Dysregulated microRNAs (miRNAs) have been implicated in the pathogenesis and progression of rectal adenocarcinoma. In this study, we aimed to identify miRNA alterations associated with the efficacy of neoadjuvant chemoradiotherapy in rectal cancer patients. High-throughput small RNA sequencing was performed to assess salivary miRNA expression profiles in 31 participants (11 rectal adenocarcinoma patients and 20 healthy volunteers). Paired saliva samples were collected from patients before and after chemoradiation. Tumor regression was classified according to the modified Ryan scheme into responders (tumor regression grade [TRG] 1-2, n = 10) and nonresponders (TRG3, n = 1). Bioinformatic integration of small non-coding RNA data revealed 37 miRNAs with distinct expression differences between patients and healthy controls. Furthermore, seven miRNAs showed significant alterations in response to radiotherapy. Among these, five candidates (hsa-miR-378a-3p, hsa-miR-203a-3p, hsa-miR-200a-5p, hsa-miR-361-5p, and hsa-miR-107) were successfully validated by RT-qPCR, displaying significantly increased salivary expression levels post-radiation compared with the pre-radiation samples (p < 0.05). Notably, hsa-miR-203a-3p, hsa-miR-200a-5p, and hsa-miR-361-5p demonstrated excellent discriminatory power for tumor regression grade (AUC > 0.7). Our findings support the involvement of specific salivary miRNAs in rectal adenocarcinoma tumor regression and highlight their potential as non-invasive biomarkers to evaluate treatment response following neoadjuvant chemoradiotherapy.

Genomic DNA methylation is an epigenetic modification that primarily occurs at CpG sites and is associated with the transcriptional repression of genes. This process plays a crucial role in maintaining cellular homeostasis and is catalyzed by a family of enzymes known as DNA methyltransferases (DNMTs), which includes DNMT1, DNMT2, DNMT3A, DNMT3B, and DNMT3L. DNMT1 is classified as a maintenance methyltransferase, whereas DNMT3A and DNMT3B are responsible for de novo methylation. Altered expression of DNMTs has been reported in various human diseases, including cancer. Cancer remains a major global health issue, with an estimated 20 million new cases and 9.7 million deaths reported in 2022. Among women, cervical cancer (CC) ranks fourth in both incidence and mortality worldwide, with persistent infection by high-risk human papillomavirus (HR-HPV) being the primary risk factor. Several studies have demonstrated that DNMT expression and activity are upregulated in CC, suggesting their potential as diagnostic and prognostic biomarkers. HR-HPV infection appears to increase DNMT expression, thereby promoting cervical carcinogenesis through aberrant methylation and subsequent silencing of tumor-suppressor genes such as PTEN, PAX1, and TSLC1. Furthermore, DNMTs are being explored as therapeutic targets in CC. In this review, we summarize the current state of the art regarding DNMTs in cervical cancer and discuss their functional roles and potential utility as diagnostic, prognostic, and therapeutic biomarkers.

Anticancer strategies targeting the DNA damage response are largely centered on a number of false hypotheses. For example, engaging apoptosis in solid tumors is universally assumed to represent a tumor suppression response. But what is "apoptosis", really? Time-lapse microscopy and other single-cell assays have revealed that engaging apoptosis in solid tumor cells is accompanied by anastasis, the homeostatic process of cell recovery from late stages of apoptosis, even after the formation of apoptotic bodies. Furthermore, apoptotic cells secrete a variety of prosurvival factors that contribute to overall tumor repopulation. Not surprisingly, numerous clinical studies reported since the 1990s have demonstrated that increased apoptosis in solid tumors is associated with cancer aggressiveness rather than representing a favorable clinical outcome. Another major false hypothesis pertains to the role of wild-type p53 in regulating apoptosis. Several recent articles addressing the challenges that have been encountered in implementing p53-based cancer therapies assume that p53 is pro-apoptotic. This assumption, which has become an almost indisputable fact, is shocking given that by mid-2000s it was already well established that p53 serves to inhibit apoptosis through upregulating ~40 anti-apoptotic proteins. The complexity of cancer cell response to therapeutic agents is discussed herein with a focus on the significance of p53-p21WAF1 signaling in suppressing the apoptosis-anastasis tumor repopulation pathway.

Cervical cancer remains a significant public health priority, particularly in low- and middle-income countries. In this context, liquid biopsy has emerged as a minimally invasive method for detecting and monitoring molecular biomarkers, offering advantages over traditional screening approaches. This systematic review included 21 studies published between 2015 and 2025 and was conducted in accordance with the PRISMA 2020 statement. The analysis examined the role of serum cytokines, circulating microRNAs (miRNAs), and circulating cell-free HPV DNA (cfHPV-DNA) in patients with cervical cancer or high-grade intraepithelial lesions. Circulating miRNAs-particularly miR-21, miR-29a, and miR-34a-are consistently associated with recurrence, tumor progression, and reduced survival. However, their immediate clinical translation remains limited by methodological variability and the lack of universal normalizers. In contrast, cfHPV-DNA, especially with ddPCR, exhibited the best study-level performance, with a specificity of 100% and a sensitivity of approximately 80-88%, across heterogeneous endpoints and analytic conditions. Consequently, cfHPV-DNA represents a promising tool for post-treatment surveillance and early detection of recurrence. Serum cytokines, such as TNF-α, IL-6, and IL-10, reflect inflammation and the tumor microenvironment. Nevertheless, their lack of standardization and variability across detection platforms restricts their reproducibility, positioning them as complementary rather than stand-alone markers. In conclusion, the evidence supports liquid biopsy as a promising tool in cervical cancer management; nonetheless, only cfHPV-DNA is currently ready for clinical application, whereas miRNAs and cytokines require multicenter validation and technical standardization before implementation.

Lung cancer remains one of the most common and lethal malignancies worldwide, with poor prognosis largely due to late-stage diagnosis and resistance to therapy. Emerging evidence indicates that long non-coding RNAs (lncRNAs) play critical roles in cancer development, metastasis, and treatment resistance. Particulate matter (PM), a major environmental pollutant and recognized Group 1 carcinogen, has been linked to lung cancer through mechanisms that may involve dysregulation of lncRNA expression. This study aimed to identify PM-responsive lncRNAs in lung cancer, and investigate their potential functional roles. Microarray analysis of lung cancer cell lines A549, H358, H292, and HCC827, exposed to PM10, revealed significant up-regulation of lnc-MTPAP-1. TUNEL staining confirmed that silencing of lnc-MTPAP-1 via siRNA resulted in increased apoptosis across all tested lines. Transcriptome analysis using next-generation sequencing showed that knockdown of lnc-MTPAP-1 altered the expression of apoptosis-related genes, with up-regulation of TNS4, MyD88, and IL6R, and down-regulation of CLPTM1L and EI24. These findings suggest that lnc-MTPAP-1 may exert anti-apoptotic effects in lung cancer cells, and be involved in pollution-induced cancer progression. Further research should explore the therapeutic potential of targeting lnc-MTPAP-1, and better understand the molecular impact of PM exposure on lung cancer pathogenesis.

Ovarian cancer (OC) is an aggressive and lethal gynecologic cancer due to its asymptomatic nature resulting in a late diagnosis. OC encompasses distinct histological subtypes, with serous OC representing the most common and aggressive form. However, within the same histological OC subtype, additional heterogeneity has been found in terms of genetic mutations and metabolic profiles probably contributing to treatment response. In cancer, metabolic reprogramming strongly involves mitochondria. Mitochondrial function can be regulated by the cAMP pathway, and its deregulation has been reported in various cancers including OC. Here we analyzed two serous OC cell lines, OC316 and OV56, and eleven human OC tissues. OC316 cell lines showed elevated cAMP level with respect to OV56. The high cAMP levels were associated with activation of thecAMP/PKA/CREB/PGC-1α axis resulting in increased mitochondrial biogenesis, respiratory chain activity, modulation of mitochondrial dynamics and apoptosis resistance. Accordingly, principal component analysis (PCA) of the twenty-three biochemical parameters, in eleven human OC tissues, classified OC into two groups showing different cAMP levels associated with distinct mitochondrial profiles. This analysis highlights a cAMP-dependent stratification revealing two mitochondrial subpopulations within serous OC. These findings indicate that the molecular heterogeneity of OC poses a challenge for understanding disease mechanisms and developing effective targeted therapies.

Patients with metastatic lung adenocarcinoma (mADC) harboring EGFR-activating mutations can benefit from first-line Osimertinib, but acquired resistance inevitably occurs. Different resistance mechanisms, on- and off-target, have been described. Here, we evaluated the prevalence of phenotypic transformation as a resistance mechanism in a consecutive series of EGFR-mutated mADC, diagnosed at our institution, and on the basis of literature data. A consecutive 3-year series of non-small cell lung cancer (NSCLC) was reviewed according to histological and molecular characteristics. A total of 100 mADCs harboring EGFR exon-19 deletions (61 cases) and the p.(L858R) mutation (39 cases) were selected. All cases were treated by first-line Osimertinib. The prevalence and type of phenotypic transformation were evaluated in patients with available rebiopsy at the time of first-line progression. A total of 32 mADC patients underwent rebiopsy upon first-line Osimertinib progression, and 23 cases had EGFR exon-19 in-frame deletions and 9 p.(L858R) mutations. Four cases showed a phenotypic transformation after a median of 15 months from the start of Osimertinib treatment. All these cases harbored EGFR exon-19 deletions and TP53 pathogenic mutations on diagnostic tumor tissues. Three cases switched to small cell lung cancer histology; in one case, a MET amplification was also detected on rebiopsy. One case changed to spindle cell carcinoma. All cases maintained the initial activating EGFR alteration. For three cases, liquid biopsy was performed at the time of progression: one was negative, one presented only an EGFR exon-19 deletion, and one presented only a MET amplification. In our study, phenotypic transformation had a considerable prevalence among EGFR-positive mADC patients treated by first-line Osimertinib. Different types of histological changes were detected as the only resistance mechanism except for one case with a simultaneously acquired MET amplification. Moreover, all cases harbored TP53 alterations, influencing treatment response. Despite the usefulness of liquid biopsy, rebiopsy should be executed whenever possible. Indeed, it remains the only tool for assessing histological transformation, which greatly impacts prognosis and treatment decisions.

Mitochondrial transcription factor A (TFAM) is essential for mitochondrial DNA (mtDNA) maintenance and function, but its role in glioblastoma (GBM) remains largely unexplored. Analysis of patient astrocytomas and TCGA datasets has revealed progressive TFAM downregulation with increasing malignancy, with the lowest expression in glycolytic/plurimetabolic (GPM) subtypes. Functional and transcriptomic profiling of mesenchymal GBM cell lines showed that TFAM silencing in GPM-type U87MG cells enhanced proliferation, S-phase entry, reactive oxygen species (ROS) production, and adhesion, while reducing motility. These changes were correlated with upregulation of LDHC and TRAF2 and downregulation of androgen receptor-linked motility genes and LOXL2. By contrast, TFAM loss in mitochondrial (MTC)-type A172 cells caused minimal phenotypic alterations, associated with elevated SOD1 expression and activation of antioxidant, mitochondrial membrane, and survival pathways, alongside suppression of oxidative phosphorylation and vesicle-trafficking genes. TFAM overexpression reduced proliferation in U87MG but had a limited impact on A172 cells. Taken together, these findings establish TFAM as a subtype-specific regulator of GBM cell proliferation, redox balance, and motility. TFAM loss drives a proliferative, ROS-sensitive phenotype in GPM-type cells, while eliciting adaptive, stress-resilient programs in MTC-type cells. This study identifies TFAM and downstream effectors, TRAF2 and LOXL2, as potential therapeutic targets, supporting the development of metabolic subtype-tailored strategies for GBM treatment.

MicroRNAs (miRNAs) are key regulators of gene expression with critical roles in oncogenic signaling. Endometrial cancer (EC) has been redefined with the identification of POLE-ultramutated tumors which, despite their hypermutated phenotype, show more favorable prognosis. We profiled miRNA expression in tumor tissues from forty (40) EC patients and twenty (20) healthy controls using qPCR panels. POLE exonuclease domain mutations (P286R, V411L) were genotyped, and subgroup analyses were conducted between POLE-mutated (n = 7) and POLE-wild-type (n = 33) tumors. Bioinformatic analyses included validated miRNA-mRNA interactions, target enrichment, and Gene Ontology (GO) pathway mapping. Comparison of EC versus healthy endometrium revealed 50 significantly dysregulated (∣log2 (FoldReg)∣ > 1 and BH FDR < 0.05) miRNAs, including up-regulation of the oncogenic hsa-miR-181a-5p, hsa-miR-23a-3p, hsa-miR-200c-3p, and down-regulation of tumor-suppressive let-7 family members. Target enrichment implicated canonical oncogenic regulators such as MYC, TP53, and VEGFA. POLE-mutated tumor analysis demonstrated a miRNA signature, with 19 miRNAs significantly down-regulated, including let-7f-5p and hsa-miR-200b-3p. Findings for the EC versus healthy endometrium comparison were validated against TCGA-UCEC sequencing data which confirmed concordant dysregulation of key miRNAs across platforms. Our findings reveal that EC is characterized by widespread miRNA deregulation, with a unique global down-regulation signature in POLE-mutated tumors. These results highlight the potential of miRNAs as complementary biomarkers for classification and potential targets in EC.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with a rising global incidence. Neurotrophins (NTs) and their receptors, including TrkA and CD271, play key roles in epidermal homeostasis and tumor progression. We showed that CD271 expression and function are critical for low- to high-risk progression of cSCC, while TrkA is highly expressed in poorly differentiated tumors. Although NTRK fusions are recognized as oncogenic drivers, the functional impact of TrkA signaling in cSCC remains underexplored. In this study, we investigated the effects of TrkA inhibition, using both the pan-Trk inhibitor K252a and siRNA-mediated silencing, on cSCC cell lines. We evaluated cell growth and invasion in vitro, using 2D and 3D cultures, and in vivo using zebrafish xenografts. TrkA inhibition significantly reduced tumor growth and invasion, with efficacy comparable to standard chemotherapeutics (5-FU, cisplatin). Additionally, TrkA blockade downregulated mitogenic and invasive markers. Importantly, TrkA inhibition enhanced the response to photodynamic therapy in cSCC spheroids. In zebrafish, Trk-targeted interventions reduced metastatic dissemination. These findings highlight TrkA as a key regulator of cSCC survival and metastasis, suggesting its potential as a therapeutic target either alone or in combination with existing treatments.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. Recent breakthroughs in research are highlighting the complex genetic and epigenetic alterations driving CRC progression. Among these, the ERK1/2 and PI3K pathways are central regulators of cellular proliferation, survival, and differentiation. The overactivation of these pathways is frequently observed in cancer and is associated with poor patient prognosis. Protein Arginine Methyltransferase 5 (PRMT5), a key epigenetic regulator, has been implicated in modulating the ERK1/2 and PI3K pathways in cancer. Previous studies, including those from our own group, are starting to suggest that targeting PRMT5 and the ERK1/2 and PI3K pathways may offer therapeutic benefits. Thus, we sought to provide further evidence of the relationship between PRMT5 and the ERK1/2 and PI3K pathways in CRC. Using patient tumor gene expression data and protein-protein interaction networks, we provide further evidence that PRMT5 is positively correlated with, and interacts with, the ERK1/2 and PI3K pathways in CRC. These findings are significant, as they further strengthen the case for the urgent need of additional research into therapeutic strategies targeting PRMT5 and the ERK1/2 and PI3K pathways in CRC.

Cutaneous T-Cell Lymphomas (CTCL) are a heterogenous group of T-cell malignancies in the skin and have poor treatment outcomes in advanced stages. CD5, a surface glycoprotein expressed on most mature T cells, has emerged as a promising target for chimeric antigen receptor (CAR) T-cell therapy in systemic T-cell lymphomas. However, its expression profile in CTCL and relevance for targeted therapy remain unclear. Notably, in CTCL, the cell surface expression of receptors, such as CD7 and CD26, tends to become downregulated on the surfaces of malignant T cells In this study, we analyzed single-cell RNA sequencing (scRNA-seq) data from patients at two institutions with mycosis fungoides (MF), the most common subtype of CTCL with a predominantly CD4 phenotype. We utilized 5 patch/plaque MF skin biopsies (majority from early-stage patients), 8 MF tumor biopsies (all from advanced-stage patients), and 8 healthy control biopsies to evaluate lesion-specific CD5 gene expression on CD4 T cells. We found that CD5 was significantly increased in malignant MF CD4 T cells compared to healthy control CD4 T cells (21.1% of MF CD4 T cells expressed CD5 vs. 5.2% of healthy control CD4 T cells, respectively). In subgroup analysis, patch/plaque stage MF biopsies showed higher expression of CD5 in CD4 T cells than tumor stage MF biopsies. Notably, 94.3% of malignant CD4+ T cells in tumor stage MF lesions exhibited complete CD5 loss compared to only 76.6% in patch-plaque MF lesions, suggesting antigen escape in tumor stage disease. These findings demonstrate that CD5 expression in CTCL is dynamic and varies based on lesion type. Our work suggests CD5 may be a viable therapeutic target in MF with patch/plaque presentations but may not be as effective in advanced stages of MF with tumor presentations. This work informs CD5 gene expression in MF based on clinical lesion type and further information is needed to clarify clinical implications as a future therapeutic target.

Mutations in IDH1/2 are frequent in Acute Myeloid Leukemia (AML), defining a molecularly distinct subgroup with therapeutic implications due to the availability of specific inhibitors. Accurate monitoring of treatment response is crucial and Droplet Digital PCR (ddPCR) offers a sensitive approach for quantifying mutational burden in IDH-mutated AML. This study aimed to optimize and validate ddPCR assays specific for IDH1 R132 and IDH2 R172/R140 mutations for future use in Minimal Residual Disease (MRD) monitoring. Four ddPCR assays were set to evaluate the trend of IDH1/2 mutations in 191 diagnostic and follow-up samples. Each validation procedure included determining the limit of blank (LOB) and limit of detection (LOD) using titration series. Moreover, in AML harboring both IDH and NPM1 mutations, we performed generalized estimating equations (GEE) to assess the association between IDH fractional abundance and NPM1 RQ-Ratio across time points. Four IDH1/2 ddPCR assays were validated, demonstrating high sensitivity with limits of detection of 0.07% for IDH1 R132H, 0.1% for IDH2 R140Q and R172K, and 0.2% for IDH1 R132C. The method also exhibited excellent intra-run reproducibility, providing consistent results for patient follow-up. Comparison of IDH and NPM1 trends during follow-up revealed a statistically significant positive correlation, both in raw (β = 0.079, p = 0.001) and ranked data (β = 0.99, p = 0.004), suggesting a co-dynamic pattern potentially useful for surrogate monitoring. While our study cannot yet define the clinical role of IDH mutation assessment by ddPCR due to the lack of comparative follow-up studies, it establishes a solid methodological foundation for standardizing minimal residual disease evaluation via ddPCR, paving the way for future prospective validation.

Genistein has anti-cancer effects, but its molecular targets in gastric adenocarcinoma (GA) are unclear. This study used single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to explore genistein's "drug-gene-cell" interactions in GA. GA- and genistein-related target genes were retrieved and intersected with differentially expressed genes identified from bulk transcriptomic data. Machine learning screened candidates, and survival analysis assessed prognosis. Molecular docking with genistein validated key genes, with molecular dynamics assessing binding stability. HSD17B1, EZH2, CCNB1, CCNB2, CDKN2A, and IGFBP6 were identified as key candidate genes with prognostic value for GA. Specifically, samples in the IGFBP6 high-expression group were associated with higher survival probability, whereas the opposite trend was observed for the other five genes. In addition, HSD17B1 was genistein's main target in GA treatment, showing a strong binding affinity with genistein (binding energy of -8.1 kcal/mol). scRNA-seq analysis indicated that HSD17B1 was predominantly expressed in epithelial cells and was significantly involved during their malignant transformation (confirmed by ST). This study identified HSD17B1 as a critical target gene for genistein in GA treatment, emphasizing its roles in the malignant transformation of epithelial cells, thus providing a theoretical foundation for understanding the therapeutic mechanism of genistein in GA.

Breast cancer remains a major global health challenge. In 2022, there were an estimated 2.3 million new cases and 670,000 deaths among women worldwide. Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer accounts for approximately 70% of breast cancer diagnoses. The treatment landscape for advanced HR+)/HER2- breast cancer has been transformed by the introduction of CDK4/6 inhibitors in the first-line setting. However, therapeutic strategies following progression on CDK4/6 inhibitors remain heterogeneous and uncertainty exists in their optimal integration in clinical practice. This review aims to systematically examine available second-line and subsequent treatment options for HR+/HER2- metastatic breast cancer after progression on CDK4/6 inhibitors, with a focus on biomarker-driven strategies and emerging therapies. The therapeutic landscape beyond CDK4/6 inhibitors includes targeted agents guided by actionable biomarkers as well as novel selective estrogen receptor degraders (SERDs). In biomarker-unselected populations, options include CDK4/6 continuation strategies, endocrine monotherapy in selected cases, and cytotoxic therapy. The integration of molecular testing via next-generation sequencing has become standard of care in guiding these decisions. However, overlapping molecular alterations and a lack of consensus on treatment sequencing pose significant challenges. Prognostic factors such as circulating tumor DNA dynamics may further refine treatment personalization. Post-CDK4/6 therapy in HR+/HER2- metastatic breast cancer is an evolving and increasingly complex area of practice. Optimal treatment selection should be tailored to both tumor biology and patient-specific factors, supported by molecular testing and high-quality evidence.

Lung cancer remains the leading cause of cancer-related mortality worldwide, accounting for nearly 1.8 million deaths annually. The present study aimed to investigate the role of miR-28-5p and miR-708-5p in lung cancer and to analyze the relationship between target gene profiles and transcriptional factor regulation. Both miRNAs that share a common seed sequence were found to be overexpressed in a cohort of 32 paired tumor and adjacent normal tissue samples collected from patients diagnosed at advanced stages (III and IV) of disease. Data from the dbDEMC database revealed that miR-28-5p exhibited variable expression across lung cancer subtypes, whereas miR-708-5p showed consistent overexpression, reinforcing its potential clinical diagnostic significance. Using the TransmiR database, we identified complex TF-miRNA regulatory networks, with both shared and distinct transcription factors controlling miR-28-5p and miR-708-5p. Pathway enrichment analysis indicated that these miRNAs regulate several cancer-associated pathways, including ECM-receptor interaction, adherens junctions, and Hippo signaling. Overall, our findings suggest that miR-708-5p may have a potential clinical application in lung cancer.

Uveal melanoma (UM) is the most prevalent primary intraocular tumor in adults. Transcription factor ZEB1 is one of the potential master regulators of melanocytes plasticity, because it is recognized as a "driver" of epithelial-to-mesenchymal transitions (EMTs) in carcinomas. We studied the correlation of tumor invasiveness with ZEB1 status and vascular endothelial growth factor/its receptor (VEGF-A/VEGFR2) in UM cells, and also with melanocyte's differentiation rate. Eight UM cell cultures were characterized by melanosomes content using an ETM. ZEB1, VEGF-A and VEGFR2 levels in UM cells were detected by RT-PCR, Western blot, ELISA and flow cytometry. Effects of siRNA-dependent ZEB1 knockdown on UM cell proliferation and their sensitivity to the VEGF-A inhibitor Eylea (aflibercept) were tested by MTT and in a real-time proliferation assay. UMs with an invasive growth type can maintain a high degree of melanocyte differentiation. All ZEB1low cells were obtained from spindle cell tumors. The sensitivity of UM cells to Eylea inversely correlated with the level of the VEGFR2 receptor. ZEB1 knockdown completely blocked VEGF-A production while anti-VEGF treatment stimulated ZEB1 increase. In UM cell cultures, ZEB1 is a positive regulator of VEGF-A expression. In addition, there is probably a ZEB1 feedback loop that is sensitive to a drop in VEGF-A concentration. The data obtained allow us to consider ZEB1 silencing as an auxiliary link for a combined strategy of killing UM cells.

The JAK2 46/1 ("GGCC") haplotype is an inherited genetic variation within the Jak2 gene locus that has become a focal point in research related to oncogenesis, particularly in myeloproliferative neoplasms (MPNs). We conducted a narrative review of landmark discoveries in hematological malignancies and Jak2, focusing on its role in oncogenesis, risk stratification, and drug resistance in MPNs. This haplotype spans several polymorphisms within the Jak2 gene. It has been found to increase susceptibility to a variety of hematologic cancers, especially when linked with the somatic JAK2 V617F mutation, which results in the alteration of the JAK/STAT pathway, which is particularly essential for hematopoiesis. The "GGCC" part is characterized by four SNPs, with the G allele of the rs10974944 SNP in this haplotype correlated with MPNs progressing to myelofibrosis. Moreover, the G allele seems to be crucial for the predisposition to onco-drug resistance onset. To conclude, identifying the 46/1 haplotype in patients may not only enhance risk stratification for JAK2-driven cancers but also guide more effective, personalized therapeutic strategies to overcome resistance. Thus, this review aims to describe current knowledge about the JAK2 46/1 haplotype as a marker for diagnosis and the prediction of disease outcome.

We previously demonstrated that in BAP1-proficient pleural mesothelioma cells, CDKN2A is critical for mediating the response to selective EZH2 inhibition and highlighted a complex interplay between epigenetic regulation and the tumor immune microenvironment. In this study, we employed a quantitative proteomic mass spectrometry approach to assess alterations in protein expression following EZH2 inhibition in BAP1- and CDKN2A-proficient mesothelioma cells cultured as spheroids. Additionally, we analyzed extracellular vesicles (EVs), which were isolated through tangential flow filtration. Flow cytometric analysis and co-culture systems were used to characterize the effects of EVs on neutrophils. Upon EZH2 inhibition, we demonstrated RAB27b and CD63 upregulation and increased release of extracellular vesicles. We found that a brief exposure to EVs derived from EZH2 inhibitor-treated cells skewed naïve neutrophils toward a pro-tumor phenotype characterized by high levels of PD-L1 and MSLN (Mesothelin) expression on the surface. These EV-elicited neutrophils suppressed T cell proliferation while enhancing tumor cell growth. Moreover, we observed changes in the EV cargo derived from EZH2 inhibitor-treated spheroids. Our findings highlight the significant role of EVs in creating an immunosuppressive microenvironment, and underscore the urgent need for further investigation into the regulation of neutrophil biology and function in the PM.

Hepatocellular carcinoma continues to be a predominant contributor to oncological fatalities, characterized by restricted treatment alternatives. Although berberine exhibits anti-neoplastic capabilities, the underlying molecular pathways in hepatic malignancy require clarification. A comprehensive computational framework was established, incorporating transcriptomic data analysis, multiple machine learning methodologies, weighted gene co-expression network analysis (WGCNA), and molecular simulation techniques to elucidate berberine's therapeutic pathways. Transcriptomic datasets from the Cancer Genome Atlas (TCGA) underwent examination to detect differentially expressed genes (DEGs). Ten machine learning methodologies screened critical targets, subsequently validated through molecular docking and 100 ns molecular dynamics simulations. Transcriptomic examination revealed 531 DEGs (341 exhibiting upregulation, 190 demonstrating downregulation) alongside 173 putative berberine interaction targets, yielding 17 intersecting candidates. Machine learning approaches consistently recognized AURKA and CDK1 as principal targets, subsequently confirmed by WGCNA as central genes. Elevated expression of both targets demonstrated correlation with unfavorable survival outcomes (p < 0.05). Computational docking analysis demonstrated robust binding interactions (AURKA: -8.2 kcal/mol; CDK1: -8.4 kcal/mol), with interaction stability validated through molecular dynamics simulations. Functional enrichment analysis unveiled targeting of cell cycle modulation, chromosome segregation, and p53 signaling networks. Berberine manifests anti-hepatocellular carcinoma activities primarily via coordinated targeting of AURKA and CDK1, essential cell cycle modulators. These discoveries provide molecular insights supporting berberine's potential as adjunctive hepatic cancer therapy.