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Hepatocellular carcinoma (HCC) poses a significant clinical challenge, necessitating the integration of immunotherapeutic approaches. Palbociclib, a selective CDK4/6 inhibitor, has demonstrated promising efficacy in preclinical HCC models and is being evaluated as a novel therapeutic option in clinical trials. Additionally, CDK4/6 inhibition induces cellular senescence, potentially influencing the tumor microenvironment and immunogenicity of cancer cells. In this study, we conducted comprehensive bioinformatic analyses using diverse HCC transcriptome datasets, including bulk and single-cell RNA-sequencing data from public databases. We also utilized human and mouse HCC cells to investigate functional aspects. Primary T cells isolated from mouse blood were employed to assess T cell immunity against HCC cells. Results revealed that CD8+ T-cell infiltration correlates with improved outcomes in HCC patients with suppressed CDK4/6 expression. Moreover, CDK4/6 expression was associated with alterations in the immune landscape and immune checkpoint expression within the liver tumor microenvironment. Furthermore, we found that treatment with Palbociclib and Doxorubicin induces cellular senescence and a senescence-associated secretory phenotype in HCC cells. Notably, pretreatment with Palbociclib augmented T cell-mediated cytotoxicity against HCC cells, despite upregulation of PD-L1, surpassing the effects of Doxorubicin pretreatment. In conclusion, our study elucidates a novel mechanism by which CDK4/6 inhibition enhances T-cell-associated cancer elimination and proposes a potential therapeutic strategy to enhance T-cell immunotherapy on HCC. [ABSTRACT FROM AUTHOR]

[Display omitted] • IL11RA mRNA therapy demonstrated efficacy in controlling tumor growth. • CD8 + T cell expansion was observed in response to IL11RA mRNA treatment. • Transcriptome analysis revealed insights into IL11RA mRNA therapy mechanisms. • Potential for enhancing overall survival with IL11RA mRNA immunotherapy. Current methods for delivering genes to target tumors face significant challenges, including off-target effects and immune responses against delivery vectors. In this study, we developed a novel approach using messenger RNA (mRNA) to encode IL11RA for local immunotherapy, aiming to harness the immune system to combat tumors. Our research uncovered a compelling correlation between IL11RA expression and CD8 + T cell levels across multiple tumor types, with elevated IL11RA expression correlating with improved overall survival. Examination of the Pan-Cancer Atlas dataset showed a significant reduction in IL11RA expression in various cancer types compared to normal tissue, raising questions about its potential role in tumorigenesis. To achieve efficient in vivo expression of IL11RA, we synthesized two mRNA sequences mimicking the wild-type protein. These mRNA sequences were formulated and capped to ensure effective delivery, resulting in robust expression within tumor sites. Our investigation into IL11RA mRNA therapy demonstrated its effectiveness in controlling tumor growth when administered both intratumorally and intravenously in mouse models. Additionally, IL11RA mRNA treatment significantly stimulated the expansion of CD8 + T cells within tumors, draining lymph nodes, and the spleen. Transcriptome analysis revealed distinct transcriptional patterns associated with T cell functions. Using multiple deconvolution algorithms, we found substantial infiltration of CD8 + T cells following IL11RA mRNA treatment, highlighting its immunomodulatory effects within the tumor microenvironment. In conclusion, IL11RA mRNA therapy presents a promising strategy for tumor regression with potential immunomodulatory effects and clinical implications for improved survival outcomes. [ABSTRACT FROM AUTHOR]

• The GARCH family models from time series analysis is introduced for the first time into machine condition monitoring. • Health indicators constructed based on GARCH and EGARCH models demonstrate the capability to detect incipient faults in bearings, verified through two experimental cases. • In accelerated degradation tests, it is established that acoustic emission signals are closely associated with damage evolution. • Acoustic emission technology can be employed for quantitative assessment of bearing damage. Recent progress in digital twin (DT) has significantly contributed to the advancement of predictive maintenance. The interaction of data between physical and virtual models is facilitated through carefully designed health indicators (HIs). Conventional condition monitoring HIs are inadequate for early-stage fault detection and lack the capacity to quantitatively assess defects. In light of this, the paper proposes HIs based on the generalised autoregressive conditional heteroskedasticity (GARCH) family time series model to characterise the evolution of bearings dynamic response, specifically the cyclostationarity of the repetitive transients. The verification of the proposed indicators is assessed using a publicly available vibration dataset and acoustic emission signals acquired from accelerated bearing degradation tests. The result shows that the GARCH oriented indicators can determine the incipient failure earlier than traditional statistical HIs and have the ability to quantify defects. Significantly, the improved Exponential GARCH model-based indicator demonstrates heightened stability throughout the monitoring process. [ABSTRACT FROM AUTHOR]

[Display omitted] • A monolithic reactor with multi-jet-channel in the circumferential array is constructed. • Two jets unaligned-impinging induces unsteady flow with local eddies and interface deformation. • The degree of two-phase dispersion is higher in the helical channel with a smaller pitch. • The throughput increases by over tenfold with the condition of a higher K L a value. A monolithic reactor with multi-jet-channel in the circumferential array (MR-MJCCA) is designed to intensify mass transfer. Effects of operating conditions and geometric parameters on the mass transfer efficiency E and overall volumetric mass transfer coefficient K L a are illustrated through experimental and numerical methods. Results show that the increased jet impingement intensity due to a higher flow rate and smaller jet diameter D p effectively enhances mass transfer. E and K L a in the MR-MJCCA possessing eight channels increase with reducing the channel depth D e and helical pitch p , yet first rise and then decline with enlarging the jet unaligned-impinging distance w. A higher two-phase interfacial area and energy dissipation rate are conducive to improving mass transfer performance in configurations with D p = 0.3 mm, D e = 1 mm, p = 5 mm, and w = 1.5 mm. Increasing the axial length of reactor elevates E whereas K L a diminishes. A reliable artificial neural network model was used to correlate K L a with key parameters. MR-MJCCA exhibits a higher K L a compared to most microreactors and the throughput increases by over tenfold, demonstrating its scalability and broader industrial applications. [ABSTRACT FROM AUTHOR]