Differences in the risk of immune-related pneumonitis between PD-1 and PD-L1 inhibitors: a meta-analysis according to the new mirror-principle and PRISMA guidelines.

PURPOSE: To compare the risk of immune-associated pneumonitis between PD-1 and PD-L1 inhibitors, the meta-analysis was designed. METHOD: The difference in risk of immune-associated pneumonitis between PD-1 and PD-L1 inhibitors was assessed by two different meta-analysis methods, the Mirror-pairing and the PRISMA guidelines. RESULTS: A total of eighty-eight reports were used for meta-analysis, while thirty-two studies were used for the Mirror-pairing. Both PD-1 and PD-L1 inhibitors (used alone or combined with chemotherapy) increased the risk of developing immune-related pneumonitis (P < 0.00001; P < 0.00001). Based on indirect analyses results (subgroup analyses), the risk of PD-L1-induced pneumonitis was weaker than that of PD-1 inhibitors when the control group was chemotherapy (OR = 3.33 vs. 5.43) or placebo (OR = 2.53 vs. 3.19), while no obvious significant differences were found (P = 0.17; P = 0.53). For the Mirror-pairing-based meta-analysis, the risk of PD-1-induced pneumonitis was significantly higher than that of PD-L1 inhibitors (OR = 1.46, 95%CI [1.08, 1.98], I2 = 0%, Z = 2.47 (P = 0.01)). However, this difference was not significant, when they were combined with chemotherapy (OR = 1.05, 95%CI [0.68, 1.60], I2 = 38%, Z = 0.21 (P = 0.84)). CONCLUSION: Both PD-1 and PD-L1 inhibitors increased the risk of immune-related pneumonitis, while the risk of PD-1-induced pneumonitis was significantly higher than that of PD-L1 inhibitors.

Withdrawn: Therapeutic effect of N-Acetyl-Seryl-Aspartyl-Proline and vasoactive intestinal peptide on COPD pathophysiology.

The above article, published online on 5 December 2022, on Wiley Online Library (https://doi.org/10.1002/jbt.23057), has been withdrawn by agreement between the journal Editor in Chief, Hari Bhat, and Wiley Periodicals, LLC. The withdrawal has been agreed due to a technical error at the publisher that caused the article to be mistakenly published online although publication had been canceled because the authors did not approve their proof.

A combined risk model for the multi-encompassing identification of heterogeneities of prognoses, biological pathway variations and immune states for sepsis patients.

BACKGROUND: Sepsis is a highly heterogeneous syndrome with stratified severity levels and immune states. Even in patients with similar clinical appearances, the underlying signal transduction pathways are significantly different. To identify the heterogeneities of sepsis from multiple angles, we aimed to establish a combined risk model including the molecular risk score for rapid mortality prediction, pathway risk score for the identification of biological pathway variations, and immunity risk score for guidance with immune-modulation therapy. METHODS: We systematically searched and screened the mRNA expression profiles of patients with sepsis in the Gene Expression Omnibus public database. The screened datasets were divided into a training cohort and a validation cohort. In the training cohort, authentic prognostic predictor characteristics (differentially expressed mRNAs, pathway activity variations and immune cells) were screened for model construction through bioinformatics analysis and univariate Cox regression, and a P value less than 0.05 of univariate Cox regression on 28-day mortality was set as the cut-off value. The combined risk model was finally established by the decision tree algorithm. In the validation cohort, the model performance was assessed and validated by C statistics and the area under the receiver operating characteristic curve (AUC). Additionally, the current models were further compared in clinical value with traditional indicators, including procalcitonin (PCT) and interleukin-8 (IL-8). RESULTS: Datasets from two sepsis cohort studies with a total of 585 consecutive sepsis patients admitted to two intensive care units were downloaded as the training cohort (n = 479) and external validation cohort (n = 106). In the training cohort, 15 molecules, 20 pathways and 4 immune cells were eventually enrolled in model construction. These prognostic factors mainly reflected hypoxia, cellular injury, metabolic disorders and immune dysregulation in sepsis patients. In the validation cohort, the AUCs of the molecular model, pathway model, immune model, and combined model were 0.81, 0.82, 0.62 and 0.873, respectively. The AUCs of the traditional biomarkers (PCT and IL-8) were 0.565 and 0.585, respectively. The survival analysis indicated that patients in the high-risk group identified by models in the current study had a poor prognosis (P < 0.05). The above results indicated that the models in this study are all superior to the traditional biomarkers for the predicting the prognosis of sepsis patients. Furthermore, the current study provides some therapeutic recommendations for patients with high risk scores identified by the three submodels. CONCLUSIONS: In summary, the present study provides opportunities for bedside tests that could quantitatively and rapidly measure heterogeneous prognosis, underlying biological pathway variations and immune dysfunction in sepsis patients. Further therapeutic recommendations for patients with high risk scores could improve the therapeutic system for sepsis.

Potential chemotherapeutic effect of betalain against human non-small cell lung cancer through PI3K/Akt/mTOR signaling pathway.

This work focuses on evaluating the therapeutic ability of betalain and its causal mechanisms in NSCLC both in vivo and in vitro. The experimental results demonstrated that betalain was able to reduce the viability of A549 cells dose dependently with undetectable toxicity toward normal human cells. Betalain also augmented the apoptotic cells of A549 and cell cycle arrest which was evidenced via increased in level of p53/p21 and decreasing levels of cyclin-D1 complex. Moreover, betalain also reduced the levels of p-PI3K, p-Akt, and mammalian target of rapamycin significantly, justifying the pro-apoptotic effect on A549 cells. The in vivo anticancer activity of betalain was determined further in nude mice injected with A549 cells. Xenograft in vivo experiments confirmed betalain administration of ameliorates the expression of pro-inflammatory cytokines, tumor markers with reduced toxic effect. Accordingly, this combined study provides significant insight on betalain as a therapeutic agent.

Pirfenidone Inhibits Hypoxic Pulmonary Hypertension through the NADPH/ROS/p38 Pathway in Adventitial Fibroblasts in the Pulmonary Artery.

Hypoxic pulmonary hypertension (HPH) is a devastating disease characterized by progressive vasoconstriction and vascular remodeling. Pirfenidone (PFD) inhibits the progression of HPH, though the molecular mechanisms remain unknown. This study is aimed at determining the role and mechanism of PFD in HPH in human pulmonary artery adventitial fibroblasts (HPAAFs), which were cultured under normal or hypoxic conditions. NOX4 and Rac1 were inhibited or overexpressed by shRNA or pcDNA3.1, respectively. Proliferation of HPAAFs was quantified by colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assays to assess cellular metabolic activity, cell counts, and ethynyldeoxyuridine (EdU) assays to detect DNA synthesis. Migration of HPAAFs was assessed by a wound healing assay. The expression levels of smooth muscle alpha-actin (a-SMA) and procollagen I (COL1A1) were assessed by RT-PCR and western blot analysis. PFD suppressed hypoxia-induced proliferation and migration of HPAAFs. Compared with the hypoxic control group, PFD reduced the expression of a-SMA and procollagen I (COL1A1). PFD reduced hypoxia-induced phosphorylation of p38 through the NOX4/reactive oxygen species (ROS) signaling pathway. Moreover, Rac1 also decreased hypoxia-induced phosphorylation of p38, without any cross-interaction with NOX4. These findings demonstrate that PFD is a novel therapeutic agent to prevent cell proliferation, migration, and fibrosis, which might be useful in inhibiting vascular remodeling in patients with HPH.

Effect of transfected induced pluripotent stem cells with Decorin gene on control of lung remodeling in allergic asthma.

Asthma is a complex respiratory disease, which is controlled by genetic and environmental factors. Type 2-dominant immune response is responsible for asthma. Decorin (Dcn) and stem cells have modulatory effect on immune system and may control tissue remodeling and asthma pathophysiology. In this study, immunomodulatory effect of transduced induced pluripotent stem cells (iPSCs) with expression of Dcn gene on allergic asthma pathophysiology was evaluated. After transduction of iPSCs with Dcn gene, allergic asthma mice were treated with iPSCs and transduced iPSCs via intrabronchial. Then, airway hyperresponsiveness (AHR), levels of interleukin (IL)-4, IL-5, IL-13, IL-33, total IgE, leukotrienes (LTs) B4, C4, hydroxyproline (HP) content, and transforming growth factor-beta (TGF-ß) were measured. Also, lung histopathology study was done. AHR, levels of IL-4, IL-5, IL-13, IL-33, total IgE, LTs B4, C4, TGF-ß, HP content, mucus secretion, goblet cell hyperplasia, and eosinophilic inflammation were controlled by iPSCs and transduced iPSCs treatment. Therapeutic effect of iPSCs could control main allergic asthma symptoms and related pathophysiologic mechanisms and the effect can be increased when applied with Dcn expression gene.

Comprehensive analyses for the coagulation and macrophage-related genes to reveal their joint roles in the prognosis and immunotherapy of lung adenocarcinoma patients.

Purpose: This study aims to explore novel biomarkers related to the coagulation process and tumor-associated macrophage (TAM) infiltration in lung adenocarcinoma (LUAD). Methods: The macrophage M2-related genes were obtained by Weighted Gene Co-expression Network Analysis (WGCNA) in bulk RNA-seq data, while the TAM marker genes were identified by analyzing the scRNA-seq data, and the coagulation-associated genes were obtained from MSigDB and KEGG databases. Survival analysis was performed for the intersectional genes. A risk score model was subsequently constructed based on the survival-related genes for prognosis prediction and validated in external datasets. Results: In total, 33 coagulation and macrophage-related (COMAR) genes were obtained, 19 of which were selected for the risk score model construction. Finally, 10 survival-associated genes (APOE, ARRB2, C1QB, F13A1, FCGR2A, FYN, ITGB2, MMP9, OLR1, and VSIG4) were involved in the COMAR risk score model. According to the risk score, patients were equally divided into low- and high-risk groups, and the prognosis of patients in the high-risk group was significantly worse than that in the low-risk group. The ROC curve indicated that the risk score model had high sensitivity and specificity, which was validated in multiple external datasets. Moreover, the model also had high efficacy in predicting the clinical outcomes of LUAD patients who received anti-PD-1/PD-L1 immunotherapy. Conclusion: The COMAR risk score model constructed in this study has excellent predictive value for the prognosis and immunotherapeutic clinical outcomes of patients with LUAD, which provides potential biomarkers for the treatment and prognostic prediction.