Clinical and Experimental Medicine最新文献

Growing research reveals that circular RNAs (circRNAs) play a major part in the progression and development of cancer. Here, we investigated the oncogenic function and regulatory mechanisms of the circRNA circACTN4 in hepatocellular carcinoma (HCC), particularly in the tumor epithelial-mesenchymal transition (EMT). In vitro functional assays (Cell Counting Kit 8, TUNEL, scratch wound healing, and invasion assays) of HCC cell lines, alongside in vivo analyses of subcutaneous tumors in nude model mice, were employed to assess the impact of circACTN4 on HCC proliferation. Interactions concerning circACTN4, microRNA (miR)-424-5p, and non-SMC condensing I complex subunit G (NCAPG) have been assessed deploying luciferase reporter assays and also quantitative reverse transcription PCR investigation of circACTN4 transcripts in HCC tissues. Findings indicated a high expression of circACTN4 in HCC, promoted proliferation, while inhibiting apoptosis of HCC cells, and correlated with poor prognosis. Mechanistically, circACTN4 served as a rival internal RNA for miR-424 5p, controlling NCAPG level and initiating the Wnt/β-catenin signaling routes, which in turn impacted the EMT machinery in HCC. According to our surveys, the circACTN4/miR-424 5p/NCAPG axis could be an intriguing candidate for therapy to address the treatment of HCC.

The role of metabolic reprogramming of the tumor immune microenvironment in cancer development and immune escape has increasingly attracted attention. However, the predictive value of differences in metabolism-immune microenvironment on the prognosis of colon cancer (CC) and the response to immunotherapy have not been elucidated. The aim of this study was to investigate changes in metabolism and immune profile of CC and to identify a reliable signature for predicting prognosis and therapeutic response. The metabolism and immune-related differential genes in CC were screened out by differential gene expression analysis. A metabolism and immune related prognostic signature was established by the least absolute shrinkage and selection operator (LASSO) Cox algorithm. The training cohort with 417 patients from The Cancer Genome Atlas (TCGA) database and the validation cohort of 232 patients from GSE17538 were used to confirm the robustness of the prognostic signature. Immunohistochemical staining scores were used to assess gene expression levels in our clinical samples. Gene ontology (GO) analysis, gene set enrichment analysis (GSEA), single nucleotide variation (SNV) analysis, immune infiltration and immune factors analysis were used to explore the characteristics of patients with different subtypes. Multiple cancer immunotherapy datasets were used to assess the response of patients with different subtypes to immune checkpoint inhibitors. We established the Metabolism and Immune-Related Prognostic Score (MIRPS) based on six genes (CD36, PCOLCE2, SCG2, CALB2, STC2, CLDN23) to predict the prognosis of CC patients. We found a correlation between MIRPS and the malignant phenotype, microsatellite subtype, mutation load, and immune escape in CC. Tumors with high MIRPS presented a higher tumor mutation load and a more prominent immunosuppressive microenvironment. This subset of patients may potentially respond well to immune checkpoint inhibitor therapy. MIRPS may be used as a novel prognostic tool for CC and have potential value for immunotherapy response prediction.

Cellular senescence is understood to be a biological process that is defined as irreversible growth arrest and was originally recognized as a tumor-suppressive mechanism that prevents further propagation of damaged cells. More recently, cellular senescence has been shown to have a dual role in prevention and tumor promotion. Senescent cells carry a senescence-associated secretory phenotype (SASP), which is altered by secretory factors including pro-inflammatory cytokines, chemokines, and other proteases, leading to the alteration of the tissue microenvironment. Though senescence would eventually halt the growth of cancerous potential cells, SASP contributes to the tumor environment by promoting inflammation, matrix remodeling, and tumor cell invasion. The paradox of tumor prevention/promotion is particularly relevant to the bone niche tumor microenvironment, where longer-lasting, chronic inflammation promotes tumor formation. Insights into a mechanistic understanding of cellular senescence and SASP provide the basis for targeted therapies, such as senolytics, which aim to eliminate senescent cells, or SASP inhibitors, which would eliminate the tumor-promoting effects of senescence. These therapeutic interventions offer significant clinical implications for treating cancer and healthy aging.

Immune checkpoint inhibitors have improved the treatment of metastatic renal cell carcinoma (RCC), with the combination of nivolumab (NIVO) and ipilimumab (IPI) showing promising results. However, not all patients benefit from these therapies, emphasizing the need for reliable, easily assessable biomarkers. This multicenter study involved 116 advanced RCC patients treated with NIVO + IPI across nine oncology centers in Poland. Blood markers such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR), eosinophils, and monocytes were assessed at baseline, after three months, and before disease progression (PD). The prognostic significance of these parameters was analyzed using linear regression, Kaplan-Meier survival analysis, and Cox regression models. After a median follow-up of 11.8 months, the progression-free survival (PFS) was 12.8 months (95% confidence interval [CI] 5.7-28.1), while the overall survival (OS) was 27.3 months (95% CI 16-not reached). Patients with an NLR increase of ≥ 25% had a PFS of 8.2 (3.1-24.7) months compared to 17.5 (8.6-28.1) months in those with a rise in < 25% (p = 0.015). Similarly, a ≥ 25% increase in PLR was linked to a PFS of 6.8 (2.8-8.3) months compared to 17.4 (8.4-28.1) months (p < 0.001). Multivariate analysis confirmed PLR as an independent predictor of PFS (HR 2.9, 95% CI 1.5-5.6, p = 0.001), while elevated eosinophil levels were associated with a reduced risk of death (HR 0.2, 95% CI 0.04-0.9, p = 0.05). No other analysis was statistically significant. NLR, PLR, and eosinophil levels may serve as valuable biomarkers for predicting treatment response in RCC patients receiving NIVO + IPI.

Anti-tumor immunotherapy was rediscovered and rejuvenated in the last two decades with the discovery of CTLA-4, PD-1 and PD-L1 and the roles in inhibiting immune function and tumor evasion of anti-tumor immune response. Following the approval of the first checkpoint inhibitor ipilimumab against CTLA-4 in melanoma in 2011, there has been a rapid development of tumor immunotherapy. Furthermore, additional positive and negative molecules among the T-cell regulatory systems have been identified that that function to fine tune the stimulatory or inhibitory immune cells and modulate their functions (checkpoint modulators). Many strategies are being explored to target macrophages, NK-cells, cytotoxic T-cells, fibroblasts, endothelial cells, cytokines and molecules involved in tumor tolerance and microbiome. Similar to agents that target checkpoint modulators, these newer targets have the potential to synergize with other classes of immunotherapeutic agents and importantly may overcome the resistance to other immunotherapies. In order to better understand the mechanism of action of all major classes of immunotherapy, design clinical trials taking advantage of different types of immunotherapeutic agents and use them rationally in clinical practice either in combination or in sequence, we propose the group all immunotherapies into three generations: with CTLA-4, PD-1 and PD-L1 inhibitors as the first generation, agents that target the checkpoint modulators as the second generation, while those that target TME as the third generation. This review discusses all three generations of immunotherapy in oncology, their mechanism of actions, major clinical trial results and indication, strategies for future clinical trial designs and rational clinical applications.

Introduction Recently, immune cells within the tumor microenvironment (TME) have become crucial in regulating cancer progression and treatment responses. The dynamic interactions between tumors and immune cells are emerging as a promising strategy to activate the host's immune system against various cancers. The development and progression of hepatocellular carcinoma (HCC) involve complex biological processes, with the role of the TME and tumor phenotypes still not fully understood. Therefore, it is essential to investigate the importance of immune cell homeostasis in HCC. Additionally, understanding the molecular mechanisms and biological functions underlying tumor-immune cell interactions is increasingly recognized as vital for improving therapeutic outcomes in clinical settings. Methods A total of 790 HCC samples were selected from public databases and real-world independent clinical cohorts. Machine learning methods, focusing on immune-related indicators, were applied to these samples. The Boruta algorithm was employed to develop an ICI score, which was used to assess patient prognosis and predict responses to immunotherapy. Additionally, a new immune subtype analysis of HCC was performed. Cellular-level experiments confirmed the interaction between TME-related factors and the tumor microenvironment in HCC. To further validate the predictive power of the ICI score, a clinical cohort study was conducted at an independent clinical center. Results By evaluating immune gene expression levels, immune cell abundance, Immunescore, and Stromalscore, we initially identified three distinct immune subtypes of HCC, each showing significant differences in survival rates and heterogeneity. Subsequently, DEGs from 1022 immune subtypes were used to classify HCC samples into three immune genotypes, each characterized by distinct prognosis and tumor immune microenvironment (TIME) profiles. Furthermore, we developed the ICI score, a novel immunophenotyping method for HCC, which revealed significant variations based on gender, stage, progression, and DNA mutation profiles (p < 0.05). The ICI score also effectively predicted responses to immunotherapies, particularly through the chemokine signaling, focal adhesion, and JAK/STAT signaling pathways. Conclusion This research demonstrated that TME and immunophenotyping clusters can enhance prognostic accuracy for HCC patients. The independent prognostic indicators identified underscore the connection between tumor phenotype and the immune environment in HCC.

Multiple myeloma (MM) is characterized by clonal plasma cell proliferation in the bone marrow, challenging prognosis prediction. We developed a gene-pairing prognostic risk model using m6A regulatory genes and a nested LASSO method. A cutoff of - 0.133 categorized MM samples into high-risk and low-risk groups. The model showed strong prognostic performance in 2088 newly diagnosed MM samples and predicted response to combination therapy (daratumumab, carfilzomib, lenalidomide, and dexamethasone) in patients who failed or relapsed from bortezomib-containing regimens, with an AUC of 0.9. It distinguished between smoldering MM and MM (cutoff: - 0.45) and between MM and plasma cell leukemia (cutoff: 0.0857). Single-cell analysis revealed higher risk scores at relapse. Combining MM cell lines and sample data, we identified potential drugs and targets (ADAT2 and NUP153) effective against high-risk MM. Integrating the m6A risk model with the International Staging System (ISS) enhanced stratification accuracy. These insights support precision treatment of MM.

Adoptive cell therapy (ACT) using natural killer (NK) cells has emerged as a promising therapeutic strategy for acute myeloid leukemia (AML), addressing challenges such as chemotherapy resistance and high relapse rates. Over the years, clinical trials and studies have explored various sources of NK cells, including ex vivo expanded NK cell lines, CAR-NK cells, peripheral blood-derived NK cells, and umbilical cord blood-derived NK cells. These therapies have demonstrated varying degrees of therapeutic efficacy, ranging from transient anti-leukemia activity to sustained remission in select patient groups. Toxicity profiles have generally shown favorable safety outcomes, with minimal incidence of severe adverse effects such as cytokine release syndrome (CRS) or graft-versus-host disease (GVHD). However, persistent challenges remain, including limited NK cell persistence, relapse, and heterogeneity in patient responses. This review provides a comprehensive analysis of clinical outcomes and toxicity profiles provided from clinical trials, clinical studies and case reports conducted in the last 15 years to judge on the efficacy, safety and applicability of using NK cells for ACT of AML. Our review highlights the significant potential of NK cell-based therapies for AML, while addressing the technical and biological challenges that must be overcome to enhance their efficacy and safety.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disorder closely linked to metabolic syndrome. Identifying novel, easily measurable biomarkers could significantly enhance the diagnosis and management of NAFLD in clinical settings. Recent studies suggest that immunoinflammatory biomarkers-specifically, the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR)-may offer diagnostic value for NAFLD. However, the effectiveness of these biomarkers has not been comprehensively assessed in this patient population. This systematic review and meta-analysis aimed to evaluate the association between these immunoinflammatory biomarkers and NAFLD. As of August 8, 2024, databases including PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus were systematically searched to compare NLR, PLR, and LMR levels in NAFLD patients and healthy controls. Study quality was assessed using the Newcastle-Ottawa Scale, and standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated (PROSPERO registry number: CRD42024580812). A total of 20 studies were included in the meta-analysis. Results indicated that NAFLD patients had significantly higher NLR levels (SMD = 0.43; 95% CI 0.28-0.58; p < 0.001) and lower PLR levels (SMD = - 0.29; 95% CI - 0.41 to - 0.17; p < 0.001) compared to controls. However, no significant difference in LMR was observed between NAFLD patients and controls(SMD = 0.08; 95% CI - 0.00 to 0.17; p = 0.051). These findings suggest that NLR and PLR may hold promise as diagnostic markers for NAFLD, while LMR appears to have limited diagnostic utility. Further research is warranted to explore the potential role of these biomarkers in tracking disease progression.

Upon stimulation and activation, mast cells (MCs) release soluble mediators, including histamine, proteases, and cytokines. These mediators are often stored within cytoplasmic granules in MCs and may be released in a granulated form. The secretion of cytokines and chemokines occurs within hours following activation, with the potential to result in chronic inflammation. In addition to their role in allergic inflammation, MCs are components of the tumor microenvironment (TME). MicroRNAs (miRNAs) are small RNA molecules that do not encode proteins, but regulate post-transcriptional gene expression by binding to the 3' non-coding regions of mRNAs. This plays a crucial role in the function of MC, including the key processes of MC proliferation, maturation, apoptosis, and activation. It has been demonstrated that miRNAs are also present in extracellular vesicles (EVs) secreted by MCs. EVs derived from MCs mediate intercellular communication by carrying miRNAs, affecting various diseases including allergic diseases, intestinal disorders, neuroinflammation, and tumors. These findings provide important insights into the therapeutic mechanisms and targets of miRNAs in MCs that affect diseases. This review discusses the relevance of miRNA production by MCs in regulating their own activity and the effect of miRNAs putatively produced by other cells in the control of MC activity and their participation in selected pathologies.