The Initial Mass Function and Disk Frequency of the Rho Ophiuchi Cloud: An Extinction-Limited Sample

We have completed an optical spectroscopic survey of an unbiased, extinction-limited sample of candidate young stars covering 1.3 square degrees of the Rho Ophiuchi star forming region. While infrared, X-ray, and optical surveys of the cloud have identified many young stellar objects (YSOs), these surveys are biased towards particular stages of stellar evolution and are not optimal for studies of the disk frequency and initial mass function.We have obtained over 300 optical spectra to help identify 135 association members based on the presence of H-alpha in emission, lithium absorption, X-ray emission, a mid-infrared excess, a common proper motion, reflection nebulosity, and/or extinction considerations. Spectral types along with R and I band photometry were used to derive effective temperatures and bolometric luminosities for association members to compare with theoretical tracks and isochrones for pre-main-sequence stars. An average age of 3.1 Myr is derived for this population which is intermediate between that of objects embedded in the cloud core of Rho Ophiuchi and low mass stars in the Upper Scorpius subgroup. Consistent with this age we find a circumstellar disk frequency of 27% plus or minus 5%. We also constructed an initial mass function for an extinction-limited sample of 123 YSOs (A_v less than or equal to 8 mag), which is consistent with the field star initial mass function for YSOs with masses > 0.2 M_sun. There may be a deficit of brown dwarfs but this result relies on completeness corrections and requires confirmation.Comment: 46 pages, 7 figures, 4 table

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Hip strength is greater in athletes who subsequently develop patellofemoral pain

Background: Hip and knee strength abnormalities have been implicated in patellofemoral pain (PFP) in multiple studies. However, the relationship is unclear, as many of these studies have been retrospective. Purpose: To compare prospective hip and knee isokinetic strength in young female athletes who subsequently went on to develop PFP relative to their uninjured, healthy peers. Study Design: Descriptive epidemiology study. Methods: Adolescent female athletes (N = 329) were tested for isokinetic strength of the knee (flexion and extension) and hip (abduction) and screened for the prevalence of PFP before their basketball seasons. After exclusion based on current PFP symptoms, 255 participants were prospectively enrolled in the study. A 1-way analysis of variance was used to determine between-group differences in incident PFP and the referent (no incident PFP) participants. Results: The cumulative incidence rate for the development of PFP was 0.97 per 1000 athlete-exposures. Female athletes who developed PFP demonstrated increased normalized hip abduction strength (normalized torque, 0.013 0.003) relative to the referent control group (normalized torque, 0.011 0.003) (P .05). Conclusion: The findings in this study indicate that young female athletes with greater hip abduction strength may be at an increased risk for the development of PFP. Previous studies that have looked at biomechanics indicated that those with PFP have greater hip adduction dynamic mechanics. Clinical Relevance: Combining the study data with previous literature, we theorize that greater hip abduction strength may be a resultant symptom of increased eccentric loading of the hip abductors associated with increased dynamic valgus biomechanics, demonstrated to underlie increased PFP incidence. Further research is needed to verify the proposed mechanistic link to the incidence of PFP

Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1+ CD8+ T cells in tumor-draining lymph nodes

In tumors, a subset of CD8+ T cells expressing the transcription factor TCF-1 drives the response to immune checkpoint blockade. We examined the mechanisms that maintain these cells in an autochthonous model of lung adenocarcinoma. Longitudinal sampling and single-cell sequencing of tumor-antigen specific TCF-1+ CD8+ T cells revealed that while intratumoral TCF-1+ CD8+ T cells acquired dysfunctional features and decreased in number as tumors progressed, TCF-1+ CD8+ T cell frequency in the tumor draining LN (dLN) remained stable. Two discrete intratumoral TCF-1+ CD8+ T cell subsets developed over time-a proliferative SlamF6+ subset and a non-cycling SlamF6- subset. Blocking dLN egress decreased the frequency of intratumoral SlamF6+ TCF-1+ CD8+ T cells. Conventional type I dendritic cell (cDC1) in dLN decreased in number with tumor progression, and Flt3L+anti-CD40 treatment recovered SlamF6+ T cell frequencies and decreased tumor burden. Thus, cDC1s in tumor dLN maintain a reservoir of TCF-1+ CD8+ T cells and their decrease contributes to failed anti-tumor immunity

Expression Analysis and Significance of PD-1, LAG-3, and TIM-3 in Human Non-Small Cell Lung Cancer Using Spatially Resolved and Multiparametric Single-Cell Analysis

Purpose: To determine the tumor tissue/cell distribution, functional associations, and clinical significance of PD-1, LAG3, and TIM-3 protein expression in human non-small cell lung cancer (NSCLC). Experimental Design: Using multiplexed quantitative immunofluorescence, we performed localized measurements of CD3, PD-1, LAG-3, and TIM-3 protein in &gt; 800 clinically annotated NSCLCs from three independent cohorts represented in tissue microarrays. Associations between the marker’s expression and major genomic alterations were studied in The Cancer Genome Atlas NSCLC dataset. Using mass cytometry (CyTOF) analysis of leukocytes collected from 20 resected NSCLCs, we determined the levels, coexpression, and functional profile of PD-1, LAG-3, and TIM-3 expressing immune cells. Finally, we measured the markers in baseline samples from 90 patients with advanced NSCLC treated with PD-1 axis blockers and known response to treatment. Results: PD-1, LAG-3, and TIM-3 were detected in tumorinfiltrating lymphocytes (TIL) from 55%, 41.5%, and 25.3% of NSCLC cases, respectively. These markers showed a prominent association with each other and limited association with major clinicopathologic variables and survival in patients not receiv-ing immunotherapy. Expression of the markers was lower in EGFR-mutated adenocarcinomas and displayed limited association with tumor mutational burden. In single-cell CyTOF analysis, PD-1 and LAG-3 were predominantly localized on T-cell subsets/NKT cells, whereas TIM-3 expression was higher in NK cells and macrophages. Coexpression of PD-1, LAG-3, and TIM-3 was associated with prominent T-cell activation (CD69/CD137), effector function (Granzyme-B), and proliferation (Ki-67), but also with elevated levels of proapoptotic markers (FAS/BIM). LAG-3 and TIM-3 were present in TIL subsets lacking PD-1 expression and showed a distinct functional profile. In baseline samples from 90 patients with advanced NSCLC treated with PD-1 axis blockers, elevated LAG-3 was significantly associated with shorter progressionfree survival. Conclusions: PD-1, LAG-3, and TIM-3 have distinct tissue/cell distribution, functional implications, and genomic correlates in human NSCLC. Expression of these immune inhibitory receptors in TILs is associated with prominent activation, but also with a proapoptotic T-cell phenotype. Elevated LAG-3 expression is associated with insensitivity to PD-1 axis blockade, suggesting independence of these immune evasion pathways