61MO Biomarker analysis of men with enzalutamide (enza)-resistant metastatic castration-resistant prostate cancer (mCRPC) treated with pembrolizumab (pembro) + enza in KEYNOTE-199

Background: In KEYNOTE-199 (NCT02787005), pembro + enza had durable antitumor activity in enza-refractory mCRPC. We evaluated the association between prespecified biomarkers and clinical outcomes. Methods: Cohorts 4 (C4; RECIST-measurable disease) and 5 (C5; nonmeasurable, bone-predominant disease) enrolled men with chemotherapy-naive mCRPC, irrespective of PD-L1 status, that progressed after initial response to enza. We evaluated TMB by whole exome sequencing (n = 64), PD-L1 combined positive score (CPS) by IHC (n = 124), and 18-gene T-cell–inflamed gene expression profile (TcellinfGEP) by NanoString (n = 51). Outcomes were DCR, PFS, PSA response, PSA progression, OS, and ORR per blinded independent review (C4 only). Significance of continuous biomarkers (CPS, TMB, GEP) was prespecified at 0.05 for 1-sided P values from logistic (ORR, DCR, PSA response) and Cox proportional hazard (PFS, OS, PSA progression) regression adjusted for ECOG PS. Results: In C4, ORR was 10% (5/48) in pts with evaluable TMB data and 12% (10/81) in pts with CPS data. In C4 and C5, 16% (10/64) and 14% (17/124) of pts with TMB and CPS data, respectively, achieved a PSA response. TMB was significantly associated with DCR (P = 0.03) and trended toward an association with PSA response (P = 0.08). TMB (AUROC [95% CI]: 0.68 [0.51-0.86]), but not CPS (0.54 [0.41-0.67]) or TcellinfGEP (0.55 [0.37-0.74]), enriched for PSA response. TMB (P = 0.04), but not CPS (P = 0.57) or TcellinfGEP (P = 0.32), was significantly associated with PSA progression. There was 1 MSI-H pt (per Promega PCR assay); this pt achieved an objective and PSA response and had PFS \u3e6 months. TMB, CPS, and TcellinfGEP were not associated with PFS or OS. There was a low prevalence of TMB ≥175 mut/exome (11%) and TcellinfGEP-high (≥−0.318; 16%). Conclusions: In this biomarker analysis of KEYNOTE-199 C4-C5, PD-L1 CPS and TcellinfGEP were not significantly associated with clinical outcome. Despite the low prevalence of TMB ≥175 mut/exome, TMB was positively associated with outcomes of pembro + enza in pts with mCRPC. The sample sizes for the exploratory analyses were small, and results should be interpreted with caution

Formation and Evolution of Planetary Systems: Upper Limits the Gas Mass in HD105

We report infrared spectroscopic observations of HD 105, a nearby ($\sim 40$ pc) and relatively young ($\sim 30$ Myr) G0 star with excess infrared continuum emission, which has been modeled as arising from an optically thin circumstellar dust disk with an inner hole of size $\gtrsim 13$ AU. We have used the high spectral resolution mode of the Infrared Spectrometer (IRS) on the Spitzer Space Telescope to search for gas emission lines from the disk. The observations reported here provide upper limits to the fluxes of H$_2$ S(0) 28$\mu$m, H$_2$ S(1) 17$\mu$m, H$_2$ S(2) 12 $\mu$m, [FeII] 26$\mu$m, [SiII] 35$\mu$m, and [SI] 25$\mu$m infrared emission lines. The H$_2$ line upper limits directly place constraints on the mass of warm molecular gas in the disk: $M({\rm H_2})< 4.6$, 3.8$\times 10^{-2}$, and $3.0\times 10^{-3}$ M$_J$ at $T= 50$, 100, and 200 K, respectively. We also compare the line flux upper limits to predictions from detailed thermal/chemical models of various gas distributions in the disk. These comparisons indicate that if the gas distribution has an inner hole with radius $r_{i,gas}$, the surface density at that inner radius is limited to values ranging from $\lesssim 3$ gm cm$^{-2}$ at $r_{i,gas}=0.5$ AU to 0.1 gm cm$^{-2}$ at $r_{i,gas}= 5-20$ AU. These values are considerably below the value for a minimum mass solar nebula, and suggest that less than 1 M$_J$ of gas (at any temperature) exists in the 1-40 AU planet-forming region. Therefore, it is unlikely that there is sufficient gas for gas giant planet formation to occur in HD 105 at this time.Comment: To appear in the Astrophysical Journa

Simvastatin ameliorates established pulmonary hypertension through a heme oxygenase-1 dependent pathway in rats

<p>Abstract</p> <p>Background</p> <p>Simvastatin has been shown to ameliorate pulmonary hypertension by several mechanisms in experimental animal models. In this study, we hypothesized that the major benefits of simvastatin in pulmonary hypertension occur via the heme oxygenase-1 pathway.</p> <p>Methods</p> <p>Simvastatin (10 mg/kgw/day) was tested in two rat models of pulmonary hypertension (PH): monocrotaline administration and chronic hypoxia. The hemodynamic changes, right heart hypertrophy, HO-1 protein expression, and heme oxygenase (HO) activity in lungs were measured in both models with and without simvastatin treatment. Tin-protoporphyrin (SnPP, 20 μmol/kg w/day), a potent inhibitor of HO activity, was used to confirm the role of HO-1.</p> <p>Results</p> <p>Simvastatin significantly ameliorated pulmonary arterial hypertension from 38.0 ± 2.2 mm Hg to 22.1 ± 1.9 mm Hg in monocrotaline-induced PH (MCT-PH) and from 33.3 ± 0.8 mm Hg to 17.5 ± 2.9 mm Hg in chronic hypoxia-induced PH (CH-PH) rats. The severity of right ventricular hypertrophy was significantly reduced by simvastatin in MCT-PH and CH-PH rats. Co-administration with SnPP abolished the benefits of simvastatin. Simvastatin significantly increased HO-1 protein expression and HO activity in the lungs of rats with PH; however co-administration of SnPP reduced HO-1 activity only. These observations indicate that the simvastatin-induced amelioration of pulmonary hypertension was directly related to the activity of HO-1, rather than its expression.</p> <p>Conclusion</p> <p>This study demonstrated that simvastatin treatment ameliorates established pulmonary hypertension primarily through an HO-1-dependent pathway.</p

HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children

Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)n repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1-expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)n repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients

Cardiac output measurement in children: comparison of Aesculon cardiac output monitor and thermodilution

BACKGROUND: We compared cardiac output (CO) measurements by the non-invasive electrical velocimetry (Aesculon) monitor with the pulmonary artery catheter (PAC) thermodilution method in children. METHODS: CO values using the Aesculon monitor and PAC thermodilution were simultaneously recorded during cardiac catheterization in children. Measurements were performed under general anaesthesia. To compare, three consecutive measurements for each patient within 3 min were obtained. The means of the three values were compared using simple regression and Bland-Altman analysis. Data were presented as mean (sd). A mean percentage of <30% was defined to indicate clinical useful reliability of the Aesculon monitor. RESULTS: A total of 50 patients with a median (range) age of 7.5 (0.5-16.5) yr were enrolled in the study. Mean CO values were 3.7 (1.5) litre min(-1) (PAC thermodilution) and 3.1 (1.7) litre min(-1) (Aesculon) monitor). Analysis for CO measurement showed a good correlation between the two methods (r=0.894; P<0.0001). The bias between the two methods was 0.66 litre min(-1) with a precision of 1.49 litre min(-1). The mean percentage error for CO measurements was 48.9% for the Aesculon monitor when compared with PAC thermodilution. CONCLUSIONS: Electrical velocimetry using the Aesculon monitor did not provide reliable CO values when compared with PAC thermodilution. Whether the Aesculon monitor can be used as a CO trend monitor has to be assessed by further investigations in patients with changing haemodynamics

Massively parallel inference systems Abstracts of the workshop on massively parallel inference systems

SIGLEAvailable from TIB Hannover: RN 7878(9103) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman