Therapeutic antibodies targeting PD-1 have made major breakthroughs in cancer treatment. However, the majority of colorectal cancer (CRC) cases are microsatellite stable (MSS) and do not respond to anti-PD-1-based immunotherapy. Combination therapy will be an ideal strategy to overcome this limitation. Gegen Qinlian decoction (GQD), a classical traditional Chinese medicine (TCM) formula, has been clinically proven to be effective in the treatment of ulcerative colitis (UC) and type 2 diabetes mellitus. Here, a systemic pharmacological study revealed that GQD acts through multiple targets and pathways in the human body. Combination therapy with GQD and anti-mouse PD-1 potently inhibited the growth of CT26 tumours in a xenograft model. Gut microbiota analysis revealed that combination therapy with GQD and anti-mouse PD-1 significantly enriched for s__Bacteroides_acidifaciens and s__uncultured_organism_g__norank_f__Bacteroidales_S24-7_group . Based on metabolomic analyses, profoundly altered metabolites were identified in the combination therapy group. Two metabolic signalling pathways, namely, glycerophospholipid metabolism and sphingolipid metabolism, were explored. In particular, we found that combination therapy with GQD and anti-mouse PD-1 significantly increased the proportion of CD8+ T cells in peripheral blood and tumour tissues. Direct treatment with GQD and anti-mouse PD-1 increased the expression of IFN-γ, which is a critical factor in antitumour immunotherapy. In addition, combination therapy with GQD and anti-mouse PD-1 downregulated PD-1 and increased IL-2 levels, suggesting that the combination therapy could effectively restore T-cell functions by suppressing inhibitory checkpoints. The application of the Chinese medicinal formula GQD with PD-1 blockade-based immunotherapy can be a novel therapeutic strategy for CRC patients with MSS tumours.
Changes in gut microbiome leaded to changes in glycerophospholipid metabolism level, which may affect the expression of immune-related cytokines IFN-γ and IL-2 in the tumor microenvironment, resulting in a different therapeutic effect of PD-1 antibody. Our findings show that changes in the gut microbiome affect the glycerophospholipid metabolic pathway, thereby regulating the therapeutic potential of PD-1 antibody in the immunotherapy of MSS-type CRC tumor-bearing mice.
BackgroundThe programmed cell death-1 receptor/programmed cell death-1 ligand (PD-1/PD-L1) pathway plays a crucial role in tumor evasion from host immunity. This study was designed to evaluate the association between circulating PD-L1/PD-1 and prognosis after cryoablation in patients with HBV-related hepatocellular carcinoma (HCC).Methodology/Principal FindingsIn the present study, 141 HBV-related HCC patients were enrolled and of those 109 patients received cryoablation. Circulating PD-L1/PD-1 expression was tested by flow cytometry, and 23 patients were simultaneously evaluated for intratumoral PD-L1 expression by immunohistochemical staining. Circulating PD-1/PD-L1 expression was associated with severity of diseases in patients with HCC, and the circulating PD-L1 expression was closely correlated with intratumoral PD-L1 expression. Of the clinical parameters, PD-1/PD-L1 expression was associated with tumor size, blood vessel invasion and BCLC staging. Moreover, PD-1/PD-L1 expression dropped after cryoablation while being elevated at the time of tumor recurrence. Patients with higher expression of circulating PD-L1, as well as circulating PD-1, had a significantly shorter overall survival and tumor-free survival than those with lower expression. Multivariate analysis confirmed that circulating PD-L1 could serve as an independent predictor of overall survival and tumor-recurrence survival in HCC patients after cryoablation.Conclusions/SignificanceUpregulation of circulating PD-L1/PD-1 is associated with poor post-cryoablation prognosis in patients with HBV-related hepatocellular carcinoma.
ObjectivesTo evaluate the dynamic changes of key morphology indicators of the lower extremities in the coronal plane with progressing medial compartment knee osteoarthritis (KOA) with an emphasis on gender‐dependent regional differences.MethodsThe radiographs of patients with non‐traumatic knee pain and varying degrees of genu varus were reviewed. Radiographs were studied in 1538 lower limbs of 883 consecutive patients who visited our hospital from January to July 2017; all patients had long‐standing anteroposterior image‐splicing radiographs taken of their lower limbs. Morphological indicators of bones and joints that can change the alignment of lower limbs or reflect cartilage wear and soft‐tissue relaxation were selected and measured with the help of picture archiving and communication systems. After comparing the data of different genders, the data of males and females was separated into three age groups, <40 years, 40–60 years, >60 years respectively, and then compared among age groups using the Kruskal‐Wallis and Mann–Whitney U tests. Scatterplots of age and all the measurements were drawn to determine the strength of the relations. The Pearson correlation test was performed to reveal correlations of measurements and age.ResultsFemoral bowing angle (FBA) and joint line convergence angle (JLCA) have obvious differences between different genders (P = 0.001, 0.000, respectively). This suggests that females have greater femoral curvature and joint space angle than males. Significant differences were found in hip‐knee‐ankle angle (HKA), FBA, distal femoral valgus resection angle (DFVRA), medial proximal tibial angle (MPTA), JLCA, and minimum joint space width (min‐JSW) by age groups in females (P = 0.000, 0.000, 0.000, 0.000, 0.003, 0.002, respectively). The difference of mechanical medial distal femoral angle (mMDFA) was significant with P values less than 0.05 deemed significant (P = 0.030). Significant correlations were found between age and all measurements (r = −0.166, 0.253, 0.270, −0.147, 0.089, −0.105, −0.076, respectively, P < 0.01). Whereas, the difference in min‐JSW by age group was the only significant one in males (P = 0.001), and no significant correlation was found between age and measurements (r = −0.107, 0.041, 0.134, −0.067, 0.079, −0.134, −0.098, respectively, P > 0.01).ConclusionsAs KOA progressed, both dynamic deformation of lower extremities and degeneration of articular cartilage could be found in females, while no obvious dynamic deformations were found in males. Dynamic deformation of lower extremities was the important feature and the major causative factor of KOA in females.
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