cell motility in vitro and in vivo. CD151(free) clustering is a strong regulator of motility even in the absence of α3 expression but requires PKCα, suggesting that CD151 can control migration independent of its integrin associations. The histologic detection of CD151(free) in prostate cancer correlates with poor patient outcome. When CD151(free) is present, patients are more likely to recur after radical prostatectomy and progression to metastatic disease is accelerated. Multivariable analysis identifies CD151(free) as an independent predictor of survival. Moreover, the detection of CD151(free) can stratify survival among patients with elevated prostate-specific antigen levels. Cumulatively, these studies demonstrate that a subpopulation of CD151 exists on the surface of tumor cells that can regulate migration independent of its integrin partner. The clinical correlation of CD151(free) with prostate cancer progression suggests that it may contribute to the disease and predict cancer progression.
Abstract The current prostate cancer (PCa) screen test, prostate-specific antigen (PSA), has a high sensitivity for PCa but low specificity for high-risk, clinically significant PCa (csPCa), ...resulting in overdiagnosis and overtreatment of non-csPCa. Early identification of csPCa while avoiding unnecessary biopsies in men with non-csPCa is challenging. We built an optimized machine learning platform (ClarityDX) and showed its utility in generating models predicting csPCa. Integrating the ClarityDX platform with blood-based biomarkers for clinically significant PCa and clinical biomarker data from a 3448-patient cohort, we developed a test to stratify patients’ risk of csPCa; called ClarityDX Prostate. When predicting high risk cancer in the validation cohort, ClarityDX Prostate showed 95% sensitivity, 35% specificity, 54% positive predictive value, and 91% negative predictive value, at a ≥ 25% threshold. Using ClarityDX Prostate at this threshold could avoid up to 35% of unnecessary prostate biopsies. ClarityDX Prostate showed higher accuracy for predicting the risk of csPCa than PSA alone and the tested model-based risk calculators. Using this test as a reflex test in men with elevated PSA levels may help patients and their healthcare providers decide if a prostate biopsy is necessary.
This paper describes the unique natural communities and biodiversity of the upwelling coastal system along the Guajira peninsula in the southern Caribbean Sea. The Guajira peninsula has a small human ...population with limited infrastructure and limited opportunities for coastal research, yet its coastal upwelling system is unique in the Tropical Western Atlantic region. This report includes both field observations along with a review of literature on the biodiversity of coastal eastern Guajira. In addition, it identifies missing information on the coastal system that is key to its management and conservation. Mangrove wetlands along with submerged aquatic vegetation (SAV) communities in a combination of consolidated and unconsolidated shorelines (e.g., rocky shores, cliffs, and beaches) form unique habitats in eastern Guajira. The diversity of these habitats is illustrated with the Bahia Hondita marine lagoon, where critical nursery habitat for several commercial valuable and endangered fisheries species, including sharks and sea turtles, is observed. Less information is available on more cryptic fauna, invertebrates, and coastal plankton species. Several anthropogenic factors are threatening species diversity in coastal Guajira, including overgrazing, mining, and target-species overfishing. Additional threats, such as extreme weather events (e.g., storms and droughts) as well as changes in coastal water quality, are also impacting species. The protection of the Guajira’s biodiversity would depend on local communities’ governance and empowerment as well as law enforcement for mining and agriculture operations. Management plans can include reducing land-based sources of pollution and building coastal resilience for climate change.
Background
Some studies, mainly in Europe, have shown a low level of sensitization to house dust mite (HDM) allergens at high altitude (HA). Differently, some others in tropical countries have shown ...a higher level. The aim of this study was to evaluate allergens sensitization, including HDM, in children with severe asthma (SA), residents at HA in a tropical middle‐income developing country.
Methods
Observational, analytical, cross‐sectional study in children aged 6‐15 years old with SA at HA (2640 m). Skin prick tests (SPT), serum IgE, exhaled fraction of nitric oxide (FENO), spirometry, and asthma questionnaire (ACT) were performed. Associations were explored by Pearson or Spearman coefficients.
Results
We included 61 children. Most patients were male (61.3%), median age: 10 years (Interquartile range IQR: 8‐12), median BMI: 17 kg/m2 (IQR: 16‐20); Median of positive SPT: 2 (IQR: 2‐3). At least one SPT was positive in 88.7% of patients and 87.9% were positive for at least one HDM. Serum IgE: 348 UI/mL (IQR: 154‐760) and FENO: 22 ppb (IQR: 9‐41). Prebronchodilator values were (% predicted): FVC: 109.7% (±15.5%), FEV1: 98.4% (±16.3); FEV1/FVC: 82% (±8%). SPT were inversely correlated with the FEV1/FVC (Rho: −0.34; 95% CI: −0.55 a −0.09; P = 0.008).
Conclusions
These children with SA living at HA in a tropical middle‐income developing country have a high prevalence of HDM sensitization. One explanation for this might be that tropical conditions, such as temperature and humidity, could modify the effect of the altitude on asthma.
PDF
