Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis

AbstractTo determine the impact of tumor progression on the reversibility of Neu-induced tumorigenesis, we have used the tetracycline regulatory system to conditionally express activated Neu in the mammary epithelium of transgenic mice. When induced with doxycycline, bitransgenic MMTV-rtTA/TetO-NeuNT mice develop multiple invasive mammary carcinomas, essentially all of which regress to a clinically undetectable state following transgene deinduction. This demonstrates that Neu-initiated tumorigenesis is reversible. Strikingly, extensive lung metastases arising from Neu-induced mammary tumors also rapidly and fully regress following the abrogation of Neu expression. However, despite the near universal dependence of both primary tumors and metastases on Neu transgene expression, most animals bearing fully regressed Neu-induced tumors ultimately develop recurrent tumors that have progressed to a Neu-independent state

Restricting datasets to classifiable samples augments discovery of immune disease biomarkers

Immunological diseases are typically heterogeneous in clinical presentation, severity and response to therapy. Biomarkers of immune diseases often reflect this variability, especially compared to their regulated behaviour in health. This leads to a common difficulty that frustrates biomarker discovery and interpretation – namely, unequal dispersion of immune disease biomarker expression between patient classes necessarily limits a biomarker’s informative range. To solve this problem, we introduce dataset restriction, a procedure that splits datasets into classifiable and unclassifiable samples. Applied to synthetic flow cytometry data, restriction identifies biomarkers that are otherwise disregarded. In advanced melanoma, restriction finds biomarkers of immune-related adverse event risk after immunotherapy and enables us to build multivariate models that accurately predict immunotherapy-related hepatitis. Hence, dataset restriction augments discovery of immune disease biomarkers, increases predictive certainty for classifiable samples and improves multivariate models incorporating biomarkers with a limited informative range. This principle can be directly extended to any classification task

System size dependence of cluster properties from two-particle angular correlations in Cu+Cu and Au+Au collisions at sNN\sqrt{s_{_{NN}}} = 200 GeV

We present results on two-particle angular correlations in Cu+Cu and Au+Au collisions at a center of mass energy per nucleon pair of 200 GeV over a broad range of pseudorapidity ($\eta$) and azimuthal angle ($\phi$) as a function of collision centrality. The PHOBOS detector at RHIC has a uniquely-large angular coverage for inclusive charged particles, which allows for the study of correlations on both long- and short-range scales. A complex two-dimensional correlation structure in $\Delta \eta$ and $\Delta \phi$ emerges, which is interpreted in the context of a cluster model. The effective cluster size and decay width are extracted from the two-particle pseudorapidity correlation functions. The effective cluster size found in semi-central Cu+Cu and Au+Au collisions is comparable to that found in proton-proton collisions but a non-trivial decrease of the size with increasing centrality is observed. Moreover, a comparison between results from Cu+Cu and Au+Au collisions shows an interesting scaling of the effective cluster size with the measured fraction of total cross section (which is related to the ratio of the impact parameter to the nuclear radius, $b/2R$), suggesting a geometric origin. Further analysis for pairs from restricted azimuthal regions shows that the effective cluster size at $\Delta\phi \sim 180^{\circ}$ drops more rapidly toward central collisions than the size at $\Delta\phi \sim 0^{\circ}$. The effect of limited $\eta$ acceptance on the cluster parameters is also addressed, and a correction is applied to present cluster parameters for full $\eta$ coverage, leading to much larger effective cluster sizes and widths than previously noted in the literature. These results should provide insight into the hot and dense medium created in heavy ion collisions.Comment: 9 pages, 8 figures, Published in Phys. Rev.

External validation of biomarkers for immune-related adverse events after immune checkpoint inhibition

Immune checkpoint inhibitors have revolutionized treatment of advanced melanoma, but commonly cause serious immune-mediated complications. The clinical ambition of reserving more aggressive therapies for patients least likely to experience immune-related adverse events (irAE) has driven an extensive search for predictive biomarkers. Here, we externally validate the performance of 59 previously reported markers of irAE risk in a new cohort of 110 patients receiving Nivolumab (anti-PD1) and Ipilimumab (anti-CTLA-4) therapy. Alone or combined, the discriminatory value of these routine clinical parameters and flow cytometry biomarkers was poor. Unsupervised clustering of flow cytometry data returned four T cell subsets with higher discriminatory capacity for colitis than previously reported populations, but they cannot be considered as reliable classifiers. Although mechanisms predisposing some patients to particular irAEs have been described, we are presently unable to capture adequate information from pre-therapy flow cytometry and clinical data to reliably predict risk of irAE in most cases

Soluble CD46 as a diagnostic marker of hepatic steatosis

Background The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) incurs substantial morbidity, mortality and healthcare costs. Detection and clinical intervention at early stages of disease improves prognosis; however, we are currently limited by a lack of reliable diagnostic tests for population screening and monitoring responses to therapy. To address this unmet need, we investigated human invariant Natural Killer T cell (iNKT) activation by fat-loaded hepatocytes, leading to the discovery that circulating soluble CD46 (sCD46) levels accurately predict hepatic steatosis. Methods sCD46 in plasma was measured using a newly developed immuno-competition assay in two independent cohorts: Prospective living liver donors (n = 156; male = 66, female = 90) and patients with liver tumours (n = 91; male = 58, female = 33). sCD46 levels were statistically evaluated as a predictor of hepatic steatosis. Findings Interleukin-4-secreting (IL-4+) iNKT cells were over-represented amongst intrahepatic lymphocytes isolated from resected human liver samples. IL-4+ iNKT cells preferentially developed in cocultures with a fat-loaded, hepatocyte-like cell line, HepaRG. This was attributed to induction of matrix metalloproteases (MMP) in fat-loaded HepaRG cells and primary human liver organoids, which led to indiscriminate cleavage of immune receptors. Loss of cell-surface CD46 resulted in unrepressed differentiation of IL-4+ iNKT cells. sCD46 levels were elevated in patients with hepatic steatosis. Discriminatory cut-off values for plasma sCD46 were found that accurately classified patients according to histological steatosis grade. Interpretation sCD46 is a reliable clinical marker of hepatic steatosis, which can be conveniently and non-invasively measured in serum and plasma samples, raising the possibility of using sCD46 levels as a diagnostic method for detecting or grading hepatic steatosis

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Observation of long-range, near-side angular correlations in proton-proton collisions at the LHC

Results on two-particle angular correlations for charged particles emitted in proton-proton collisions at center-of-mass energies of 0.9, 2.36, and 7 TeV are presented, using data collected with the CMS detector over a broad range of pseudorapidity (η) and azimuthal angle (ϕ). Short-range correlations in Δη, which are studied in minimum bias events, are characterized using a simple “independent cluster” parametrization in order to quantify their strength (cluster size) and their extent in η (cluster decay width). Long-range azimuthal correlations are studied differentially as a function of charged particle multiplicity and particle transverse momentum using a 980 nb[superscript −1] data set at 7 TeV. In high multiplicity events, a pronounced structure emerges in the two-dimensional correlation function for particle pairs with intermediate p [subscript T] of 1–3 GeV/c, 2.0 < |Δη| < 4.8 and Δϕ ≈ 0. This is the first observation of such a long-range, near-side feature in two-particle correlation functions in pp or p[−over]p collisions

Search for the standard model Higgs boson decaying to bottom quarks in pp collisions at √s = 7 TeV

A search for the standard model Higgs boson (H) decaying to b[bar over b] when produced in association with weak vector bosons (V) is reported for the following modes: W(μν)H, W(eν)H, Z(μμ)H, Z(ee)H and Z(νν)H. The search is performed in a data sample corresponding to an integrated luminosity of 4.7 fb[superscript −1], recorded by the CMS detector in proton–proton collisions at the LHC with a center-of-mass energy of 7 TeV. No significant excess of events above the expectation from background is observed. Upper limits on the VH production cross section times the H→b[bar over b] branching ratio, with respect to the expectations for a standard model Higgs boson, are derived for a Higgs boson in the mass range 110–135 GeV. In this range, the observed 95% confidence level upper limits vary from 3.4 to 7.5 times the standard model prediction; the corresponding expected limits vary from 2.7 to 6.7 times the standard model prediction.European Organization for Nuclear ResearchUnited States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio