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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.

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.

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.

Innovative cancer treatments are needed for metastatic tumors that currently do not have adequate therapies. This review highlights recent progress in suicide gene small extracellular vesicles, particularly exosomes as a new form of intracellular anti-cancer drug. Suicide gene exosomes are produced by tumor-targeting human mesenchymal stem cells that have been genetically modified to express the yeast cytosine deaminase::uracil phosphoribosyl transferase fused gene (yCD::UPRT) along with the prodrug 5-fluorocytosine (5-FC). The yCD::UPRT-MSC-secretome containing tumor targeted exosomes, convert 5-FC into the cytotoxic compound 5-fluorouracil (5-FU) and its metabolites within the tumor environment. The second popular system we are investigating involves the suicide gene exosomes derived from thymidine kinase of Herpes Simplex Virus in conjunction with a prodrug ganciclovir. Extracellular vesicles secreted by tumor associated cells contribute to tumor growth and metastasis. When these cells are transduced with yCD::UPRT suicide gene, they can act as a source of therapeutic exosomes capable of intracellularly converting nontoxic prodrug 5-FC to a cytotoxic 5-FU. Combined action of suicide gene exosomes from MSCs and cancer associated fibroblasts (CAFs) is a promising platform for aggressive tumors treatment. Furthermore, suicide gene exosomes can be enhanced with additional anti-cancer drugs and customized for targeted delivery. In this review, we trace the history of these findings, present therapeutic outcomes from in vitro and in vivo studies, and explore the future potential of therapeutically beneficial exosomes for cancer treatment.

Immune checkpoint dynamics within the bone marrow critically shape disease evolution and therapeutic responses in multiple myeloma (MM). To delineate immune remodeling in the bone marrow (BM) during plasma cell malignancy evolution, we profiled inhibitory (PD-1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA, and 2B4) and co-stimulatory (ICOS, CD27, DNAM-1, 4-1BB, and OX40) checkpoints across adaptive and select innate compartments in healthy donors (HD, n=25), MGUS (n=17), newly diagnosed MM (NDMM, n=57), and relapsed/relapsed-refractory MM (MM, n=72; on-treatment n=27, off-treatment n=12). Progressive disease featured loss of mature, memory, and activated/proliferating B cell subsets and an NDMM-specific expansion of plasmablasts/plasma cells. B cell maturation was accompanied by broad remodeling of inhibitory receptors (notably reduced PD-1, TIM-3, TIGIT, and 2B4 on mature B cells; decreased CTLA-4 on activated B cells and plasmablasts/plasma cells; and reduced TIM-3, LAG-3, and 2B4 on plasmablasts/plasma cells) alongside selective co-stimulatory changes (OX40 decreased on mature B cells; CD27 loss on activated and plasmablast/plasma compartments; divergent 4-1BB regulation). T cell compartments showed early CD4⁺ expansion with CD8⁺ cytotoxic reduction and checkpoint shifts: broad PD-1 downregulation with subset-restricted increases in LAG-3, TIM-3, TIGIT, and BTLA; variable upregulation of CD27, DNAM-1, and ICOS; and consistent 4-1BB loss. NKT and γδ T cell frequencies were stable, but their checkpoints were reconfigured: NKT cells exhibited decreased PD-1 and 4-1BB and increased TIGIT, LAG-3, and DNAM-1, whereas γδ T cells showed reduced CTLA-4, BTLA, and the co-stimulatory receptor OX40. Innate NK cells demonstrated reduced frequency and phenotypic shifts, including decreased TIM-3 and PD-1, loss of 4-1BB and OX40, stage-specific increases in TIGIT and 2B4, and elevated DNAM-1. Checkpoint alterations, such as low TIGIT or CTLA-4 and elevated OX40 expression, were correlated with superior progression-free survival. MM progression entails extensive, stage- and subset-specific remodeling of inhibitory and activating immune checkpoints in the BM, with implications for immunotherapeutic targeting.

Small cell lung cancer (SCLC) has a dismal prognosis with a low 2-year survival rate. Chemotherapy for recurrent SCLC fails invariably, and novel tumor targets are needed. Here, the effects of agents targeting the peroxisome proliferator-activated receptors (PPARs) in SCLC are investigated. Initial screening of 96 PPAR-directed agents was performed in two SCLC CTC-derived lines (BHGc10, BHGc16). Compounds showing high cytotoxicity were subsequently tested in two pleural effusion-derived lines (S457, S1392) and the SCLC line NCI-H69. Several PPARs emerged as actionable targets: eight PPARγ ligands and nine ligands for PPARα, PPARα/δ, or PPARβ/δ. For the six most effective compounds, treatment-induced protein changes were further profiled in BHGc16 using protein arrays. Cytotoxicity varied by compound, while the PPARγ agonist pioglitazone and the PPARα agonist fenofibrate were preferentially active in CTC lines, DG172 hydrochloride was selective for pleural effusion-derived lines, while rosiglitazone maleate, cloxiquine, and agrimol B showed no selectivity. Mechanistically, in the CTC-derived cell line BHGc16, these six PPAR-directed agents increased pro-apoptotic proteins (Bax, Bad, caspase-3/9), decreased anti-apoptotic and invasion proteins (Bcl-2, Bcl-XL, c-FLIP-L, ICAM-1, CXCR4), and suppressed Akt/mTOR, MEK/ERK, p38 MAPK, and JAK2/STAT3 signaling. These findings support PPARs as clinically relevant targets in SCLC, with PPAR-directed agents showing cytotoxic effects comparable to those reported in other malignancies. Such agents may aid SCLC treatment and help delineate biological differences between CTCs and resident tumor cells.

Long non-coding RNAs (lncRNAs) are known to participate in leukemia development, but the molecular mechanisms of many remain unclear. The expression of LINC00324 was examined in peripheral blood samples from leukemia patients and in leukemia cell lines by RT-qPCR. Functional studies were performed to evaluate how LINC00324 overexpression or knockdown affected cell proliferation and apoptosis. Flow cytometry was used to detect apoptosis. Western blotting was applied to measure Ki-67, BAX, Bcl-2, and PTEN protein levels. Dual-luciferase reporter assays were used to confirm the interaction among LINC00324, miR-10b-5p, and PTEN. LINC00324 expression was markedly reduced in leukemia samples and cell lines. Upregulation of LINC00324 inhibited the proliferation of Jurkat and HL-60 cells and increased apoptosis, while its silencing produced the opposite trend. Western blotting showed that LINC00324 overexpression decreased Ki-67 and Bcl-2 but increased BAX expression. Rescue experiments demonstrated that miR-10b-5p mimics reversed, whereas inhibitors restored, the effects of LINC00324. Bioinformatics prediction and luciferase validation identified PTEN as a direct target of miR-10b-5p, and LINC00324 enhanced PTEN expression by sponging miR-10b-5p. LINC00324 regulates the proliferation and apoptosis of leukemia cells through the miR-10b-5p/PTEN axis. These findings add to the understanding of lncRNA-mediated regulatory mechanisms in leukemia.

Infratentorial brain metastases (BMs) are life-threatening because of the unique anatomical features and physiological functions of the posterior cranial fossa. However, the comparative prognosis of infratentorial BM and supratentorial BM remains poorly understood. We conducted a matching comparison of the prognosis between non-small cell lung cancer (NSCLC) patients with and without infratentorial BM and analyzed prognostic factors, including the radiotherapy (RT) method. 392 NSCLC patients who underwent brain RT from July 2010 until June 2023 were analyzed. After 1:1 propensity matching, we compared 115 patients with only supratentorial BMs (supraT-alone group) and 115 patients with infratentorial ± supratentorial BMs (infraT ± supraT group). We assessed intracranial control and overall survival (OS) using Kaplan-Meier and Cox regression. There was no statistical difference for extracranial progression-free survival (PFS), intracranial local PFS, or distant PFS. The supraT-alone group had significantly better OS (median: 35.3 vs. 24.2 months, p=0.021). The supraT-alone group in the multivariate analysis had BM resection (p=0.031), targeted therapy (p<0.001), and immune therapy (p=0.006) associated with improved OS. The infraT ± supraT group had RT method (p=0.002), ≤60 years of age (p=0.002), targeted therapy (p=0.017), and number of extracranial metastases (p<0.001) when reporting OS. We confirmed that WBRT+boost and SRT improved OS compared to WBRT alone. There was no statistical difference in OS for WBRT+boost and SRT. The overall grade 3-4 acute toxicities were similar for both groups. Our study suggests that infratentorial BMs in NSCLC lead to worse OS. However, local high-dose RT strategies (SRT or WBRT+boost) may confer survival benefits to patients who present with infratentorial involvement.

PAF15 is an oncogene and is overexpressed across multiple malignancies. However, its biological role in melanoma remains largely unclear. In this research, bioinformatics analysis (GEPIA2, TCGA, CancerSEA) confirmed transcriptional PAF15 overexpression in melanoma, correlating with a poor prognosis and implicating pathways involved in cell cycle, proliferation, DNA damage, and repair. Immunohistochemical analysis further confirmed high expression of PAF15 protein in clinical melanoma tissues. Subsequently, the impact of PAF15 on melanoma cell proliferation and cell cycle progression was quantified through MTT assay and propidium iodide staining. Annexin V staining and immunofluorescence were used to assess apoptosis and DNA damage. Markers associated with these biological pathways were evaluated by western blot. Evaluation of PAF15-mediated tumorigenic effects was performed using a subcutaneous xenograft model. The results revealed that PAF15 knockdown markedly suppressed melanoma cell proliferation through the induction of G0/G1 phase cell cycle arrest. Additionally, PAF15 knockdown triggered genomic instability, as evidenced by increased DNA damage markers, and promoted caspase-dependent apoptosis. Furthermore, PAF15 knockdown suppressed the growth of xenograft tumors in vivo. Notably, these tumor-inhibiting effects of PAF15 knockdown were effectively rescued upon PAF15 reconstitution. Summed up, these findings establish PAF15 as both a prognostic indicator for unfavorable clinical outcomes and a promising therapeutic vulnerability in melanoma.