Integrated single-cell transcriptome and TCR profiles of hepatocellular carcinoma highlight the convergence on interferon signaling during immunotherapy

Article

Author: Ren, Jing ; Lyu, Cheng ; Xu, Chang ; Xu, Huanhuan ; Li, Tianhao ; Liu, Changqing ; Li, Xiaobo ; Zhang, Mingshuo ; Kong, Dan ; Hao, Dapeng ; Guo, Shengnan ; Hou, Zepeng ; Wang, Guangyu ; Zhang, Mingjie

BackgroundDespite the success of immune checkpoint inhibitor (ICI)-based combination therapies in hepatocellular carcinoma (HCC), its effectiveness remains confined to a subset of patients. The development of reliable, predictive markers is important for accurate patient stratification and further mechanistic understanding of therapy response.MethodsWe comprehensively analyzed paired single-cell RNA transcriptome and T-cell repertoire profiles from 14 HCC ascites samples, collected from 7 patients before and after treatment with the combination of sintilimab (anti-PD-1) and bevacizumab (anti-VEGF).ResultsWe identify a widespread convergence on interferon (IFN) signaling across various immune cell lineages in treatment-responsive patients with HCC, indicating a common transcriptional state transition in the immune microenvironment linked to immunotherapy response in HCC. Strong IFN signaling marks CD8+T cells with larger clonal expansion and enhanced cytotoxicity, macrophages toward M1-like polarization and strong T-cell recruitment ability, dendritic cells with increased antigen presentation capacity, as well as highly cytotoxic natural killer cells and activated B cells. By translating our finding to cohorts of patients with HCC, we demonstrate the specificity of IFN-signaling in the prognosis of patients with HCC and its ability to predict immunotherapy response.ConclusionsThis study provides a unique single-cell resource with clonal and longitudinal resolution during ICI therapy and reveals IFN signaling as a biomarker of immunotherapy response in HCC, suggesting a beneficial effect by combining IFN inducers with ICIs for patients with HCC.

01 Oct 2024·Journal of the Formosan Medical Association

Aerosol particle dispersion in spontaneous breathing training of oxygen delivery tracheostomized patients on prolonged mechanical ventilation

Article

Author: Jerng, Jih-Shuin ; Lin, Feng-Ching ; Chen, Yung-Hsuan ; Ku, Shih-Chi ; Kuo, Yao-Wen

BACKGROUNDTracheostomized patients undergoing liberation from mechanical ventilation (MV) are exposed to the ambient environment through humidified air, potentially heightening aerosol particle dispersion. This study was designed to evaluate the patterns of aerosol dispersion during spontaneous breathing trials in such patients weaning from prolonged MV.METHODSParticle Number Concentrations (PNC) at varying distances from tracheostomized patients in a specialized weaning unit were quantified using low-cost particle sensors, calibrated against a Condensation Particle Counter. Different oxygen delivery methods, including T-piece and collar mask both with the humidifier or with a small volume nebulizer (SVN), and simple collar mask, were employed. The PNC at various distances and across different oxygen devices were compared using the Kruskal-Wallis test.RESULTSOf nine patients receiving prolonged MV, five underwent major surgery, and eight were successfully weaned from ventilation. PNCs at distances ranging from 30 cm to 300 cm showed no significant disparity (H(4) = 8.993, p = 0.061). However, significant differences in PNC were noted among oxygen delivery methods, with Bonferroni-adjusted pairwise comparisons highlighting differences between T-piece or collar mask with SVN and other devices.CONCLUSIONAerosol dispersion within 300 cm of the patient was not significantly different, while the nebulization significantly enhances ambient aerosol dispersion in tracheostomized patients on prolonged MV.

01 Sep 2024·Rheumatology

Genetic changes from type I interferons and JAK inhibitors: clues to drivers of juvenile dermatomyositis

Article

Author: Covert, Lauren T ; Truskey, George A ; Prinz, Joseph A ; Swain-Lenz, Devjanee ; Dvergsten, Jeffrey

AbstractObjectiveTo better understand the pathogenesis of juvenile dermatomyositis (JDM), we examined the effect of the cytokines type I interferons (IFN I) and JAK inhibitor drugs (JAKi) on gene expression in bioengineered pediatric skeletal muscle.MethodsMyoblasts from three healthy pediatric donors were used to create three-dimensional skeletal muscle units termed myobundles. Myobundles were treated with IFN I, either IFNα or IFNβ. A subset of IFNβ-exposed myobundles was treated with JAKi tofacitinib or baricitinib. RNA sequencing analysis was performed on all myobundles.ResultsSeventy-six myobundles were analysed. Principal component analysis showed donor-specific clusters of gene expression across IFNα and IFNβ-exposed myobundles in a dose-dependent manner. Both cytokines upregulated interferon response and proinflammatory genes; however, IFNβ led to more significant upregulation. Key downregulated pathways involved oxidative phosphorylation, fatty acid metabolism and myogenesis genes. Addition of tofacitinib or baricitinib moderated the gene expression induced by IFNβ, with partial reversal of upregulated inflammatory and downregulated myogenesis pathways. Baricitinib altered genetic profiles more than tofacitinib.ConclusionIFNβ leads to more pro-inflammatory gene upregulation than IFNα, correlating to greater decrease in contractile protein gene expression and reduced contractile force. JAK inhibitors, baricitinib more so than tofacitinib, partially reverse IFN I-induced genetic changes. Increased IFN I exposure in healthy bioengineered skeletal muscle leads to IFN-inducible gene expression, inflammatory pathway enrichment, and myogenesis gene downregulation, consistent with what is observed in JDM.

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Indication	Highest Phase	Country/Location	Organization	Date
Herpes Simplex	Phase 2	CN	Beijing Kawin Technology Share-Holding Co., Ltd.	27 Apr 2023
Herpangina	Phase 2	-	Beijing Kawin Technology Share-Holding Co., Ltd.	-

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