The efficacy and immunological effects of upadacitinib in the treatment of moderate-to-severe Chinese atopic dermatitis patients.

Upadacitinib has received approval for the treatment of atopic dermatitis (AD) with favorable response in clinical trials. However, real-world research on its efficacy remains relatively limited. To bridge this gap, we conducted a prospective cohort study involving 25 Chinese patients with moderate-to-severe AD. These patients received a daily dose of 15 mg of upadacitinib. Our objective was to assess the real-world efficacy of upadacitinib and its impact on the immune system. Clinical assessments were conducted at baseline, 4 weeks, 8 weeks, and 12 weeks following treatment initiation. The findings revealed that upadacitinib treatment significantly improved the clinical scores of the patients. Regarding immunological markers, upadacitinib led to a significant reduction in peripheral blood eosinophils, as well as a decrease in neutrophil count. Furthermore, upadacitinib treatment resulted in an overall decrease in Th1, Th2, and Th17/22-type cytokines, as well as other inflammatory factors. Importantly, for the first time, we observed a notable reduction in both IL-22+CD4+ T cells and serum IL-22 levels in all treated patients, including those with recalcitrant AD who had previously shown inadequate responses to systemic treatments like dupilumab. Currently, international guidelines position upadacitinib as a second-line option following the failure of systemic treatments like dupilumab. Our findings provide valuable insights into the real-world effectiveness and immunological impacts of upadacitinib, which can aid in better understanding and implementation of the drug in clinical practice.

Androgen receptor and MYC transcriptomes are equilibrated in multilayer regulatory circuitries in prostate cancer.

BACKGROUND: The discovery of androgen receptor (AR) having transrepression effects completes the circle of its functionalities as a typical transcription factor, which intrinsically bears dual functions of activation and repression linked to co-factor competition and redistribution. Indeed, AR dual functions are exemplified by locus-wide regulation of the oncogenic 8q24-MYC region. METHODS: RT-qPCR assay and public RNA-profiling datasets were used to assess MYC transcription in androgen-sensitive cell lines. Public ChIP-seq and RNA-Seq datasets were computed to evaluate AR-MYC direct and indirect signatures. Gene sets in typical MYC and AR pathways were monitored to validate their cross-talks. Bio-informatics and chromosome conformation capture (3C) assay were performed in the AR gene locus to examine androgen-elicited distal regulation. Finally, co-factor re-distribution were globally tracked between AR and MYC binding sites. RESULTS: In this report, we found MYC responded negatively to androgen with hypersensitivity, rivaling AR natural functions as an innate androgen effector. Furthermore, both direct and indirect AR and MYC transcriptional programs were actively in equilibration. With established androgen-mediated versus MYC-mediated gene subsets, we validated AR and MYC pathways were both bidirectional and extensively entangled. In addition, we determined that the AR gene locus resembled the MYC gene region and both loci were androgen-repressed via epigenetics and chromatin architectural alterations. Significantly, transcriptional factor profiling along the prostate cancer (PCa) genome exposed that PCa transcriptomes were dynamically equilibrated between AR-binding site and MYC-binding site. CONCLUSION: Together, our findings stratified AR-MYC interactions that are extensively wired and intricately organized to compensate for essential PCa transcriptional programs and neutralize excessive signaling.