Abstract
Motivation
Clustering patient omic data is integral to developing precision medicine because it allows the identification of disease subtypes. A current major challenge is the integration ...multi-omic data to identify a shared structure and reduce noise. Cluster analysis is also increasingly applied on single-omic data, for example, in single cell RNA-seq analysis for clustering the transcriptomes of individual cells. This technology has clinical implications. Our motivation was therefore to develop a flexible and effective spectral clustering tool for both single and multi-omic data.
Results
We present Spectrum, a new spectral clustering method for complex omic data. Spectrum uses a self-tuning density-aware kernel we developed that enhances the similarity between points that share common nearest neighbours. It uses a tensor product graph data integration and diffusion procedure to reduce noise and reveal underlying structures. Spectrum contains a new method for finding the optimal number of clusters (K) involving eigenvector distribution analysis. Spectrum can automatically find K for both Gaussian and non-Gaussian structures. We demonstrate across 21 real expression datasets that Spectrum gives improved runtimes and better clustering results relative to other methods.
Availability and implementation
Spectrum is available as an R software package from CRAN https://cran.r-project.org/web/packages/Spectrum/index.html.
Supplementary information
Supplementary data are available at Bioinformatics online.
Systemic Autoimmune Rheumatic Diseases, including Rheumatoid Arthritis, Systemic Lupus Erythematosus and Sjogren’s syndrome, are characterised by a loss of immune tolerance and chronic inflammation. ...There is marked heterogeneity in clinical and molecular phenotypes in each condition, and the aetiology of these is unclear. NF-κB is an inducible transcription factor that is critical in the physiological inflammatory response, and which has been implicated in chronic inflammation. Genome-wide association studies have linked risk alleles related to the NF-κB pathway to the pathogenesis of multiple Systemic Autoimmune Rheumatic Diseases. This review describes how cell- and pathway-specific NF-κB activation contribute to the spectrum of clinical phenotypes and molecular pathotypes in rheumatic disease. Potential clinical applications are explored, including therapeutic interventions and utilisation of NF-κB as a biomarker of disease subtypes and treatment response.
•NF-κB-related genetic variants have been identified in most Systemic Autoimmune Rheumatic Diseases.•Dysregulated NF-κB is present in most SARDs.•Cell-specific NF-κB dysregulation may influence the site of inflammation.•Cell- and pathway-specific NF-κB activity corresponds with RA synovial pathotypes.
Summary Background The current American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system does not have sufficient details to encompass the variety of ...soft-tissue sarcomas, and available prognostic methods need refinement. We aimed to develop and externally validate two prediction nomograms for overall survival and distant metastases in patients with soft-tissue sarcoma in their extremities. Methods Consecutive patients who had had an operation at the Istituto Nazionale Tumori (Milan, Italy), from Jan 1, 1994, to Dec 31, 2013, formed the development cohort. Three cohorts of patient data from the Institut Gustave Roussy (Villejuif, France; from Jan 1, 1996, to May 15, 2012), Mount Sinai Hospital (Toronto, ON, Canada; from Jan 1, 1994, to Dec 31, 2013), and the Royal Marsden Hospital (London, UK; from Jan 1, 2006, to Dec 31, 2013) formed the external validation cohorts. We developed the nomogram for overall survival using a Cox multivariable model, and a Fine and Gray multivariable model for the distant metastases nomogram. We applied a backward procedure for variables selection for both nomograms. We assessed nomogram model performance by examining overall accuracy (Brier score), calibration (calibration plots and Hosmer–Lemeshow calibration test), and discrimination (Harrell C index). We plotted decision curves to evaluate the clinical usefulness of the two nomograms. Findings 1452 patients were included in the development cohort, with 420 patients included in the French validation cohort, 1436 patients in the Canadian validation cohort, and 444 patients in the UK validation cohort. In the development cohort, 10-year overall survival was 72·9% (95% CI 70·2–75·7) and 10-year crude cumulative incidence of distant metastases was 25·0% (95% CI 22·7–27·5). For the overall survival nomogram, the variables selected applying a backward procedure in the multivariable Cox model (patient's age, tumour size, Fédération Française des Centres de Lutte Contre le Cancer FNCLCC grade, and histological subtype) had a significant effect on overall survival. The same variables, except for patient age, were selected for the distant metastases nomogram. In the development cohort, the Harrell C index for overall survival was 0·767 (95% CI 0·743–0·789) and for distant metastases was 0·759 (0·736–0·781). In the validation cohorts, the Harrell C index for overall survival and distant metastases were 0·698 (0·638–0·754) and 0·652 (0·605–0·699; French), 0·775 (0·754–0·796) and 0·744 (0·720–0·768; Canadian), and 0·762 (0·720–0·806) and 0·749 (0·707–0·791; UK). The two nomograms both performed well in terms of discrimination (ability to distinguish between patients who have had an event from those who have not) and calibration (accuracy of nomogram prediction) when applied to the validation cohorts. Interpretation Our nomograms are reliable prognostic methods that can be used to predict overall survival and distant metastases in patients after surgical resection of soft-tissue sarcoma of the extremities. These nomograms can be offered to clinicians to improve their abilities to assess patient prognosis, strengthen the prognosis-based decision making, enhance patient stratification, and inform patients in the clinic. Funding None.
Accumulation of lactate in the tissue microenvironment is a feature of both inflammatory disease and cancer. Here, we assess the response of immune cells to lactate in the context of chronic ...inflammation. We report that lactate accumulation in the inflamed tissue contributes to the upregulation of the lactate transporter SLC5A12 by human CD4+ T cells. SLC5A12-mediated lactate uptake into CD4+ T cells induces a reshaping of their effector phenotype, resulting in increased IL17 production via nuclear PKM2/STAT3 and enhanced fatty acid synthesis. It also leads to CD4+ T cell retention in the inflamed tissue as a consequence of reduced glycolysis and enhanced fatty acid synthesis. Furthermore, antibody-mediated blockade of SLC5A12 ameliorates the disease severity in a murine model of arthritis. Finally, we propose that lactate/SLC5A12-induced metabolic reprogramming is a distinctive feature of lymphoid synovitis in rheumatoid arthritis patients and a potential therapeutic target in chronic inflammatory disorders.
Display omitted
•Lactate induces the expression of SLC5A12 on human CD4+ T cells in the inflamed tissue•Lactate promotes CD4+ T cell IL17 production via PKM2/STAT3 signaling and FA synthesis•Lactate inhibits CD4+ T cell motility via increased FA synthesis and reduced glycolysis•SLC5A12 blockade ameliorates the disease severity in a murine model of arthritis
With buildup in the inflamed tissue, lactate can exacerbate the inflammatory response. Pucino et al. report that lactate induces expression of its own transporter, SLC5A12, driving lactate uptake into CD4+ T cells and resulting in increased IL17 production via PKM2/STAT3 signaling and enhanced fatty acid synthesis. They provide evidence that targeting SLC5A12 may ameliorate chronic inflammatory disorders.
Objective To determine outcomes at age 3 years in babies born before 27 completed weeks’ gestation in 2006, and to evaluate changes in outcome since 1995 for babies born between 22 and 25 weeks’ ...gestation.Design Prospective national cohort studies, EPICure and EPICure 2.Setting Hospital and home based evaluations, England.Participants 1031 surviving babies born in 2006 before 27 completed weeks’ gestation. Outcomes for 584 babies born at 22-25 weeks’ gestation were compared with those of 260 surviving babies of the same gestational age born in 1995.Main outcome measures Survival to age 3 years, impairment (2008 consensus definitions), and developmental scores. Multiple imputation was used to account for the high proportion of missing data in the 2006 cohort.Results Of the 576 babies evaluated after birth in 2006, 13.4% (n=77) were categorised as having severe impairment and 11.8% (n=68) moderate impairment. The prevalence of neurodevelopmental impairment was significantly associated with length of gestation, with greater impairment as gestational age decreased: 45% at 22-23 weeks, 30% at 24 weeks, 25% at 25 weeks, and 20% at 26 weeks (P<0.001). Cerebral palsy was present in 83 (14%) survivors. Mean developmental quotients were lower than those of the general population (normal values 100 (SD 15)) and showed a direct relation with gestational age: 80 (SD 21) at 22-23 weeks, 87 (19) at 24 weeks, 88 (19) at 25 weeks, and 91 (18) at 26 weeks. These results did not differ significantly after imputation. Comparing imputed outcomes between the 2006 and 1995 cohorts, the proportion of survivors born between 22 and 25 weeks’ gestation with severe disability, using 1995 definitions, was 18% (95% confidence interval 14% to 24%) in 1995 and 19% (14% to 23%) in 2006. Fewer survivors had shunted hydrocephalus or seizures. Survival of babies admitted for neonatal care increased from 39% (35% to 43%) in 1995 to 52% (49% to 55%) in 2006, an increase of 13% (8% to 18%), and survival without disability increased from 23% (20% to 26%) in 1995 to 34% (31% to 37%) in 2006, an increase of 11% (6% to 16%). Conclusion Survival and impairment in early childhood are both closely related to gestational age for babies born at less than 27 weeks’ gestation. Using multiple imputation to account for the high proportion of missing values, a higher proportion of babies admitted for neonatal care now survive without disability, particularly those born at gestational ages 24 and 25 weeks.
Biomarkers are needed for predicting the effectiveness of disease modifying antirheumatic drugs (DMARDs). Here, using functional lipid mediator profiling and deeply phenotyped patients with early ...rheumatoid arthritis (RA), we observe that peripheral blood specialized pro-resolving mediator (SPM) concentrations are linked with both DMARD responsiveness and disease pathotype. Machine learning analysis demonstrates that baseline plasma concentrations of resolvin D4, 10S, 17S-dihydroxy-docosapentaenoic acid, 15R-Lipoxin (LX)A
and n-3 docosapentaenoic-derived Maresin 1 are predictive of DMARD responsiveness at 6 months. Assessment of circulating SPM concentrations 6-months after treatment initiation establishes that differences between responders and non-responders are maintained, with a decrease in SPM concentrations in patients resistant to DMARD therapy. These findings elucidate the potential utility of plasma SPM concentrations as biomarkers of DMARD responsiveness in RA.
Research summary: We investigate the extent to which firms rely on supranational institutional safeguards versus their non-market capabilities to offset the risks of investing abroad. We argue that ...firms with non-market capabilities are insensitive to supranational institutional safeguards when choosing the location of their international investments. We show that supranational agreements between an investor's home and host nation, operationalized as bilateral investment treaties (BITs), increase the likelihood of investment, but there is substantial firm heterogeneity with respect to this relationship. Firms with various forms of non-market capabilities are not sensitive to BITs, whereas other firms are more likely to invest under BITs. We advance the understanding of how firm non-market capabilities can substitute for supranational institutional arrangements in addressing risks associated with host country institutional weaknesses. Managerial summary: The risk of expropriation is one of the main concerns companies have when investing abroad. Because of this, many countries implement bilateral investment treaties (BITs) to safeguard foreign investments, alleviate foreign investor concerns, and promote investments. We show that only those companies without political competence or political connections favor countries with BITs when choosing where to invest. Companies with political competence or political connections, on the other hand, ignore BITs and apparently rely on their ability to influence governments whenever their foreign investments face expropriation threats. As a result, politically connected or competent companies can enter markets most of their competitors lacking these capabilities shy away from. They can, therefore, do business in environments in which they face less competition.
ABSTRACT
We present and characterize the galaxy shape catalogue from the first 3 yr of Dark Energy Survey (DES) observations, over an effective area of 4143 deg2 of the southern sky. We describe our ...data analysis process and our self-calibrating shear measurement pipeline metacalibration, which builds and improves upon the pipeline used in the DES Year 1 analysis in several aspects. The DES Year 3 weak-lensing shape catalogue consists of 100 204 026 galaxies, measured in the riz bands, resulting in a weighted source number density of neff = 5.59 gal arcmin−2 and corresponding shape noise σe = 0.261. We perform a battery of internal null tests on the catalogue, including tests on systematics related to the point spread function (PSF) modelling, spurious catalogue B-mode signals, catalogue contamination, and galaxy properties.
The synthesis and reactivity of an ambiphilic iridium complex IrCl(PPh3)(L1) (1; L1 = P(N(o-N(2-pyridyl)C6H4)2)) featuring a chelating nontrigonal phosphorus triamide ligand is reported. The ...tandem Lewis basic Ir and Lewis acidic P of 1 achieve a two-site oxidative addition of phenol giving the iridaphenoxyphosphorane species IrHCl(PPh3)(L1 OPh) (3′). In contrast, reactions of 1 with benzenethiol and benzeneselenol do not engage L1 and instead proceed via metal-centered oxidative addition of the chalcogen–hydrogen bond. These findings establish metal–ligand cooperation involving nonspectator reactivity of tricoordinate phosphorus ligands.
PDF
