Acute lymphoblastic leukemia (ALL) is a hematological malignancy characterized by aberrant proliferation and accumulation of lymphoid precursor cells within the bone marrow. The tyrosine kinase inhibitor (TKI), imatinib mesylate, has played a significant role in the treatment of Philadelphia chromosome-positive ALL (Ph + ALL). However, the achievement of durable and sustained therapeutic success remains a challenge due to the development of TKI resistance during the clinical course.The primary objective of this investigation is to propose a novel and efficacious treatment approach through drug repositioning, targeting ALL and its Ph + subtype by identifying and addressing differentially expressed genes (DEGs). This study involves a comprehensive analysis of transcriptome datasets pertaining to ALL and Ph + ALL in order to identify DEGs associated with the progression of these diseases to identify possible repurposable drugs that target identified hub proteins.The outcomes of this research have unveiled 698 disease-related DEGs for ALL and 100 for Ph + ALL. Furthermore, a subset of drugs, specifically glipizide for Ph + ALL, and maytansine and isoprenaline for ALL, have been identified as potential candidates for therapeutic intervention. Subsequently, cytotoxicity assessments were performed to confirm the in vitro cytotoxic effects of these selected drugs on both ALL and Ph + ALL cell lines.In conclusion, this study offers a promising avenue for the management of ALL and Ph + ALL through drug repurposed drugs. Further investigations are necessary to elucidate the mechanisms underlying cell death, and clinical trials are recommended to validate the promising results obtained through drug repositioning strategies.

Tumor mutation burden (TMB) has profound implications for personalized cancer therapy, particularly immunotherapy. However, the size of the panel and the cutoff values for an accurate determination of TMB are still controversial. In this study, a pan-cancer analysis was performed on 22 cancer types from The Cancer Genome Atlas. The efficiency of gene panels of different sizes and the effect of cutoff values in accurate TMB determination was assessed on a large cohort using Whole Exome Sequencing data ( n = 9929 patients) as the gold standard. Gene panels of four different sizes (i.e., 0.44–2.54 Mb) were selected for comparative analyses. The heterogeneity of TMB within and between cancer types is observed to be very high, and it becomes possible to obtain the exact TMB value as the size of the panel increases. In panels with limited size, it is particularly difficult to recognize patients with low TMB. In addition, the use of a general TMB cutoff can be quite misleading. The optimal cutoff value varies between 5 and 20, depending on the TMB distribution of the different tumor types. The use of comprehensive gene panels and the optimization of TMB cutoff values for different cancer types can make TMB a robust biomarker in precision oncology. Moreover, optimization of TMB can help accelerate translational medicine research, and by extension, delivery of personalized cancer care in the future.

Papillary thyroid carcinoma (PTC) typically exhibits a favorable prognosis; however, lymph node and distant metastases continue to present significant clinical challenges. Plectin isoform 1d (PLEC 1d) contributes to myofiber integrity and is implicated in cytoskeletal organization and cancer cell motility, but its role in PTC progression is largely unknown. In this study, PLEC 1d expression was examined by RT-PCR in three PTC cell lines (MDA-T32, MDA-T41, MDA-T120) and normal thyroid cells (Nthy-ori-3-1). CRISPR-Cas9-mediated knockdown (KD) of PLEC 1d was performed in MDA-T41 cells, with KD efficiency confirmed by RT-qPCR. Cell proliferation and migration were assessed using EdU incorporation and wound-healing assays, respectively. RNA sequencing (RNA-seq) combined with RT-qPCR and Western blotting was employed to identify downstream targets. Accordingly, PLEC 1d mRNA and total plectin protein levels were substantially elevated only in MDA-T41 cells. PLEC 1d KD reduced proliferation by 6.6% and migration by 26%. Transcriptomic analysis revealed 170 differentially expressed genes, including significant downregulation of LAMA4, MMP1, and HEY1. HEY1 downregulation was confirmed at both mRNA and protein levels. Although LAMA4 and MMP1 were also downregulated following PLEC 1d KD, LAMA4 mRNA expression varied across PTC cell lines, suggesting cell-line-specific regulation. Notably, MMP1 was consistently upregulated at the mRNA level in all PTC cell lines, while HEY1 showed elevated expression at both the transcript and protein levels. Collectively, these findings indicate that PLEC 1d enhances cell migration and may contribute to cellular processes associated with metastatic behavior in a subset of PTC cells, potentially through a HEY1-dependent mechanism.

Background/Objectives: Circulating tumor cells (CTCs) play a central role in metastasis by enabling tumor dissemination through the bloodstream. However, the molecular transition from CTC-negative (CTC⁻) to CTC-positive (CTC⁺) states and their associated systemic remodeling remain poorly understood. Methods: We performed a transcriptomic comparison between CTC⁺, CTC⁻, and healthy individuals using RNA-seq data and a bioinformatics pipeline. Differentially expressed genes (DEGs) were subjected to functional enrichment, protein–protein interaction (PPI) analysis, survival modeling, and drug perturbation prediction to delineate the molecular determinants of CTC emergence and persistence. Results: Primary tumors from CTC⁺ patients exhibited distinct transcriptomic profiles characterized by the upregulation of genes involved in PI3K-Akt signaling, extracellular matrix organization, and chromatin regulation (e.g., HDAC1, JUN, KLK10), alongside the downregulation of immune activation pathways, including complement, B-cell receptor (BCR), and T-cell receptor (TCR) signaling. Multi-gene survival models derived from upregulated (KLK10, MEOX2, IRS4, RND2) and downregulated (ALDH3A1, PPP2R2B, IGF1R) hub genes significantly stratified patient outcomes (HR = 1.74–2.44, p < 0.01). In contrast, primary tumors from CTC⁻ patients displayed early systemic transcriptional alterations relative to healthy controls, with 1700+ DEGs linked to MAPK/ERK and receptor tyrosine kinase (RTK) signaling pathways, suggesting pre-metastatic immune reprogramming even before CTC detection. Drug repurposing analysis identified Trichostatin A, BX-795, and Alvocidib as candidate compounds capable of reversing the CTC⁺ transcriptional signature. Conclusions: Rather than supporting a strictly binary view of CTC status, our findings are consistent with a transcriptional continuum of distinct yet partially overlapping primary-tumor transcriptional states associated with CTC⁻ and CTC⁺ status, highlighting a molecular shift from immune suppression to epigenetic adaptation that facilitates hematogenous dissemination. The identified multi-gene prognostic panels and small-molecule candidates provide a foundation for CTC-targeted therapeutic strategies and early detection biomarkers in breast cancer.

Glioblastoma (GBM) remains one of the most aggressive human malignancies, and its biological diversity is largely shaped by the isocitrate dehydrogenase (IDH) mutation status. Although apoptosis, autophagy, and ferroptosis have each been implicated in GBM pathophysiology, their coordinated regulation through the immunoproteasome (i-PSM) axis has not been systematically explored. Here, we integrated transcriptomic datasets from The Cancer Genome Atlas and The Chinese Glioma Genome Atlas with immune deconvolution and network analyses to map the IDH-specific crosstalk between i-PSM components and cell death programs. We identified a nine-gene signature (i.e., CD14, HMOX1, CTSB, CTSS, RRAS, BAK1, FTH1, PRKCD, and CYBB ) that captures IDH-dependent immune and metabolic divergence. IDH-mutant (IDHmt) astrocytomas exhibited coordinated upregulation of HMOX1 and CD14 , suggesting an actively maintained, immunosuppressive niche rather than a merely “immune-cold” state. Receiver operating characteristic analyses demonstrated strong discrimination of IDH status (area under the curve ≥ 0.92 for key genes), whereas structure-guided docking nominated rational, multipathway combinations such as temozolomide + bortezomib, luteolin, or lovastatin. Collectively, this integrative omics approach reframes IDHmt GBM as a redox- and myeloid-driven suppressive ecosystem and provides a systems-level rationale for personalized, IDH-informed therapeutic strategies.