Multi-omic profiling reveals potential biomarkers of hepatocellular carcinoma prognosis and therapy response among mitochondria-associated cell death genes in the context of 3P medicine.

Background: Cancer cell growth, metastasis, and drug resistance are major challenges in treating liver hepatocellular carcinoma (LIHC). However, the lack of comprehensive and reliable models hamper the effectiveness of the predictive, preventive, and personalized medicine (PPPM/3PM) strategy in managing LIHC. Methods: Leveraging seven distinct patterns of mitochondrial cell death (MCD), we conducted a multi-omic screening of MCD-related genes. A novel machine learning framework was developed, integrating 10 machine learning algorithms with 67 different combinations to establish a consensus mitochondrial cell death index (MCDI). This index underwent rigorous evaluation across training, validation, and in-house clinical cohorts. A comprehensive multi-omics analysis encompassing bulk, single-cell, and spatial transcriptomics was employed to achieve a deeper insight into the constructed signature. The response of risk subgroups to immunotherapy and targeted therapy was evaluated and validated. RT-qPCR, western blotting, and immunohistochemical staining were utilized for findings validation. Results: Nine critical differentially expressed MCD-related genes were identified in LIHC. A consensus MCDI was constructed based on a 67-combination machine learning computational framework, demonstrating outstanding performance in predicting prognosis and clinical translation. MCDI correlated with immune infiltration, Tumor Immune Dysfunction and Exclusion (TIDE) score and sorafenib sensitivity. Findings were validated experimentally. Moreover, we identified PAK1IP1 as the most important gene for predicting LIHC prognosis and validated its potential as an indicator of prognosis and sorafenib response in our in-house clinical cohorts. Conclusion: This study developed a novel predictive model for LIHC, namely MCDI. Incorporating MCDI into the PPPM framework will enhance clinical decision-making processes and optimize individualized treatment strategies for LIHC patients. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00362-8.

First-in-human phase 2 trial with mite allergoids coupled to mannan in subcutaneous and sublingual immunotherapy.

BACKGROUND: Polymerized allergens conjugated to non-oxidized mannan (PM-allergoids) are novel vaccines targeting dendritic cells (DCs). Previous experimental data indicate that PM-allergoids are readily taken up by DCs and induce Treg cells. This first-in-human study was aimed to evaluate safety and to find the optimal dose of house dust mite PM-allergoid (PM-HDM) administered subcutaneously (SC) or sublingually (SL). METHODS: In a randomized, double-blind, double-dummy, placebo-controlled trial, 196 subjects received placebo or PM-HDM at 500, 1000, 3000, or 5000 mannan-conjugated therapeutic units (mTU)/mL in 9-arm groups for 4 months. All subjects received 5 SC doses (0.5 ml each) every 30 days plus 0.2 ml SL daily. The primary efficacy outcome was the improvement of titrated nasal provocation tests (NPT) with D. pteronyssinus at baseline and at the end of the study. All adverse events and reactions were recorded and assessed. Secondary outcomes were the combination of symptom and medication scores (CSMS) and serological markers. RESULTS: No moderate or severe adverse reactions were reported. Subjects improving the NPT after treatment ranged from 45% to 62% in active SC, 44% to 61% in active SL and 16% in placebo groups. Statistical differences between placebo and active groups were all significant above 500 mTU, being the highest with 3000 mTU SL (p = 0.004) and 5000 mTU SC (p = 0.011). CSMS improvement over placebo reached 70% (p < 0.001) in active 3000 mTU SC and 40% (p = 0.015) in 5000 mTU SL groups. CONCLUSIONS: PM-HDM immunotherapy was safe and successful in achieving primary and secondary clinical outcomes in SC and SL at either 3000 or 5000 mTU/ml.

Predictive Value of Tumor Mutation Burden for PD-1/PD-L1 Inhibitors Treatment on Non-small Cell Lung Cancer: A Meta-analysis / 肿瘤防治研究

Objective To investigate the relation between TMB and the efficiency of PD-1/PD-L1 inhibitors treatment for non-small-cell lung cancer. Methods Studies were searched from PubMed, Embase, Cochrane Library database, Chinese Biomedical Literature Database and Wanfang Database up to March 25, 2020. RevMan 5.3 software and STATA15.0 were used for analysis. Results Twelve literatures were involved, including 1209 patients. TMB significantly improved PFS (HR=0.54, 95%CI: 0.42-0.70, P < 0.001) but reduced the ORR (OR=4.41, 95%CI: 2.54-7.63, P < 0.001) of NSCLC patients treated with PD-1/PD-L1 inhibitors. The subgroup analyses showed that the predictive value of TMB was significant in non-small cell lung cancer treated by PD-1/PD-L1 inhibitors combined with anti-CTLA-4 therapy or chemotherapy. No significant publication bias was observed by the Begg's test and Egger's test. Conclusion High tumor mutation burden may predict the improved PFS of non-small cell lung cancer by PD-1/PD-L1 inhibitors treatment, but its predictive value for OS, ORR and long-term survival need more exploration.

Transcriptome analysis and safety profile of the early-phase clinical response to an adjuvanted grass allergoid immunotherapy.

BACKGROUND: Specific immunotherapy is the only type of disease-modifying treatment, which induces rapid desensitization and long-term sustained unresponsiveness in patients with seasonal allergic rhinoconjunctivitis. The safety and tolerability of a new cumulative dose regimen of 35600 SU Grass MATA MPL for subcutaneous immunotherapy were assessed in pre-seasonal, single-blind, placebo controlled Phase I clinical study. Underlying immunological mechanisms were explored using transcriptome analysis of peripheral blood mononuclear cells. METHODS: Study subjects with a history of moderate to severe seasonal allergic rhinitis and/or conjunctivitis (SAR) due to grass (Pooideae) pollen exposure were randomized on a 1:1 ratio to receive either six 1.0 mL injections of cumulative dose regimen 35600 SU of Grass MATA MPL or placebo. The study consisted of three periods: screening, randomization and treatment and End of Study period. Blood samples were taken for clinical safety laboratory assessments and for the assessment of gene expression analysis during screening visit and End of Study visit. The safety statistics was calculated using Fisher's exact test. Delta Delta Ct method analysis of RT2 Profiler PCR Array gene expression results was used to calculate changes in gene expression level. Genes with the absolute value of log2 fold change greater than ±1.1 and p-value less than 0.05 were identified as differentially expressed and underwent IPA data analysis. RESULTS: The results of the study indicated that the higher cumulative dose regimen of the immunotherapy was well-tolerated. Changes in gene expression profile were associated with early immune responses implicating innate and adaptive immune mechanisms. Pathways and mechanistic network analysis via IPA mapped differentially expressed genes onto canonical pathways related to T cell differentiation, cytokine signalling and Th1/Th2 activation pathways. The transcriptome findings of the study could be further verified in large-scale field studies in order to explore their potential as predictive markers of successful immunotherapy. CONCLUSIONS: The higher dose cumulative regime 35600 SU of Grass MATA MPL vaccine was well tolerated and safe. Molecular markers IL-27, IL-10, IL-4, TNF, IFNγ, TGFß and TLR4 were the main predicted molecular drivers of the observed gene expression changes following early stages of SIT with Grass MATA MPL immunotherapy.

[Expression of eosinophils and IL-33 levels in peripheral blood of patients with allergic rhinitis].

Objective:To investigate the relationship between the count of eosinophils(EOS) in peripheral blood and the serum levels of IL-33, and to discuss the relations among serum levels of IL-33, the count of EOS, visual analog scale (VAS) in different groups.Method:According to different treatments, the patients are divided into three groups: the untreated allergic rhinitis (AR) group (group A), the AR group who had been treated subcutaneous imunotherapy (SCIT) for at least a year (group B) and the AR complicated with allergic asthma group who had been treated subcutaneous imunotherapy (SCIT) for at least a year (gourp C). All subjects were conducted blood cell analysis, and EOS were counted. The serum levels of IL-33 were measured by enzyme linked immune (ELISA), and the obtained date were analysed by GraphPad.Prism 5.0 and SPSS 22.0.AR patients were asked to fill out VAS and were assessed nasal symptoms.Result:The serum levels of IL-33 in the group A were higher than that in other subjects (P<0.05).The serum levels of IL-33 in the group B showed no significant difference between the group B and the group C (P> 0.05).The serum levels of IL-33 in the group B were higher than that in the control group (P<0.05).The serum levels of IL-33 in the group C were higher than that in the control group (P<0.05).The count of EOS in the group A were higher than that in other subjects, and there is no difference between with each other (P> 0.05).The VAS in the group A were higher than that in the group B (P<0.05) and there is no significant difference between the group A and the group C (P<0.05).There is no difference between the group B and the group C(P<0.05).After at least one-year SCIT, the symptoms of AR patients were obviously relieved, such as consciously rhinobyon, rhinorrhea, sneezing and so on. Spearman test showed the serum levels of IL-33 in the AR patients has a weak correlation with the count of eosinophils (P> 0.05, r=0.287).Conclusion:SCIT is an effective treatment for AR patients. role on AR, which can alleviate the symptoms of patients, also can reduce the levels of IL-33 and the count of EOS in peripheral blood.

Lung-derived innate cytokines: new epigenetic targets of allergen-specific sublingual immunotherapy.

OBJECTIVES: Sublingual allergen-specific immunotherapy is a safe and effective method for treatment of IgE-mediated respiratory allergies; however, the underlying mechanisms are not fully understood. This study was planned to test whether sublingual immunotherapy (SLIT) can exert epigenetic mechanisms through which the airway allergic responses can be extinguished. MATERIALS AND METHODS: BALB/c mice were sensitized intraperitoneally and challenged intranasally. Then, they received sublingual treatment with recombinant Che a 2 (rChe a 2), a major allergen of Chenopodium album. After SLIT, allergen-specific antibodies in sera, cytokine profiles of spleen cell cultures, mRNA and protein expression of lung-derived IL-33, IL-25, and TSLP (thymic stromal lymphopoietin), and histone modifications of these three genes were assessed. RESULTS: Following Immunotherapy, systemic immune responses shifted from Th2 to Th1 profile as demonstrated by significant decrease in IgE and IL-4 and substantial increase in IgG2a and IFN-γ. At local site, mRNA and protein levels of lung-derived pro-inflammatory cytokines IL-33 and TSLP were markedly down-regulated following SLIT that was associated with marked enrichment of trimethylated lysine 27 of histone H3 at promoter regions of these two cytokines. CONCLUSION: In our study, sublingual immunotherapy with recombinant allergen effectively attenuated allergic immune responses, at least partly, by induction of distinct histone modifications at specific loci. Additionally, the lung-derived pro-allergic cytokines IL-33 and TSLP could be promising mucosal candidates for either monitoring allergic conditions or therapeutic approaches.