Comprehensive Immune Monitoring of Clinical Trials to Advance Human Immunotherapy.

The success of immunotherapy has led to a myriad of clinical trials accompanied by efforts to gain mechanistic insight and identify predictive signatures for personalization. However, many immune monitoring technologies face investigator bias, missing unanticipated cellular responses in limited clinical material. We present here a mass cytometry (CyTOF) workflow for standardized, systems-level biomarker discovery in immunotherapy trials. To broadly enumerate immune cell identity and activity, we established and extensively assessed a reference panel of 33 antibodies to cover major cell subsets, simultaneously quantifying activation and immune checkpoint molecules in a single assay. This assay enumerates ≥98% of peripheral immune cells with ≥4 positively identifying antigens. Robustness and reproducibility are demonstrated on multiple samples types, across two research centers and by orthogonal measurements. Using automated analysis, we identify stratifying immune signatures in bone marrow transplantation-associated graft-versus-host disease. Together, this validated workflow ensures comprehensive immunophenotypic analysis and data comparability and will accelerate biomarker discovery

CD39 delineates chimeric antigen receptor regulatory T cell subsets with distinct cytotoxic & regulatory functions against human islets

Human regulatory T cells (Treg) suppress other immune cells. Their dysfunction contributes to the pathophysiology of autoimmune diseases, including type 1 diabetes (T1D). Infusion of Tregs is being clinically evaluated as a novel way to prevent or treat T1D. Genetic modification of Tregs, most notably through the introduction of a chimeric antigen receptor (CAR) targeting Tregs to pancreatic islets, may improve their efficacy. We evaluated CAR targeting of human Tregs to monocytes, a human β cell line and human islet β cells in vitro. Targeting of HLA-A2-CAR (A2-CAR) bulk Tregs to HLA-A2+ cells resulted in dichotomous cytotoxic killing of human monocytes and islet β cells. In exploring subsets and mechanisms that may explain this pattern, we found that CD39 expression segregated CAR Treg cytotoxicity. CAR Tregs from individuals with more CD39low/- Tregs and from individuals with genetic polymorphism associated with lower CD39 expression (rs10748643) had more cytotoxicity. Isolated CD39− CAR Tregs had elevated granzyme B expression and cytotoxicity compared to the CD39+ CAR Treg subset. Genetic overexpression of CD39 in CD39low CAR Tregs reduced their cytotoxicity. Importantly, β cells upregulated protein surface expression of PD-L1 and PD-L2 in response to A2-CAR Tregs. Blockade of PD-L1/PD-L2 increased β cell death in A2-CAR Treg co-cultures suggesting that the PD-1/PD-L1 pathway is important in protecting islet β cells in the setting of CAR immunotherapy. In summary, introduction of CAR can enhance biological differences in subsets of Tregs. CD39+ Tregs represent a safer choice for CAR Treg therapies targeting tissues for tolerance induction

Sexual orientation and symptoms of common mental disorder or low wellbeing: combined meta-analysis of 12 UK population health surveys

Background Previous studies have indicated increased risk of mental disorder symptoms, suicide and substance misuse in lesbian, gay and bisexual (LGB) adults, compared to heterosexual adults. Our aims were to determine an estimate of the association between sexual orientation identity and poor mental health and wellbeing among adults from 12 population surveys in the UK, and to consider whether effects differed for specific subgroups of the population. Methods Individual data were pooled from the British Cohort Study 2012, Health Survey for England 2011, 2012 and 2013, Scottish Health Survey 2008 to 2013, Longitudinal Study of Young People in England 2009/10 and Understanding Society 2011/12. Individual participant meta-analysis was used to pool estimates from each study, allowing for between-study variation. Results Of 94,818 participants, 1.1 % identified as lesbian/gay, 0.9 % as bisexual, 0.8 % as ‘other’ and 97.2 % as heterosexual. Adjusting for a range of covariates, adults who identified as lesbian/gay had higher prevalence of common mental disorder when compared to heterosexuals, but the association was different in different age groups: apparent for those under 35 (OR = 1.78, 95 % CI 1.40, 2.26), weaker at age 35–54.9 (OR = 1.42, 95 % CI 1.10, 1.84), but strongest at age 55+ (OR = 2.06, 95 % CI 1.29, 3.31). These effects were stronger for bisexual adults, similar for those identifying as ‘other’, and similar for 'low wellbeing'. Conclusions In the UK, LGB adults have higher prevalence of poor mental health and low wellbeing when compared to heterosexuals, particularly younger and older LGB adults. Sexual orientation identity should be measured routinely in all health studies and in administrative data in the UK in order to influence national and local policy development and service delivery. These results reiterate the need for local government, NHS providers and public health policy makers to consider how to address inequalities in mental health among these minority groups

Type IIb Supernova SN 2011dh: Spectra and Photometry from the Ultraviolet to the Near-Infrared

We report spectroscopic and photometric observations of the Type IIb SN 2011dh obtained between 4 and 34 days after the estimated date of explosion (May 31.5 UT). The data cover a wide wavelength range from 2,000 Angstroms in the UV to 2.4 microns in the NIR. Optical spectra provide line profiles and velocity measurements of HI, HeI, CaII and FeII that trace the composition and kinematics of the SN. NIR spectra show that helium is present in the atmosphere as early as 11 days after the explosion. A UV spectrum obtained with the STIS reveals that the UV flux for SN 2011dh is low compared to other SN IIb. The HI and HeI velocities in SN 2011dh are separated by about 4,000 km/s at all phases. We estimate that the H-shell of SN 2011dh is about 8 times less massive than the shell of SN 1993J and about 3 times more massive than the shell of SN 2008ax. Light curves (LC) for twelve passbands are presented. The maximum bolometric luminosity of $1.8 \pm 0.2 \times 10^{42}$ erg s$^{-1}$ occurred about 22 days after the explosion. NIR emission provides more than 30% of the total bolometric flux at the beginning of our observations and increases to nearly 50% of the total by day 34. The UV produces 16% of the total flux on day 4, 5% on day 9 and 1% on day 34. We compare the bolometric light curves of SN 2011dh, SN 2008ax and SN 1993J. The LC are very different for the first twelve days after the explosions but all three SN IIb display similar peak luminosities, times of peak, decline rates and colors after maximum. This suggests that the progenitors of these SN IIb may have had similar compositions and masses but they exploded inside hydrogen shells that that have a wide range of masses. The detailed observations presented here will help evaluate theoretical models for this supernova and lead to a better understanding of SN IIb.Comment: 23 pages, 14 figures, 9 tables, accepted by Ap

Comprehensive Immune Monitoring of Clinical Trials to Advance Human Immunotherapy

The success of immunotherapy has led to a myriad of clinical trials accompanied by efforts to gain mechanistic insight and identify predictive signatures for personalization. However, many immune monitoring technologies face investigator bias, missing unanticipated cellular responses in limited clinical material. We present here a mass cytometry (CyTOF) workflow for standardized, systems-level biomarker discovery in immunotherapy trials. To broadly enumerate immune cell identity and activity, we established and extensively assessed a reference panel of 33 antibodies to cover major cell subsets, simultaneously quantifying activation and immune checkpoint molecules in a single assay. This assay enumerates >= 98% of peripheral immune cells with >= 4 positively identifying antigens. Robustness and reproducibility are demonstrated on multiple samples types, across two research centers and by orthogonal measurements. Using automated analysis, we identify stratifying immune signatures in bone marrow transplantation-associated graft-versus-host disease. Together, this validated workflow ensures comprehensive immunophenotypic analysis and data comparability and will accelerate biomarker discovery

Consistency of cosmic microwave background temperature measurements in three frequency bands in the 2500-square-degree SPT-SZ survey

We present an internal consistency test of South Pole Telescope (SPT) measurements of the cosmic microwave background (CMB) temperature anisotropy using three-band data from the SPT-SZ survey. These measurements are made from observations of ~2500 deg^2 of sky in three frequency bands centered at 95, 150, and 220 GHz. We combine the information from these three bands into six semi-independent estimates of the CMB power spectrum (three single-frequency power spectra and three cross-frequency spectra) over the multipole range 650 < l < 3000. We subtract an estimate of foreground power from each power spectrum and evaluate the consistency among the resulting CMB-only spectra. We determine that the six foreground-cleaned power spectra are consistent with the null hypothesis, in which the six cleaned spectra contain only CMB power and noise. A fit of the data to this model results in a chi-squared value of 236.3 for 235 degrees of freedom, and the probability to exceed this chi-squared value is 46%.Comment: 21 pages, 4 figures, current version matches version published in JCA

Extragalactic millimeter-wave point source catalog, number counts and statistics from 771 square degrees of the SPT-SZ Survey

We present a point source catalog from 771 square degrees of the South Pole Telescope Sunyaev Zel'dovich (SPT-SZ) survey at 95, 150, and 220 GHz. We detect 1545 sources above 4.5 sigma significance in at least one band. Based on their relative brightness between survey bands, we classify the sources into two populations, one dominated by synchrotron emission from active galactic nuclei, and one dominated by thermal emission from dust-enshrouded star-forming galaxies. We find 1238 synchrotron and 307 dusty sources. We cross-match all sources against external catalogs and find 189 unidentified synchrotron sources and 189 unidentified dusty sources. The dusty sources without counterparts are good candidates for high-redshift, strongly lensed submillimeter galaxies. We derive number counts for each population from 1 Jy down to roughly 9, 5, and 11 mJy at 95, 150, and 220 GHz. We compare these counts with galaxy population models and find that none of the models we consider for either population provide a good fit to the measured counts in all three bands. The disparities imply that these measurements will be an important input to the next generation of millimeter-wave extragalactic source population models.Comment: 23 pages, 8 figures, submitted to Ap

A Comparison of Cosmological Parameters Determined from CMB Temperature Power Spectra from the South Pole Telescope and the Planck Satellite

The Planck cosmic microwave background (CMB) temperature data are best fit with a LCDM model that is in mild tension with constraints from other cosmological probes. The South Pole Telescope (SPT) 2540 $\text{deg}^2$ SPT-SZ survey offers measurements on sub-degree angular scales (multipoles $650 \leq \ell \leq 2500$) with sufficient precision to use as an independent check of the Planck data. Here we build on the recent joint analysis of the SPT-SZ and Planck data in \citet{hou17} by comparing LCDM parameter estimates using the temperature power spectrum from both data sets in the SPT-SZ survey region. We also restrict the multipole range used in parameter fitting to focus on modes measured well by both SPT and Planck, thereby greatly reducing sample variance as a driver of parameter differences and creating a stringent test for systematic errors. We find no evidence of systematic errors from such tests. When we expand the maximum multipole of SPT data used, we see low-significance shifts in the angular scale of the sound horizon and the physical baryon and cold dark matter densities, with a resulting trend to higher Hubble constant. When we compare SPT and Planck data on the SPT-SZ sky patch to Planck full-sky data but keep the multipole range restricted, we find differences in the parameters $n_s$ and $A_se^{-2\tau}$. We perform further checks, investigating instrumental effects and modeling assumptions, and we find no evidence that the effects investigated are responsible for any of the parameter shifts. Taken together, these tests reveal no evidence for systematic errors in SPT or Planck data in the overlapping sky coverage and multipole range and, at most, weak evidence for a breakdown of LCDM or systematic errors influencing either the Planck data outside the SPT-SZ survey area or the SPT data at $\ell >2000$.Comment: 14 pages, 7 figures. Updated 1 figure and expanded on the reasoning for fixing the affect of lensing on the power spectrum instead of varying Alen