The aim of this study was to evaluate the efficacy and safety of afatinib combined with oral metronomic vinorelbine as a second-line treatment for patients with advanced lung squamous cell carcinoma (LSCC). A retrospective analysis was conducted on 38 patients with advanced LSCC who had failed first-line platinum-based doublet chemotherapy combined with immunotherapy between January 2022 and June 2024. All patients received afatinib (30 mg or 40 mg orally once daily) combined with oral metronomic vinorelbine (20 mg or 30 mg orally three times weekly on Monday, Wednesday, and Friday) until disease progression or unacceptable toxicity. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints included overall survival (OS), disease control rate (DCR), and treatment-related adverse events (TRAEs). Based on the data, the ORR was 26.3%, and the DCR was 68.4%. The median PFS was 5.0 months (95% CI: 4.7-5.4), and the median OS was 9.0 months (95% CI: 8.6-10.0). Grade ≥3 TRAEs occurred in 23.7% (9/38) of patients, including diarrhea (5.3%), rash (5.3%), neutropenia (5.3%), stomatitis (2.6%), and fatigue (2.6%). No grade 4-5 TRAEs or treatment-related deaths occurred. To conclude, the combination of afatinib and oral metronomic vinorelbine demonstrates promising antitumor activity and a manageable safety profile as a second-line treatment for advanced LSCC. This combo could represent an option as second-line after failure of chemo+IO.
Wilms' tumor (WT) represents a kidney carcinoma predominantly affecting children aged five years and younger. Heterogeneous nuclear ribonucleoprotein D (hnRNPD), an RNA-binding protein, has been implicated in oncogenic processes across various tumor types, whereas its expression pattern and biological function in WT remain largely unknown. hnRNPD expression within WT tissues was evaluated using publicly available databases, and co-expressed genes were identified through bioinformatic analysis. In vitro, hnRNPD expression in WT cell lines 17.94 and HFWT was modulated via gene silencing or overexpression. We subsequently carried out functional assays to assess cell proliferation and apoptosis. Molecular experiments were conducted to determine p38 mitogen-activated protein kinase (p38 MAPK) pathway activation status within cells with altered hnRNPD expression. Furthermore, SB203580 was utilized to pharmacologically inhibit this pathway to investigate the mechanism of hnRNPD in regulating WT cell proliferation. Data showed that hnRNPD was upregulated in WT tissues and cells. Silencing hnRNPD significantly inhibited WT cell proliferation and promoted apoptosis. Conversely, overexpression of hnRNPD produced the opposing effects. MAPK14, the gene encoding the p38α isoform of p38 MAPK, was identified as a core gene within the hnRNPD co-expression network. Furthermore, the phosphorylation level of p38 MAPK in WT cells was markedly elevated compared to that in normal cells. However, inhibition of the p38 MAPK pathway using SB203580 suppressed WT cell proliferation. Notably, SB203580 effectively counteracted the pro-proliferative effect of hnRNPD overexpression on malignant WT cell growth. In conclusion, hnRNPD is highly expressed in WT and plays a significant role in promoting the malignant proliferation of WT cells. The underlying molecular mechanism involves the regulation of p38 MAPK signaling pathway activation.
In a recent study, the exogenous administration of angiotensin 1-7 (Ang 1,7) together with melatonin, 5-methoxytryptamine, and cannabidiol increased 1-year survival in advanced cancer patients, underlining the utility of neuromodulation in oncology. We now report a single-arm interventional study to evaluate the effectiveness of introducing Ang 1-7 in the neuroimmune regime, including pineal indoles and cannabinoids. Two cohorts of patients with advanced solid tumors refractory to standard oncologic treatments and with an estimated life expectancy of less than six months were studied. The full neuroimmune regimen cohort consisted of 100 consecutive patients treated over the last three years with Ang 1-7, pineal indoles, and cannabinoids, while the comparator cohort included 212 consecutive patients treated between 2015 and 2019 with pineal indoles and cannabinoids alone. Gastroprotected capsules of Ang 1-7 coupled with cyclodextrin were administered at 0.5 mg p.o. twice/day. Melatonin (100 mg) and 5-methoxytryptamine (20 mg) were given p.o. at bedtime and in the early afternoon, respectively. Cannabidiol or cannabigerol (in the case of glioblastoma) was given at 20 mg p.o. twice/day. Clinical response, disease control, and overall survival, along with the lymphocyte-to-monocyte ratio, were evaluated. In the full regimen cohort, disease control was achieved in 67 of 100 patients, with objective tumor regression observed in 23%. In the comparator cohort, disease control was obtained in 111 of 212 patients, with objective regression in 8%. Three-year overall survival was significantly higher in the full regimen cohort (37%) compared with the comparator cohort (19%). Both treatments were associated with a significant increase in the lymphocyte-to-monocyte ratio, suggesting an improvement in systemic immune status. The addition of Ang 1-7 to a neuroimmune regimen combining pineal indoles and cannabinoids was associated with improved disease control and long-term survival in patients with end-stage solid tumors lacking effective therapeutic options.
Colorectal cancer is one of the most commonly diagnosed cancers worldwide. Mortality rates and limited therapeutic options justify the development of reliable preclinical research models, as their translational value remains limited. Simple in vitro models do not recapitulate tumor heterogeneity, while in vivo research faces ethical concerns and interspecies differences. Patient-derived organoids offer a physiologically more relevant platform that retains the genetic, epigenetic, and phenotypic characteristics of the original tumor. Tumor-derived organoids enable precise investigation of novel treatments, functional genomics, and modeling of cancer development. Integration with CRISPR/Cas9 gene editing further enables accurate manipulation of specific genes to study carcinogenesis and therapeutic resistance. This review highlights recent advances in the use of organoids for colorectal cancer research and explores the potential of gene-edited organoids to discover the genetic and molecular mechanisms underlying colorectal cancer development, progression, and treatment resistance.
Until 2020, patients with acute myeloid leukemia (AML) who were not suitable for intensive treatment were mostly limited to symptomatic and palliative care, or to low-intensity regimens including low-dose cytosine-arabinoside (ARA-C) and azacitidine (AZA) monotherapy, which didn't bring much benefit. The situation changed with the arrival of venetoclax, a Bcl-2 inhibitor that causes leukemic cells to rapidly undergo apoptosis. The aim of our retrospective study was to summarize the treatment outcomes of all newly diagnosed patients with AML, unsuitable for intensive chemotherapy, treated with a combination of venetoclax and AZA at the Department of Hematology and Transfusion Medicine, University Hospital in Bratislava from January 1, 2021, to December 31, 2025. A total of 108 patients underwent treatment with a median follow-up of 35.9 months; median age was 69.5 years (47-84 years), and median number of cycles was 3 (1-34). Induction mortality rate was 7.4%, and tumor lysis syndrome occurred in 4.5%. The overall response rate, which included the number of complete remissions, complete remissions with incomplete hematopoietic recovery, and morphologically leukemia-free status (CR/CRi/MLFS), was 64%, the median overall survival was 9 months, and disease-free survival was 8 months. As of December 31, 2025, 23 patients are alive, and 85 have died. The main cause of death was the progression of the disease. The main contribution of our study is the finding that shortening the duration of venetoclax treatment maintains efficacy. There was no significant difference in remission rate achieved or in overall survival based on the number of days of venetoclax administration (<14 vs. 14 vs. 21 vs. 28 days). The combination of AZA and venetoclax in AML has proven to be highly effective in inducing complete remission, usually immediately after the first cycle. Unfortunately, remission is not long-lasting, relapses are frequent, and the median overall survival in real-world data is 7.9 to 13.6 months.
Radiation-induced lung injury (RILI) remains a major dose-limiting toxicity in thoracic radiotherapy, with risk prediction relying primarily on dosimetric parameters, which show significant individual heterogeneity. This study aimed to evaluate dynamic changes in peripheral blood T-cell immune checkpoints as predictive biomarkers for ≥ Grade 2 RILI. In this prospective observational study, 274 lung cancer patients receiving thoracic radiotherapy were enrolled. Peripheral blood T-cell subsets (PD-1/CD28 expression on CD4+ and CD8+ cells) were analyzed by flow cytometry before radiotherapy (W0) and at week 2 (W2). The primary endpoint was ≥ Grade 2 RILI, assessed using CTCAE v4.0. With a median follow-up of 19 months, 87 patients (31.8%) developed ≥ Grade 2 RILI. Multivariate Cox analysis identified immunotherapy (HR=1.61, p=0.044), high mean lung dose (HR=2.33, p=0.002), and elevated levels of CD8+PD-1+ (W2, HR=2.18, p=0.030) and CD8+CD28+ (W2, HR=1.73, p=0.025) T cells as independent risk factors. Dynamic monitoring of CD8+PD-1+ and CD8+CD28+ T cells early during radiotherapy provides a novel and independent biological indicator for predicting RILI risk, complementing traditional dosimetric assessment.
Follicular fluid is a complex biological microenvironment essential for oocyte maturation and folliculogenesis. Alterations in follicular fluid composition have been associated with reproductive disorders reflecting compromised oocyte quality. Emerging evidence suggests that malignancies also significantly alter the composition of follicular fluid, potentially compromising the follicular microenvironment and impacting fertility preservation outcomes. Interestingly, the follicular fluid itself exhibits tumor-initiating and tumor-promoting properties, inducing DNA damage, pro-inflammatory signaling, mild proliferation, and suppressing apoptosis. Understanding cancer-associated follicular fluid alterations may improve fertility care, identify early biomarkers, and inform strategies for ovarian cancer prevention and therapy. This review aims to summarize current knowledge on how cancer can alter follicular fluid composition and its role in ovarian malignancies.
Prostate cancer (PCa) is a leading cause of cancer-related mortality among men. This study aims to investigate the regulatory effect of microRNA (miR)-5681b, a potential upstream miR of Beclin-1, on PCa cell proliferation and apoptosis. Two PCa cell lines (PC3 and LNCaP cells) with relatively low miR-5681b expression were treated with miR-5681b mimic, pcDNA3.1-Beclin-1, or an autophagy activator rapamycin. A xenograft tumor model was established in nude mice, and the tumor-bearing mice were treated with agomir miR-5681b. The levels of miR-5681b, Beclin-1 mRNA, and apoptosis- and autophagy-associated proteins were evaluated using western blot and RT-qPCR. The binding between Beclin-1 and miR-5681b was testified by dual-luciferase reporter gene assay. Cell biological behaviors, as well as Ki-67-positive cells and apoptosis in mouse tumor tissues, were examined. The results showed that miR-5681b was downregulated in PCa cells and targeted Beclin-1. miR-5681b overexpression in PCa cells significantly suppressed cell proliferation and B-cell lymphoma 2 (Bcl-2) levels while augmenting cell apoptosis and the levels of Bcl-2-associated X (Bax) and cleaved caspase-3. Importantly, miR-5681b inhibited PCa cell proliferation and autophagy but promoted PCa cell apoptosis, whereas Beclin-1 upregulation reversed these effects. Activating autophagy also reversed miR-5681b-regulated proliferation and apoptosis of PCa cells. In vivo, miR-5681b overexpression inhibited PCa tumor growth by modulating the Beclin-1-mediated autophagy pathway. Collectively, these findings suggested that miR-5681b was lowly expressed in PCa cells, and miR-5681b overexpression inhibited autophagy by targeting Beclin-1, thereby suppressing the growth of PCa.
Human non-small cell lung cancer (NSCLC) is an inflammation-related disease. Although IL-17-induced NSCLC cell proliferation that can be regulated by transcription factors has been demonstrated, the role and mechanism of other regulatory molecules, such as long noncoding RNAs (lncRNAs), in cell proliferation remains unclear. In this study, we screened and verified the expression of aberrant lncRNAs in NSCLC cell lines (H1299 and PC9) stimulated with IL-17, and found that LINC01518 was not only overexpressed, but also enhanced cell proliferation through IL-17/IL-17RA. Further mechanism investigation discovered that IL-17-upregulated LINC01518 was mainly localized in the cytoplasm, and it could combine with miR-20a-5p through a "sponge" function, decreasing miR-20a-5p induction, while LINC01518 and miR-20a-5p co-overexpression could partially reverse the cell proliferation mediated by LINC01518 alone. LINC01518 increase or miR-20a-5p decrease could elevate E2F1 level boosting H1299 cell proliferation exposed to IL-17, while miR-20a-5p and E2F1 co-overexpression partially restored the cell proliferation inhibition from miR-20a-5p upregulation. Besides, the xenograft tumor experiments of mice confirmed that LINC01518 overexpression indeed promoted tumor growth, cell proliferation, miR-20a-5p downregulation, and E2F1 upregulation. While LINC01518 knockdown reduced tumor growth, cell proliferation, miR-20a-5p downregulation, and E2F1 upregulation induced by IL-17 stimulation. Taken together, these findings reveal that the LINC01518/miR-20a-5p/E2F1 axis contributes to IL-17-induced cell proliferation in NSCLC.
Gallbladder cancer (GBC) is the most common and aggressive type of tumor occurring in the biliary system. Several studies have indicated the possible functions of circular RNAs (circRNAs) in GBC tumorigenesis. This research aimed to explore the roles of a novel circRNA, circ-ZEB1 (hsa_circ_0093509), in GBC. The expressions of circ-ZEB1, miR-144-3p, and ZEB2 in GBC cells were detected using RT-qPCR or western blot. The subcellular localization of circ-ZEB1 in GBC cells was determined. The function of circ-ZEB1, miR-144-3p, and ZEB2 in GBC cells was assessed by using CCK-8, EdU staining, colony formation, or Transwell assays. The relationship among miR-144-3p and corresponding targets, circ-ZEB1 and ZEB2, was confirmed. Additionally, xenograft experiments were conducted to assess the role of circ-ZEB1 in tumor growth in vivo. circ-ZEB1 was predominantly found in the cytoplasmic region of GBC cells and was upregulated in the GBC cell lines. Suppression of circ-ZEB1 reduced the proliferation and migration of GBC-SD and SGC-996 cells. Knockdown of circ-ZEB1 attenuates tumor growth in vivo. Mechanistically, circ-ZEB1 sponged miR-144-3p, which targeted ZEB2. Additionally, inhibition of miR-144-3p rescues the effects of circ-ZEB1 or ZEB2 knockdown. These results clarified a vital role of the circ-ZEB1/miR-144-3p/ZEB2 axis in GBC advancement, and may serve as a novel therapeutic target for GBC treatment.
Cancer stemness is a major therapeutic challenge in oncology. This study investigated the functional role and molecular mechanism of cell division cycle-associated 8 (CDCA8) in non-small cell lung cancer (NSCLC) stem cells. In this study, NSCLC and paracancerous tissues were collected. The lung adenocarcinoma cell line A549 and the lung squamous cell carcinoma cell line NCI-H520 were used. The stem-like cell population in A549 and NCI-H520 was isolated by CD44+ fluorescence-activated cell sorting. Gene expression was detected by quantitative real-time PCR, western blotting, and immunohistochemical staining. Cell stemness was assessed by biomarker (SOX and NANOG) expression detection, colony formation assay, and sphere-formation assay. Cell migration and invasion ability were determined by the Transwell experiment. Our results showed that CDCA8 expression was higher in NSCLC tissues than in paracancerous tissues. CDCA8 overexpression enhanced stemness properties, as evidenced by increased biomarker expression and colony formation, larger sphere size, and enhanced migratory/invasive capacity. Conversely, CDCA8 knockdown had the opposite effect. Mechanistically, we identified Y-box binding protein 1 (YBX1) as a direct binding protein of CDCA8 mRNA that positively regulated CDCA8 expression. YBX1 overexpression had a similar effect to CDCA8. Furthermore, recovery experiments revealed that the stemness-promoting effect of YBX1 was reversed by CDCA8 knockdown. These findings were further validated in xenograft models, confirming that the YBX1/CDCA8 axis promoted tumorigenesis in vivo. Collectively, our study reveals that YBX1 enhances cell stemness and metastasis of NSCLC by promoting CDCA8 expression. Our findings established a new mechanism that maintains NSCLC stemness and may provide novel biomarkers.
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma in the world. It exhibits high heterogeneity and invasiveness and is prone to developing treatment resistance. Therefore, there is an urgent need for good prognostic evaluation indicators and therapeutic targets. In recent years, immunotherapy has become a research hotspot for DLBCL. Tumor-associated neutrophil (TAN) is widely expressed in various tumors and is an important component of the immune microenvironment. However, there have been few studies on the role of TAN in DLBCL. This study has demonstrated that CD66b, which is a marker of TAN, is a good prognostic marker of DLBCL and its expression is related to the prognosis of DLBCL patients. The expression level of CD66b is also closely correlated with the objective response rate of the R-CHOP treatment regimen in DLBCL patients with non-GCB subtype. The expression level of CD66b has a high reference value for the determination of the treatment plan. The combined detection of CD66b and PD-L1/PD-L2 is of significance to predict the prognosis of DLBCL patients.
The objective of this study was to explore the effect of (-)-guaiol on lung cancer using experimental validation, mRNA sequencing, and network pharmacology. Potential targets of (-)-guaiol and lung cancer were identified through SwissTargetPrediction, TCMSP, PharmMapper, OMIM, GeneCards, and DisGeNET databases. Common targets were analyzed using PPI network, topological screening, and functional enrichment using STRING, Cytoscape, and Metascape. Molecular docking with core targets was performed, along with molecular dynamics. In vitro assays (cell counting kit-8 assay, colony formation, wound healing, Transwell, western blot) and in vivo studies (subcutaneous xenograft modeling in nude mice, immunohistochemistry, mRNA sequencing) were conducted to validate the anti-tumor effects and mechanisms of (-)-guaiol compared with the control group. Through multi-database prediction, 153 (-)-guaiol targets and 91 common lung cancer targets were identified. Protein-protein interaction (PPI) network analysis screened 21 core targets (including ESR1, EGFR, etc.). GO and KEGG enrichment analyses revealed that these targets are involved in the regulation of pathways such as fatty acid metabolism. Molecular docking and molecular dynamics results demonstrated that (-)-guaiol possessed a favorable binding affinity toward the target proteins SRC, PTGS2, GSK3B, PPARG, ESR1, and HSP90AA1. mRNA sequencing indicated that the gene expression levels of both PPARG and CD36 were downregulated in lung cancer tissues of mice treated with (-)-guaiol compared with the control group. Combining the results of molecular docking, molecular dynamics, and mRNA sequencing, we selected the PPARG-related signaling pathway for subsequent experiments. Both in vivo and in vitro experiments validated that (-)-guaiol inhibits lung cancer cell proliferation, invasion, and xenograft tumor growth in mice by downregulating the PPARG pathway. To conclude, our results demonstrated that (-)-guaiol suppresses lung cancer progression through downregulation of the fatty acid oxidation-related pathway mediated by PPARG.
Chemoresistance greatly impairs the effectiveness of chemotherapy in gastric cancer (GC) patients. According to our prior results, Cadherin-17 (CDH17) contributes to chemoresistance in GC through activating the Wnt/β-catenin pathway; however, its specific molecular mechanisms require further elucidation. We compared the Wnt/β-catenin pathway activation levels between cisplatin (DDP)-resistant GC cell lines and their parental cell lines. Subsequently, we carried out loss-of-function and gain-of-function tests to investigate CDH17 for its effect on regulating β-catenin expression, nuclear transport, as well as transcriptional activity within DDP-resistant GC cells. Additionally, CDH17 was examined for its role in the expression of four ABC transporters using molecular assays. Finally, rescue experiments were carried out using the Wnt signaling pathway agonist CP21R7 and inhibitor IWR-1 to elucidate the specific mechanism of CDH17 in promoting chemotherapy resistance of GC cells. The results showed that the activation level of the Wnt/β-catenin signaling pathway was significantly elevated in DDP-resistant GC cell lines compared to their parental cell lines. Silencing CDH17 resulted in reduced expression, impaired nuclear translocation, and decreased transcriptional activity of β-catenin, whereas overexpression of CDH17 had the opposite effects. Notably, CDH17 was shown to specifically regulate the expression of ABCB1 (protein name: P-glycoprotein, P-gp) in resistant cells, with no observable impact on the other three ABC transporters (ABCC1, ABCG2, and ABCC2) examined. Importantly, treatment with IWR-1 effectively reversed the enhancing effect of CDH17 overexpression on P-gp protein expression, as well as its suppressive effects on DDP accumulation and chemosensitivity. Conversely, administration of CP21R7 attenuated the inhibitory consequences of CDH17 silencing on P-gp expression, DDP efflux, and drug resistance. In conclusion, CDH17 promotes the expression and nuclear translocation of β-catenin in GC cells, leading to activation of the Wnt/β-catenin signaling pathway, which subsequently upregulates ABCB1/P-gp expression and enhances cellular capacity for DDP efflux. These findings imply that targeting CDH17 could be a potential strategy for overcoming chemotherapy resistance in GC.
Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by various types of collagen. Abnormal activation of DDR1 is closely related to the occurrence and development of solid tumors and plays an important role in the regulation of cell adhesion, survival, proliferation, migration, and invasion. Thus, DDR1 is a promising therapeutic target in the field of oncology. This review introduces the structural characteristics of DDR1, focusing on its role in tumor progression and related signaling pathways. It also explores the relationship between DDR1 and tumor chemotherapy resistance, and elaborates on the current research status and development prospects for inhibitors and antibodies targeting DDR1. Thus, the DDR1 inhibition strategy may serve as a new alternative for treating cancer patients.
Glioblastoma multiforme is the most malignant and incurable primary brain tumor. Infiltrative growth of gliomas into surrounding brain tissue may cause the presence of normal cells in glioma cultures. The aim of this study is to develop a simple, rapid method for detecting normal cells in short-term glioma cultures, to be applied primarily to personalized glioma treatment. Cell lines with permanent cell growth consist solely of cancer cells. Here, we examined two glioblastoma cell lines (8-MG-BA and 170-MG-BA), one brain metastatic carcinoma cell line (135-BCA), five short-term glioblastomas, and five human "glia-like" cultures using scanning electron microscopy (SEM), standard phase contrast microscopy, and GFAP immunofluorescence. All cells in glioblastoma and carcinoma cell lines were covered with microvilli of varying density, 4/5 of short-term glioblastoma cultures contained 1-3% cells with sparse microvilli, and one culture (139-GBM) showed microvilli in 15-20% of the cells and a higher percentage of GFAP-positive cells. A rare occurrence (less than 1%) of cells bearing microvilli was observed in all "glia-like" cultures. Using SEM, we observed similar cells with microvilli in both glioblastoma cell lines, but in the 135-BCA line, the microvilli were significantly shorter. Microvilli rarely occurred on normal "glia-like" cells. Based on this observation, we conclude that our 4/5 of short-term glioblastoma cultures contain predominantly normal "glia-like" cells. SEM could be a valuable method for distinguishing normal and tumor cells in short-term glioblastoma cultures, which have similar morphologies at light microscopy and immunophenotypes. We conclude that microvilli are characteristic of a specific tumor cell surface topography compared to "glia-like" cells.
Despite advances in treatment, acute myeloid leukemia (AML) remains a formidable therapeutic challenge, highlighting the urgent need for novel biomarkers and therapeutic targets. The choline transporter SLC44A1 has been implicated in cancer progression; however, its role in AML remains largely unexplored. Here, we investigated the clinical relevance and molecular mechanisms of SLC44A1 in AML. Analysis of The Cancer Genome Atlas (TCGA) datasets revealed significant upregulation of SLC44A1 in AML patients, correlating with poor patient prognosis. Functional studies demonstrated that SLC44A1 knockdown markedly inhibited AML cell proliferation and enhanced chemosensitivity to cytarabine and venetoclax. RNA sequencing and pathway analysis identified the NOTCH signaling pathway as a key downstream target of SLC44A1, which was further validated by western blot. Collectively, our findings establish SLC44A1 as a crucial regulator of AML progression and chemoresistance, highlighting its dual potential as a prognostic biomarker and a therapeutic target.
Developing non-invasive prognostic biomarkers remains critical to improving personalized cancer care. Growth differentiation factor-15 (GDF-15), a TGF-β family cytokine, plays a key role in tumorigenesis and immune evasion. Circulating GDF-15 serves as a biomarker for cancer prognosis, and DNA methylation (DNAm)-predicted GDF-15 has been linked to mortality risk in the general population. However, the association between DNAm-predicted GDF-15 and mortality risk in cancer survivors remains unexplored. We analyzed the association between DNAm-predicted GDF-15 and all-cause, long-term all-cause, and cancer mortality risks using a cohort of 343 cancer survivors from the National Health and Nutrition Examination Survey (NHANES) 1999-2002 with a median follow-up of 138 months. Multivariable Cox regression reporting hazard ratios (HRs) and 95% confidence intervals (CIs) demonstrated that each 1-standard deviation (SD) increment in DNAm-predicted GDF-15 was associated with a 60% higher all-cause mortality risk adjusted with model 1 of age and sex, and a 54% greater all-cause mortality risk in model 2 adjusted additionally for ethnicity, education, smoking, and coronary heart disease. Participants in the high GDF-15 tertile showed a 201% and 166% higher mortality risk in model 1 and model 2, respectively (both p for trend <0.0001) compared to the low tertile. Its association with long-term mortality risk remains unchanged. Stratified analyses indicated consistent relationships across multiple subgroups. Kaplan-Meier and competing risk analyses revealed a graded increase in cancer mortality risk across ascending GDF-15 tertiles; Cox models confirmed a significant positive association per 1-SD increment in the unadjusted model and model 1, which remained consistent in direction and magnitude in model 2, with a marginally significant (p=0.052). The current study provided evidence that DNAm-predicted GDF-15, an alternative and precise estimate of GDF-15 based on DNA methylation, is positively associated with all-cause and long-term all-cause mortality risks and showed a trend of positive association with cancer mortality among cancer survivors. Future larger longitudinal studies with serial DNAm-predicted GDF-15 assessments are needed to verify potential causal links.
Diffuse pleural mesothelioma (PM) is a rare malignant neoplasm with an extremely poor prognosis. Prognostic assessment remains challenging, highlighting the urgent need for reliable biomarkers to guide precise and effective therapy. Programmed death ligand 1 (PD-L1) has been suggested as a predictive biomarker for PM, but existing data are limited and controversial. Although advances have been made in understanding cancer-associated fibroblasts (CAFs) within the PM tumor microenvironment, their clinical and prognostic significance remains poorly elucidated. A retrospective analysis of 51 pathologically diagnosed PM was performed. We evaluated clinicopathological factors (including tumoral PD-L1, stromal α-SMA, and Ki-67 percentage by immunohistochemistry) and analyzed their correlation with overall survival (OS) using Kaplan-Meier and multivariate Cox regression. A total of 12 potential prognostic factors were evaluated in the univariate analysis, and 6 factors were found to be significantly associated with a poor prognosis in PM patients. Multivariate analysis identified histological classification, TNM stage, and PD-L1 expression as independent prognostic factors in PM patients. Stromal α-SMA positivity, a marker of poor prognosis, was significantly correlated with male, non-epithelioid subtype, and a high Ki-67 index. Moreover, α-SMA positivity tended to show an increased likelihood of PD-L1 expression (p=0.065). The expression of tumor PD-L1 could serve as an adverse prognostic factor for PM patients. Its potential association with tumor stromal α-SMA expression warrants further investigation, particularly in the context of unmet needs in tumor immunotherapy.
The incidence of thyroid cancer is rising worldwide, underscoring the urgent need for novel molecular targets in the management of aggressive disease. This study identifies bystin-like protein (BYSL) as a previously unrecognized oncogenic driver in thyroid carcinoma. Comprehensive analyses of clinical specimens, established cell lines, and patient-derived tumor-like clusters revealed that BYSL is significantly upregulated in thyroid malignancies and is strongly correlated with adverse patient outcomes. Functional assays demonstrated that BYSL promotes tumor cell proliferation, migration, and invasion while suppressing apoptosis. Mechanistically, BYSL interacts directly with DEAD-box helicase 49 (DDX49) to form a functional protein complex that impairs the biogenesis of the tumor suppressor miR-145-5p by inhibiting its DICER-mediated processing. Dual knockdown of BYSL and DDX49 synergistically suppressed tumor growth and induced apoptosis in patient-derived tumor-like cell clusters, with these effects reversed by inhibition of miR-145-5p. Collectively, these findings demonstrate the BYSL-DDX49 complex as a pivotal modulator of thyroid cancer progression and underscore its promise as a therapeutic intervention for restoring tumor-suppressive pathways.
