•Real world datasets are needed to assess biomarker performances in daily routine practice.•The stromal CD8+TILs were found to be the strongest predictor for PFS and OS in advanced NSCLC on anti-PD-1 ...monotherapy.•The combination of stromal CD8+TILs, albumin and LDH best predicted OS.
Immune checkpoint inhibitors (ICI), such as anti-PD-1 agents, have become part of the standard of care treatment of advanced non-small cell lung cancer (NSCLC). Predictive biomarkers are needed to identify patients that benefit from anti-PD-1 treatments. Tumor infiltrating lymphocytes (TILs) and PD-L1 are major players in the ICI mechanism of action. In this study, we assess the impact of real-world clinicopathological variables, including TILs and PD-L1, on anti-PD-1 efficacy.
We performed a monocenter retrospective study in advanced NSCLC treated with nivolumab or pembrolizumab between January 2015 and February 2019. The impact of baseline clinical and pathological variables was assessed by univariate and multivariate models. TILs, defined as CD8+T-cells, and PD-L1 were scored in tumor and stroma, and correlated with progression free survival (PFS) and overall survival (OS).
We included 366 patients of whom 141 were assessed for tumor and stromal TILs. The median follow-up time was 487 days. In the whole cohort, PFS was associated with high tumor PD-L1, high albumin and good performance. OS was associated with low LDH, high albumin, good performance and ‘first-line treatment’. In the TILs subcohort, stromal TILs had the strongest impact on PFS and OS. Stromal TILs were a stronger marker for PFS and OS than tumoral TILs, tumoral PD-L1 or stromal PD-L1. Remaining factors for PFS and OS were albumin and albumin with LDH, respectively.
This real-world study on clinicopathological features shows that stromal CD8 + TILs were the strongest predictor for PFS and OS in patients with advanced NSCLC on anti-PD-1 therapy. Other predictors for PFS and OS included albumin and albumin together with LDH, respectively. This study highlights the pivotal role of the stromal compartment in the mechanisms of action of ICI, and the need for further studies aiming to overcome this stromal firewall.
Adinazolam and its metabolites inhibit 3Hflunitrazepam binding in-vitro. The binding affinities of these compounds is significantly enhanced in the presence of 10-5 M muscimol, indicating that both ...adinazolam and its metabolites are benzodiazepine agonists. In-vivo metabolism of adinazolam results in the formation of active metabolites.
Summer flounder, Paralichthys dentatus, were fed diets with various protein levels (36.6%, 40.0%, 47.7%, 51.9%, and 56.5%), and the effect of these levels on growth and blood parameters was measured. ...Fish fed the highest protein level gained significantly (P< 0.05) more weight than those fed lower levels of protein. There were no significant (P> 0.05) differences among mean feed conversion ratios (FCR), protein efficiency ratios (PER), net protein utilization (NPU), or mean percent total body moisture, protein, lipid, or ash content. Fish fed diets with 52 or 56% protein had red blood cell counts that were significantly (P< 0.05) higher than fish fed diets with lower protein levels. In addition, hematocrits were significantly (P< 0.001) correlated to dietary protein. There were no significant differences among mean total protein, triglyceride, glucose or phosphate. However, blood calcium levels varied with diet. Data indicate that summer flounder protein requirements are near those suggested for other flatfish.
Next-generation sequencing in cancer research may reveal germline variants of clinical significance. We report patient preferences for return of results and the prevalence of incidental pathogenic ...germline variants (PGVs).
Targeted exome sequencing of 202 genes was carried out in 1000 advanced cancers using tumor and normal DNA in a research laboratory. Pathogenic variants in 18 genes, recommended for return by The American College of Medical Genetics and Genomics, as well as PALB2, were considered actionable. Patient preferences of return of incidental germline results were collected. Return of results was initiated with genetic counseling and repeat CLIA testing.
Of the 1000 patients who underwent sequencing, 43 had likely PGVs: APC (1), BRCA1 (11), BRCA2 (10), TP53 (10), MSH2 (1), MSH6 (4), PALB2 (2), PTEN (2), TSC2 (1), and RB1 (1). Twenty (47%) of 43 variants were previously known based on clinical genetic testing. Of the 1167 patients who consented for a germline testing protocol, 1157 (99%) desired to be informed of incidental results. Twenty-three previously unrecognized mutations identified in the research environment were confirmed with an orthogonal CLIA platform. All patients approached decided to proceed with formal genetic counseling; in all cases where formal genetic testing was carried out, the germline variant of concern validated with clinical genetic testing.
In this series, 2.3% patients had previously unrecognized pathogenic germline mutations in 19 cancer-related genes. Thus, genomic sequencing must be accompanied by a plan for return of germline results, in partnership with genetic counseling.
Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may ...improve pregnancy outcomes in women who have bleeding in early pregnancy.
We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data.
A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval CI, 1.00 to 1.07; P = 0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P = 0.08). The incidence of adverse events did not differ significantly between the groups.
Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439.).
Although several studies have emphasized the role of the anterior cingulate cortex (ACC) in associating actions with reward value, its role in guiding choices on the basis of changes in reward value ...has not been assessed. Accordingly, we compared rhesus monkeys with ACC lesions and controls on object- and action-based reinforcer devaluation tasks. Monkeys were required to associate an object or an action with one of two reward outcomes, and we assessed the monkey's shift in choices of objects or actions after changes in the value of 1 outcome. No group differences emerged on either task. For comparison, we tested the same monkeys on their ability to make choices guided by reward contingency in object- and action-based reversal learning tasks. Monkeys with ACC lesions were impaired in using rewarded trials to sustain the selection of the correct object during object reversal learning. They were also impaired in using errors to guide choices in action reversal learning. These data indicate that the role of the ACC is not restricted to linking specific actions with reward outcomes, as previously reported. Instead, the data suggest a more general role for the ACC in using information about reward and nonreward to sustain effective choice behavior.
Withdrawal from a donor insemination programme Danesh-Meyer, H V; Gillett, W R; Daniels, K R
Australian & New Zealand journal of obstetrics & gynaecology,
19/May , Letnik:
33, Številka:
2
Journal Article
Recenzirano
The aim of this study was to examine the factors that influenced the withdrawal of couples from a regional donor insemination programme. Demographic, medical, treatment and outcome data were ...prospectively recorded on 375 referrals. One hundred and eight women had conceived at least 1 normal pregnancy. Withdrawals from the programme, without pregnancy, accounted for 165 couples, whilst 47 had begun treatment, and a further 29 were on the waiting list. Thirty nine (24%) of those withdrawing did so without notice or reason. Most of these (33) were in couples waiting to begin treatment. Natural conception, adoption, identifiable medical or social reasons (including separation) and moving to another region were the predominant causes for withdrawing. Women who had entered the programme because of their partner's oligospermia had a high natural conception rate. Age, socioeconomic status, geographic location and length of infertility did not affect the withdrawal rate.
Because nutrient-sensing nuclear and cytosolic acetylation mediates cellular autophagy, we investigated whether mitochondrial acetylation modulates mitochondrial autophagy (mitophagy). Knockdown of ...GCN5L1, a component of the mitochondrial acetyltransferase machinery, diminished mitochondrial protein acetylation and augmented mitochondrial enrichment of autophagy mediators. This program was disrupted by SIRT3 knockdown. Chronic GCN5L1 depletion increased mitochondrial turnover and reduced mitochondrial protein content and/or mass. In parallel, mitochondria showed blunted respiration and enhanced 'stress-resilience'. Genetic disruption of autophagy mediators Atg5 and p62 (also known as SQSTM1), as well as GCN5L1 reconstitution, abolished deacetylation-induced mitochondrial autophagy. Interestingly, this program is independent of the mitophagy E3-ligase Parkin (also known as PARK2). Taken together, these data suggest that deacetylation of mitochondrial proteins initiates mitochondrial autophagy in a canonical autophagy-mediator-dependent program and shows that modulation of this regulatory program has ameliorative mitochondrial homeostatic effects.
ABSTRACT We compute upper limits on the nanohertz-frequency isotropic stochastic gravitational wave background (GWB) using the 9 year data set from the North American Nanohertz Observatory for ...Gravitational Waves (NANOGrav) collaboration. Well-tested Bayesian techniques are used to set upper limits on the dimensionless strain amplitude (at a frequency of 1 yr−1) for a GWB from supermassive black hole binaries of A gw < 1.5 × 10 − 15 . We also parameterize the GWB spectrum with a broken power-law model by placing priors on the strain amplitude derived from simulations of Sesana and McWilliams et al. Using Bayesian model selection we find that the data favor a broken power law to a pure power law with odds ratios of 2.2 and 22 to one for the Sesana and McWilliams prior models, respectively. Using the broken power-law analysis we construct posterior distributions on environmental factors that drive the binary to the GW-driven regime including the stellar mass density for stellar-scattering, mass accretion rate for circumbinary disk interaction, and orbital eccentricity for eccentric binaries, marking the first time that the shape of the GWB spectrum has been used to make astrophysical inferences. Returning to a power-law model, we place stringent limits on the energy density of relic GWs, gw ( f ) h 2 < 4.2 × 10 − 10 . Our limit on the cosmic string GWB, gw ( f ) h 2 < 2.2 × 10 − 10 , translates to a conservative limit on the cosmic string tension with G < 3.3 × 10 − 8 , a factor of four better than the joint Planck and high-l cosmic microwave background data from other experiments.
PDF
