In an exploratory analysis, we investigated the association between programmed death ligand 1 (PD-L1), tumor mutational burden (TMB), T-cell-inflamed gene expression profile (TcellinfGEP), and ...stromal signature with outcomes of pembrolizumab in urothelial carcinoma (UC).
Patients with advanced UC received first-line pembrolizumab 200 mg every 3 weeks in the single-arm phase II KEYNOTE-052 trial (NCT02335424) and salvage pembrolizumab 200 mg every 3 weeks or chemotherapy (paclitaxel/docetaxel/vinflunine) in the randomized phase III KEYNOTE-045 trial (NCT02256436). The association of each biomarker (continuous variable) with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was evaluated using logistic regression (ORR) and Cox PH (PFS, OS), adjusted for ECOG PS; nominal P values were calculated without multiplicity adjustment (one-sided, pembrolizumab; two-sided, chemotherapy). Significance was prespecified at α = 0.05.
In KEYNOTE-052, PD-L1, TMB, and TcellinfGEP were significantly associated with improved outcomes; stromal signature was significantly associated with worse outcomes. In KEYNOTE-045, although findings for TMB and TcellinfGEP with pembrolizumab were consistent with those of KEYNOTE-052, PD-L1 was not significantly associated with improved outcomes, nor was stromal signature associated with worse outcomes with pembrolizumab; chemotherapy was not associated with outcomes in a consistent manner for any of the biomarkers. Hazard ratio (HR) estimates at prespecified cutoffs showed an advantage for pembrolizumab versus chemotherapy regardless of PD-L1 or TMB, with a trend toward lower HRs in the combined positive score ≥10 and the TMB ≥175 mutation/exome subgroup. For TcellinfGEP, PFS and OS HRs were lower in the TcellinfGEP-nonlow subgroup regardless of treatment.
Multiple biomarkers characterizing the tumor microenvironment may help predict response to pembrolizumab monotherapy in UC, and potential clinical utility of these biomarkers may be context-dependent.
The serotonin 2A (5-HT
2A
) and metabotropic glutamate 2 (mGlu2) receptors regulate each other and are associated with schizophrenia. The Roman high- (RHA-I) and the Roman low- (RLA-I) avoidance rat ...strains present well-differentiated behavioral profiles, with the RHA-I strain emerging as a putative genetic rat model of schizophrenia-related features. The RHA-I strain shows increased 5-HT
2A
and decreased mGlu2 receptor binding levels in prefrontal cortex (PFC). Here, we looked for differences in gene expression and transcriptional regulation of these receptors. The striatum (STR) was included in the analysis. 5-HT
2A
, 5-HT
1A
, and mGlu2 mRNA and
3
Hketanserin binding levels were measured in brain homogenates. As expected, 5-HT
2A
binding was significantly increased in PFC in the RHA-I rats, while no difference in binding was observed in STR. Surprisingly, 5-HT
2A
gene expression was unchanged in PFC but significantly decreased in STR. mGlu2 receptor gene expression was significantly decreased in both PFC and STR. No differences were observed for the 5-HT
1A
receptor. Chromatin immunoprecipitation assay revealed increased trimethylation of histone 3 at lysine 27 (H3K27me3) at the promoter region of the
HTR2A
gene in the STR. We further looked at the Akt/GSK3 signaling pathway, a downstream point of convergence of the serotonin and glutamate system, and found increased phosphorylation levels of GSK3β at tyrosine 216 and increased β-catenin levels in the PFC of the RHA-I rats. These results reveal region-specific regulation of the 5-HT
2A
receptor in the RHA-I rats probably due to absence of mGlu2 receptor that may result in differential regulation of downstream pathways.
Among the 'most wanted' targets in cancer therapy is the oncogene MYC, which coordinates key transcriptional programs in tumor development and maintenance. It has, however, long been considered ...undruggable. OMO-103 is a MYC inhibitor consisting of a 91-amino acid miniprotein. Here we present results from a phase 1 study of OMO-103 in advanced solid tumors, established to examine safety and tolerability as primary outcomes and pharmacokinetics, recommended phase 2 dose and preliminary signs of activity as secondary ones. A classical 3 + 3 design was used for dose escalation of weekly intravenous, single-agent OMO-103 administration in 21-day cycles, encompassing six dose levels (DLs). A total of 22 patients were enrolled, with treatment maintained until disease progression. The most common adverse events were grade 1 infusion-related reactions, occurring in ten patients. One dose-limiting toxicity occurred at DL5. Pharmacokinetics showed nonlinearity, with tissue saturation signs at DL5 and a terminal half-life in serum of 40 h. Of the 19 patients evaluable for response, 12 reached the predefined 9-week time point for assessment of drug antitumor activity, eight of those showing stable disease by computed tomography. One patient defined as stable disease by response evaluation criteria in solid tumors showed a 49% reduction in total tumor volume at best response. Transcriptomic analysis supported target engagement in tumor biopsies. In addition, we identified soluble factors that are potential pharmacodynamic and predictive response markers. Based on all these data, the recommended phase 2 dose was determined as DL5 (6.48 mg kg
).ClinicalTrials.gov identifier: NCT04808362 .
Precarious manhood beliefs portray manhood, relative to womanhood, as a social status that is hard to earn, easy to lose, and proven via public action. Here, we present cross-cultural data on a brief ...measure of precarious manhood beliefs (the Precarious Manhood Beliefs scale PMB) that covaries meaningfully with other cross-culturally validated gender ideologies and with country-level indices of gender equality and human development. Using data from university samples in 62 countries across 13 world regions (N = 33,417), we demonstrate: (1) the psychometric isomorphism of the PMB (i.e., its comparability in meaning and statistical properties across the individual and country levels); (2) the PMB’s distinctness from, and associations with, ambivalent sexism and ambivalence toward men; and (3) associations of the PMB with nation-level gender equality and human development. Findings are discussed in terms of their statistical and theoretical implications for understanding widely-held beliefs about the precariousness of the male gender role.
Se analiza el concepto de datos abiertos, que debe cumplir muchos más requisitos que el de estar simplemente accesibles a través de internet en cualquier formato. Se ofrecen algunos ejemplos sobre la ...importancia de los repositorios de datos científicos en abierto para favorecer la transparencia en el desarrollo de la ciencia y evitar el fraude científico, y se ponen de manifiesto algunos de los problemas en la gestión de estos repositorios de datos.
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