Treg and Oligoclonal Expansion of Terminal Effector CD8+ T Cell as Key Players in Multiple Myeloma

The classical paradigm of host-tumor interaction, i.e. elimination, equilibrium, and escape (EEE), is reflected in the clinical behavior of myeloma which progresses from the premalignant condition, Monoclonal Gammopathy of Unknown Significance (MGUS). Despite the role of other immune cells, CD4+ regulatory T cells (Treg) and cytotoxic CD8+ T cells have emerged as the dominant effectors of host control of the myeloma clone. Progression from MGUS to myeloma is associated with alterations in Tregs and terminal effector CD8+ T cells (TTE). These changes involve CD39 and CD69 expression, affecting the adenosine pathway and residency in the bone marrow (BM) microenvironment, together with oligoclonal expansion within CD8+ TTE cells. In this mini-review article, in the context of earlier data, we summarize our recent understanding of Treg involvement in the adenosine pathway, the significance of oligoclonal expansion within CD8+ TTE cells and BM-residency of CD8+ TTE cells in MGUS and newly diagnosed multiple myeloma patients

The SAMI Galaxy Survey: Unveiling the nature of kinematically offset active galactic nuclei

We have observed two kinematically offset active galactic nuclei (AGN), whose ionised gas is at a different line-of-sight velocity to their host galaxies, with the SAMI integral field spectrograph (IFS). One of the galaxies shows gas kinematics very different to the stellar kinematics, indicating a recent merger or accretion event. We demonstrate that the star formation associated with this event was triggered within the last 100 Myr. The other galaxy shows simple disc rotation in both gas and stellar kinematics, aligned with each other, but in the central region has signatures of an outflow driven by the AGN. Other than the outflow, neither galaxy shows any discontinuity in the ionised gas kinematics at the galaxy's centre. We conclude that in these two cases there is no direct evidence of the AGN being in a supermassive black hole binary system. Our study demonstrates that selecting kinematically offset AGN from single-fibre spectroscopy provides, by definition, samples of kinematically peculiar objects, but IFS or other data are required to determine their true nature.Comment: MNRAS accepted. 14 pages, 11 figure

Overall Health and the Influence of Physical Therapy on Physical Function Following Total Ankle Arthroplasty

Background: The overall health and the importance of physical therapy for people following total ankle arthroplasty (TAA) have been understudied. Our purpose was to characterize the overall health of patients following TAA, and explore the frequency, influence, and patient-perceived value of physical therapy. Methods: People who received a TAA participated in this retrospective cohort online survey study. The survey included medical history questions and items from the Patient-Reported Outcomes Measurement Information System (PROMIS) Short Forms. Seven PROMIS domains, reflecting the biopsychosocial model of care (physical, mental, social), were included to examine participant overall health status in comparison to the general population. Items regarding physical therapy participation (yes/no), number of visits, and perceived value (scale 0-10; 10 = extremely helpful) were also included. Descriptive statistics were generated for participant characteristics, PROMIS domain T scores, and physical therapy questions. The influence of participant characteristics or physical therapy visits on PROMIS domain T scores that scored below the population mean were examined with multiple linear regression or ordinal regression. Results: The response rate was 61% (n=95). Average postoperative time was approximately 3 years (mean [SD]: 40.0 [35.3] months). Physical function and ability to participate in social roles and activities domain T scores were at least 1 SD below the population mean. Most patients received physical therapy (86%; 17.1 [11.0] visits) and found it helpful (7.2 [3.0]). Participant characteristics were minimally predictive of physical function and social participation T scores. Number of physical therapy visits predicted physical function T scores (P = .03). Conclusions: Most health domain scores approached the population mean. Physical therapy was perceived to have a high value, and greater visits were related to greater physical function. However, lower physical function and social participation scores suggest that postoperative care directed toward these domains could improve the value of TAA and promote overall health

The SAMI Galaxy Survey: Gas Streaming and Dynamical M/L in Rotationally Supported Systems

Line-of-sight velocities of gas and stars can constrain dark matter (DM) within rotationally supported galaxies if they trace circular orbits extensively. Photometric asymmetries may signify non-circular motions, requiring spectra with dense spatial coverage. Our integral-field spectroscopy of 178 galaxies spanned the mass range of the SAMI Galaxy Survey. We derived circular speed curves (CSCs) of gas and stars from non-parametric Diskfit fits out to $r\sim2r_e$. For 12/14 with measured H I profiles, ionized gas and H I maximum velocities agreed. We fitted mass-follows-light models to 163 galaxies by approximating the radial starlight profile as nested, very flattened mass homeoids viewed as a S\'ersic form. Fitting broad-band SEDs to SDSS images gave median stellar mass/light 1.7 assuming a Kroupa IMF vs. 2.6 dynamically. Two-thirds of the dynamical mass/light measures were consistent with star+remnant IMFs. One-fifth required upscaled starlight to fit, hence comparable mass of unobserved baryons and/or DM distributed similarly across the SAMI aperture that came to dominate motions as the starlight CSC declined rapidly. The rest had mass distributed differently from starlight. Subtracting fits of S\'ersic profiles to 13 VIKING Z-band images revealed residual weak bars. Near the bar PA, we assessed m = 2 streaming velocities, and found deviations usually <30 km/s from the CSC; three showed no deviation. Thus, asymmetries rarely influenced our CSCs despite co-located shock-indicating, emission-line flux ratios in more than 2/3.Comment: 21 pages, 15 figures. Accepted to MNRA

The SAMI Galaxy Survey: Asymmetry in Gas Kinematics and its links to Stellar Mass and Star Formation

We study the properties of kinematically disturbed galaxies in the SAMI Galaxy Survey using a quantitative criterion, based on kinemetry (Krajnovic et al.). The approach, similar to the application of kinemetry by Shapiro et al. uses ionised gas kinematics, probed by H{\alpha} emission. By this method 23+/-7% of our 360-galaxy sub-sample of the SAMI Galaxy Survey are kinematically asymmetric. Visual classifications agree with our kinemetric results for 90% of asymmetric and 95% of normal galaxies. We find stellar mass and kinematic asymmetry are inversely correlated and that kinematic asymmetry is both more frequent and stronger in low-mass galaxies. This builds on previous studies that found high fractions of kinematic asymmetry in low mass galaxies using a variety of different methods. Concentration of star forma- tion and kinematic disturbance are found to be correlated, confirming results found in previous work. This effect is stronger for high mass galaxies (log(M*) > 10) and indicates that kinematic disturbance is linked to centrally concentrated star formation. Comparison of the inner (within 0.5Re) and outer H{\alpha} equivalent widths of asymmetric and normal galaxies shows a small but significant increase in inner equivalent width for asymmetric galaxies.Comment: 29 pages, 21 figure

The SAMI Galaxy Survey: Shocks and Outflows in a normal star-forming galaxy

We demonstrate the feasibility and potential of using large integral field spectroscopic surveys to investigate the prevalence of galactic-scale outflows in the local Universe. Using integral field data from SAMI and the Wide Field Spectrograph, we study the nature of an isolated disk galaxy, SDSS J090005.05+000446.7 (z = 0.05386). In the integral field datasets, the galaxy presents skewed line profiles changing with position in the galaxy. The skewed line profiles are caused by different kinematic components overlapping in the line-of-sight direction. We perform spectral decomposition to separate the line profiles in each spatial pixel as combinations of (1) a narrow kinematic component consistent with HII regions, (2) a broad kinematic component consistent with shock excitation, and (3) an intermediate component consistent with shock excitation and photoionisation mixing. The three kinematic components have distinctly different velocity fields, velocity dispersions, line ratios, and electron densities. We model the line ratios, velocity dispersions, and electron densities with our MAPPINGS IV shock and photoionisation models, and we reach remarkable agreement between the data and the models. The models demonstrate that the different emission line properties are caused by major galactic outflows that introduce shock excitation in addition to photoionisation by star-forming activities. Interstellar shocks embedded in the outflows shock-excite and compress the gas, causing the elevated line ratios, velocity dispersions, and electron densities observed in the broad kinematic component. We argue from energy considerations that, with the lack of a powerful active galactic nucleus, the outflows are likely to be driven by starburst activities. Our results set a benchmark of the type of analysis that can be achieved by the SAMI Galaxy Survey on large numbers of galaxies.Comment: 17 pages, 15 figures. Accepted to MNRAS. References update

The SAMI Galaxy Survey: Towards a unified dynamical scaling relation for galaxies of all types

We take advantage of the first data from the Sydney-AAO Multi-object Integral field (SAMI) Galaxy Survey to investigate the relation between the kinematics of gas and stars, and stellar mass in a comprehensive sample of nearby galaxies. We find that all 235 objects in our sample, regardless of their morphology, lie on a tight relation linking stellar mass ($M_{*}$) to internal velocity quantified by the $S_{0.5}$ parameter, which combines the contribution of both dispersion ($\sigma$) and rotational velocity ($V_{rot}$) to the dynamical support of a galaxy ($S_{0.5}=\sqrt{0.5V_{rot}^{2}+\sigma^{2}}$). Our results are independent of the baryonic component from which $\sigma$ and $V_{rot}$ are estimated, as the $S_{0.5}$ of stars and gas agree remarkably well. This represents a significant improvement compared to the canonical $M_{*}$ vs. $V_{rot}$ and $M_{*}$ vs. $\sigma$ relations. Not only is no sample pruning necessary, but also stellar and gas kinematics can be used simultaneously, as the effect of asymmetric drift is taken into account once $V_{rot}$ and $\sigma$ are combined. Our findings illustrate how the combination of dispersion and rotational velocities for both gas and stars can provide us with a single dynamical scaling relation valid for galaxies of all morphologies across at least the stellar mass range 8.5$<log(M_{*}/M_{\odot})<$11. Such relation appears to be more general and at least as tight as any other dynamical scaling relation, representing a unique tool for investigating the link between galaxy kinematics and baryonic content, and a less biased comparison with theoretical models.Comment: 6 pages, 4 figures. Accepted for publication in ApJ Letter

Multiple myeloma causes clonal T-cell immunosenescence: Identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade

© 2016 Macmillan Publishers Limited. Tumour-induced dysfunction of cytotoxic T cells in patients with multiple myeloma (MM) may contribute to immune escape and be responsible for the lack of therapeutic efficacy of immune checkpoint blockade. We therefore investigated dysfunctional clonal T cells in MM and demonstrated immunosenescence but not exhaustion as a predominant feature. T-cell clones were detected in 75% of MM patients and their prognostic significance was revalidated in a new post-immunomodulatory drug cohort. The cells exhibited a senescent secretory effector phenotype: KLRG-1+/CD57+/CD160+/CD28-. Normal-for-age telomere lengths indicate that senescence is telomere independent and potentially reversible. p38-mitogen-activated protein kinase, p16 and p21 signalling pathways known to induce senescence were not elevated. Telomerase activity was found to be elevated and this may explain how normal telomere lengths are maintained in senescent cells. T-cell receptor signalling checkpoints were normal but elevated SMAD levels associated with T-cell inactivation were detected and may provide a potential target for the reversal of clonal T-cell dysfunction in MM. Low programmed death 1 and cytotoxic T-lymphocyte-associated antigen 4 expression detected on T-cell clones infers that these cells are not exhausted but suggests that there would be a suboptimal response to immune checkpoint blockade in MM. Our data suggest that other immunostimulatory strategies are required in MM

Long-term survival in multiple myeloma is associated with a distinct immunological profile, which includes proliferative cytotoxic T-cell clones and a favourable Treg/Th17 balance

Despite improved outcomes in multiple myeloma (MM), a cure remains elusive. However, even before the current therapeutic era, 5% of patients survived >10 years and we propose that immune factors contribute to this longer survival. We identified patient