Dalsgaardcummings4843

A high density of CD8

tumor infiltrating lymphocytes (TILs) is associated with improved survival in multiple cancers, but its prognostic role in prostate cancer remains controversial. The aim of our study was to evaluate the prognostic value of CD8

TILs in prostate cancer patients undergoing radical prostatectomy (RP). We hypothesized that elevated density of CD8

TILs in the RP specimen would correlate with improved clinical outcomes. This information may be helpful for future immunotherapy clinical trial design and treatment selection.

Tumor microarrays constructed from 230 patients with localized prostate cancers who underwent RP from 2006 to 2012 at Roswell Park Comprehensive Cancer Center were analyzed retrospectively using immunohistochemistry. CD8

cell density was evaluated using a computerized scoring system. The cohorts were separated by CD8

TIL density at the 25th percentile (i.e., low<quartile 1 and high≥quartile 1). The quartile 1 threshold was chosen through a "minimal pvalue apprprognostic value of CD8

TIL density, the CD8

cell density in the matched normal prostate tissue was not associated with any clinical outcomes.

Intratumoral CD8

T-cell infiltration in the RP specimen is independently associated with improved survival after RP in this high-risk prostate cancer cohort. Pre-RP immunomodulation that promotes intratumoral CD8

cytotoxic T-cell infiltration may be beneficial for this population.

Intratumoral CD8+ T-cell infiltration in the RP specimen is independently associated with improved survival after RP in this high-risk prostate cancer cohort. Pre-RP immunomodulation that promotes intratumoral CD8+ cytotoxic T-cell infiltration may be beneficial for this population.Carfilzomib-lenalidomide-dexamethasone (KRd) has been approved for the treatment of relapsed/refractory multiple myeloma (RRMM). We conducted a retrospective analysis of 197 RRMM patients (pts) between January 2016 and March 2018 in six Italian hematologic centers, with the aim to evaluate efficacy and safety of KRd in real-life. At KRd initiation 27% carried high risk cytogenetic abnormalities (HRCA) [del17p and/or t(4;14) and/or t(14;16)], median number of prior lines of therapy was 2 (1-8), nearly all pts (96%) received prior bortezomib (18% refractory) while 45% were exposed to lenalidomide (R; 22% refractory). At the median of 12.5 months, 52% of the pts had discontinued treatment, mainly (66%) for progression. Main grade 3-4 adverse events were neutropenia (21%), infections (11%), and hypertension (6%). Overall, the response rate was 88%. The median progression-free survival (PFS) was 19.8 months and 1-year overall survival (OS) rate was 80.6%. By subgroup analysis, extended PFS and OS were observed for pts who received ≤2 prior lines of therapy (HR = 0.42, p less then 0.001 and HR = 0.35, p = 0.001, respectively), not refractory to prior R (HR = 0.37, p less then 0.001, and HR = 0.47, p = 0.024), without HRCA (HR = 0.33, p = 0.005 and HR = 0.26, p = 0.016) and achieving ≥ very good partial response (VGPR; HR = 0.17, p less then 0.001 and HR = 0.18, p less then 0.001). In conclusion, KRd demonstrated to be effective in RRMM pts treated in real-world setting, without new safety concerns. Better survival outcomes emerged for pts with ≤2 prior lines of therapy, achieving at least a VGPR, and without HRCA.Mass cytometry is attracting significant attention for enabling spatiotemporal high-throughput single-cell analysis. As the first demonstration of the simultaneous detection of single-cell proteins and untargeted metabolites, a multi-dimensional organic mass-cytometry system was established by a simple microfluidic chip connected to a nanoelectrospray mass spectrometer, providing useful heterogeneous information about the cells. A series of mass probes with online-dissociated mass tags were developed, ensuring the semi-quantification of cell-surface proteins and the compatibility of endogenous metabolite detection at the single-cell level. Six cell surface antigens and ≈100 metabolites from three ovarian-cancer cell types and two breast-cancer cell types were successfully monitored and contributed to highly sensitive and specific cell typing. Doxorubicin-resistant cancer-cell analysis confirmed the applications in distinguishing rare cell phenotypes. The proposed system is simple, extensible, and promising for cell typing, drug-resistance analysis of tumor cells, and clinical diagnosis and therapy at the single-cell level.

Develop a population pharmacokinetic model describing propofol pharmacokinetics in (pre)term neonates and infants, that can be used for precision dosing (e.g. STS inhibitor during target-controlled infusion) of propofol in this population.

A nonlinear mixed effects pharmacokinetic analysis (Monolix 2018R2) was performed, based on a pooled study population in 107 (pre)term neonates and infants.

In total, 836 blood samples were collected from 66 (pre)term neonates and 41 infants originating from 3 studies. Body weight (BW) of the pooled study population was 3.050 (0.580-11.440) kg, postmenstrual age (PMA) was 36.56 (27.00-43.00) weeks and postnatal age (PNA) was 1.14 (0-104.00) weeks (median and min-max range). A 3-compartment structural model was identified and the effect of BW was modelled using fixed allometric exponents. Elimination clearance maturation was modelled accounting for the maturational effect on elimination clearance until birth (by gestational age [GA]) and postpartum (by PNA and GA). The extrapolated other physio-anatomical changes may explain the changes in central distribution volume. The developed model may serve as a prior for propofol dose finding and target-controlled infusion in (preterm) neonates.Factor H-related protein 1 (FHR-1) is a member of the factor H protein family, which is involved in regulating innate immune complement reactions. Genetic modification of the encoding gene, CFHR1 on human chromosome 1, is involved in diseases such as age-related macular degeneration, C3 glomerulopathy and atypical haemolytic uraemic syndrome, indicating an important role for FHR-1 in human health. Recent research data demonstrate that FHR-1 levels increase in IgA nephropathy and anti-neutrophilic cytoplasmic autoantibodies (ANCA) vasculitis and that FHR-1 induces strong inflammation in monocytes on necrotic-type surfaces, suggesting a complement-independent role. These new results increase our knowledge about the role of this complement protein in pathology and provide a new therapeutic target, particularly in the context of inflammatory diseases induced by necrosis. This review summarizes current knowledge about FHR-1 and discusses its role in complement reactions and inflammation.