Drug resistance limits the long-term survival of patients with multiple myeloma. The role of tRNA-derived fragments (tsRNAs) in bortezomib resistance in myeloma remains unknown. In this study, the most significantly upregulated tsRNA in relapsed/refractory myeloma was screened. RNA interference was used to explore the function of this tsRNA. The mechanism of the tsRNA-mediated resistance was explored by Ago-RIP-sequencing, dual-luciferase reporter assay, and transmission electron microscopy. tRF-17-8SPOL52 was identified as the most highly expressed tsRNA in relapsed/refractory myeloma. tRF-17-8SPOL52 promoted bortezomib resistance in vitro and in vivo. Ago-RIP-sequencing and dual-luciferase reporter assay showed that tRF-17-8SPOL52 negatively regulated RUBCN. Data from Ago-silenced myeloma cells suggested that the regulation of RUBCN by tRF-17-8SPOL52 was Ago-dependent. Further research showed increased autophagy induced by tRF-17-8SPOL52. In constructed RUBCN overexpressed or inhibited myeloma cells, tRF-17-8SPOL52 promoted cell autophagy by inhibiting RUBCN. Rescue experiments with chloroquine and rapamycin showed that tRF-17-8SPOL52 mediated bortezomib resistance by promoting autophagy. We concluded that tRF-17-8SPOL52 activates autophagy by inhibiting RUBCN in an Ago-dependent manner, which in turn leads to bortezomib resistance in myeloma.

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations are common in intrahepatic cholangiocarcinoma (ICC), but their prognostic value is unclear. Using a large data set, we assessed their impact in resected and nonresected ICC.

Despite increasing evidence supporting the validity and utility of pharmacogenomic (PGx)-guided prescribing, clinical PGx testing in oncology remains limited. However, expanding professional guidelines and recommendations have accelerated PGx implementation efforts in the United States. Given the availability of actionable PGx guidelines for several medications commonly prescribed to patients with cancer, this study evaluated US oncologists' knowledge, attitudes, and perceived barriers regarding PGx-guided medication management.

TRK inhibitors (TRKis) have transformed the therapeutic landscape for patients with neurotrophic tyrosine receptor kinase (NTRK) gene fusion-positive tumors. However, approval of TRKis is based on evidence derived mainly from small, pooled, single-arm clinical trial cohorts. The REALTRK registry aims to describe real-world molecular diagnostic practices, treatment patterns, and clinical outcomes for adult patients with NTRK fusion-positive cancers.

Relapsed and refractory acute myeloid leukemia (AML) remains difficult to treat, in part because leukemic cells adapt to nucleoside analogue-induced replication stress. Here, we identify thymidine kinase 1 (TK1) as a functional contributor to chemotherapy resistance in AML. Integrated analyses of TCGA, Beat AML, and murine chemoresistant AML transcriptomes revealed that high TK1 expression was associated with adverse outcome, cytarabine resistance, and enrichment of nucleotide salvage programs. In Mll-Af9/Setd2-mutant AML cells, TK1 upregulation coincided with reduced de novo nucleotide synthesis, sustained BrdU incorporation, attenuated replication stress signaling, and resistance to daunorubicin plus cytarabine. Genetic suppression of Tk1 impaired DNA synthesis, increased replication-associated DNA damage, and restored chemosensitivity. Mechanistically, TK1 accumulation was linked to impaired APC/C-CDH1 activity, and manipulation of Cdh1 altered TK1 abundance, replication stress tolerance, and drug response. Combined topoisomerase I and WEE1 inhibition increased CDH1 expression, reduced TK1 abundance, enforced replication stress, and induced leukemic cell death. In relapsed/refractory AML patient-derived xenograft models, this combination reduced leukemic burden and prolonged survival, particularly in TK1-high AML. These findings define a CDH1-TK1-associated program that promotes salvage-dependent replication stress tolerance and nominate TK1 as a candidate biomarker for replication stress-targeted therapy.

Although Poly(A)-binding protein cytoplasmic 1 like (PABPC1L) has been studied in specific cancer types, its broader potential as a prognostic biomarker remains uninvestigated, and the systematic pan-cancer analysis is currently lacking. We performed an integrated pan-cancer analysis of PABPC1L expression and function in 33 human malignant tumors. Associations between PABPC1L expression and tumor mutational burden (TMB), microsatellite instability (MSI), tumor microenvironment composition, drug sensitivity, and response to immune checkpoint blockade (ICB) were also evaluated. A gastric cancer (GC) single-cell RNA sequencing dataset was analyzed to examine the correlation between PABPC1L expression and intercellular communication networks. The relationship between PABPC1L and PD-L1 expression was investigated in human colorectal cancer (CRC) tissue. Functional validation experiments were performed in CRC and GC cell lines. PABPC1L expression was consistently upregulated in multiple cancer types and significantly associated with poor patient prognosis. Notably, PABPC1L was identified as an immunomodulatory factor. It influenced the expression of multiple immune-related genes, regulates immune cell infiltration, and correlates with the outcomes following ICB therapy. Single-cell RNA sequencing analysis of GC further indicated that PABPC1L was involved in intercellular communication networks, including immune cells. In CRC, elevated PABPC1L expression was observed in tumor tissues and positively correlated with PD-L1 levels. Functional experiments confirmed that PABPC1L promoted cell proliferation, regulated cell cycle, and impaired the sensitivity of gastric and colorectal cells to 5-FU. In conclusion, PABPC1L is identified as exhibiting oncogenic properties and is proposed to function as a key regulator of tumorigenesis and immunotherapy resistance.

Given that gastric cancer is a highly heterogeneous malignant tumor, approximately 70%-80% of patients exhibit an immune "cold tumor" phenotype, resulting in a limited response rate to immune checkpoint inhibitor monotherapy. Paclitaxel is a commonly used chemotherapeutic drug for gastric cancer. Recent studies have found that paclitaxel can promote mitochondrial DNA (mtDNA) release by inducing BAK-dependent apoptosis and mitochondrial reactive oxygen species production. However, whether this process activates the cGAS-STING innate immune pathway to transform the "cold tumor" into a "hot tumor" has not been systematically analyzed. This article reviews the proposed dual pathways through which paclitaxel regulates mitochondrial DNA release: the BAK/BAX-mediated apoptotic pathway and the mitochondrial permeability transition pore (mPTP)-opening non-apoptotic pathway. Also, it elucidates the potential the molecular mechanism by which paclitaxel activates the cGAS-STING signaling axis to drive type I interferon response and promote CD8 + T cell infiltration. The translational potential of leveraging this mechanism for combining chemotherapy with immunotherapy in gastric cancer is also discussed. By integrating existing experimental evidence and theoretical frameworks, we hypothesize that core components of the mPTP could serve as biomarkers to predict the efficacy of combination therapy, which may provide new ideas for the establishment of precise combination therapy for gastric cancer with clear mechanisms, though prospective validation is urgently needed.

Connexin-43 (Cx43), GAP-43 and actin are involved in cellular communication and cytoskeletal dynamics in gliomas, yet their clinical relevance remains largely unclear. We investigated their expression and association with survival and tumor characteristics in IDH-mutant and IDH-wildtype gliomas.

ISA-2011B is a phosphatidylinositol-4-phosphate 5-kinase-α (PIP5K1α) inhibitor that has been reported to be selective in suppressing the growth of prostate, breast and hepatic cancer cells. Here, cell viability of 2-dimensional (2D) cultures and 3-dimensional (3D) spheroids of four colorectal cancer (CRC) cell lines with different mutations were evaluated after treatment with the drug ISA-2011B.

In their recent study, Maniar et al. demonstrated context-dependent phenotypic effects of hypoxia-reoxygenation in breast cancer cell lines [1]. These included enhanced proliferation, invasion, clonogenicity, and chemoresistance. While these findings provide important insights into tumor adaptation under fluctuating oxygen conditions, several mechanistic aspects remain insufficiently explored. In this correspondence, we highlight the absence of molecular characterization of hypoxia-inducible factor (HIF) signaling, despite its central role in mediating hypoxic responses. We also discuss the lack of direct assessment of reactive oxygen species (ROS), which were proposed as key drivers of the observed phenotypic changes. Also, the increase in migration and clonogenicity suggests the potential involvement of epithelial-mesenchymal transition (EMT) which was not evaluated. Finally, we mention the limitations of two-dimensional culture models and the potential value of three-dimensional systems in improving translational relevance.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive and lethal thyroid malignancies, with limited effective treatment options. We aimed to identify previously unreported gene alterations and evaluate the potential for clinically actionable targeted therapies in ATC using the largest single next-generation sequencing (NGS) cohort to date.

Sarcomatoid transformation in clear cell renal cell carcinoma (ccRCC) is associated with highly aggressive clinical behaviour and poor prognosis. The molecular basis underlying this transformation remains poorly defined.

Cervical cancer progression is driven not only by persistent high-risk human papillomavirus infection but also by multilayered post-transcriptional regulatory networks that reshape tumor cell behavior and the tumor microenvironment. Among these regulators, circular RNAs (circRNAs) have emerged as pivotal modulators of oncogenic signaling. Initially characterized as competing endogenous RNAs (ceRNAs), circRNAs were shown to promote cervical cancer growth, invasion, and chemoresistance by derepressing key oncogenic targets. However, recent evidence expands this paradigm, revealing that circRNAs are subject to epitranscriptomic modification and function as dynamic scaffolds integrating RNA-binding proteins, translational machinery, inflammatory signaling, and metabolic pathways. In cervical cancer, m6A-dependent regulation and reader-mediated translational control enhance circRNA stability and amplify oncogenic outputs, linking RNA modification to metabolic reprogramming and hypoxia adaptation. Concurrently, circRNAs modulate inflammatory cascades such as IL6/JAK/STAT3 and NF-κB, contributing to immune suppression and tumor microenvironment remodeling. These tumor-intrinsic and immune-extrinsic mechanisms converge on metastatic reprogramming, enabling lipid metabolic flexibility, lymphangiogenesis, autophagy activation, and therapeutic resistance. This review synthesizes current evidence to propose a unified regulatory landscape in which circRNAs function as central nodes connecting ceRNA circuits, epitranscriptomic modulation, immune signaling, and metabolic plasticity. Unlike previous reviews that primarily summarized circRNA-mediated ceRNA networks, canonical oncogenic pathways, or biomarker potential, this review adopts a systems-level perspective and critically integrates epitranscriptomic regulation, RNA-binding protein interactions, immune-inflammatory signaling, metabolic plasticity, and metastatic reprogramming. We further distinguish directly validated cervical cancer mechanisms from emerging or hypothetical regulatory layers, thereby providing a clearer conceptual framework for future mechanistic and translational studies.

Identifying upstream molecular regulators linking tumor proliferation with immune-related alterations remains an important challenge in cancer therapy. NTMT1 (METTL11A), a protein N-terminal methyltransferase, has been implicated in tumorigenesis; however, its role in coordinating tumor-immune interaction is poorly understood.

To investigate the association between polycystic ovary syndrome (PCOS) and miscarriage risk and to explore the potential causal effect.

Multiple endocrine neoplasia type 2B (MEN2B) is a rare autosomal dominant genetic disorder caused by activating germline mutations in the RET proto-oncogene, typically arising during embryogenesis. The syndrome is characterized by the coexistence of medullary thyroid carcinoma, pheochromocytoma, gastrointestinal ganglioneuromas, and diffuse mucosal neuromas, the latter representing a pathognomonic clinical feature. In pediatric patients, mucosal neuromas most commonly involve the oral cavity, whereas laryngeal or other airway involvement is exceedingly rare and often underrecognized.

Myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML) harboring TP53 mutations are defined by extreme genomic instability, complex karyotypes (CK), and poor prognosis. While large-scale chromosomal imbalances are common in CK-MDS/AML, the synergy between focal amplifications of signaling drivers and the disruption of transcriptional regulators remains poorly elucidated.

MET exon 14 skipping is an actionable oncogenic driver in non-small cell lung carcinoma (NSCLC); however, noncanonical splice-region variants are frequently classified as variants of unknown significance (VUS), which may result in missed therapeutic opportunities and highlight limitations in current DNA next-generation sequencing (NGS) reporting criteria. We report a patient with pulmonary sarcomatoid carcinoma harboring a noncanonical MET splice donor-proximal indel (c.3022_3028 + 13delinsA), initially interpreted as a VUS, who achieved a rapid and durable response to capmatinib. Subsequent RNA sequencing and droplet digital PCR (ddPCR) confirmed MET exon 14 skipping, supporting the value of orthogonal transcript-level validation for exon-adjacent variants.

Programmed cell death represents a fundamental process in maintaining organismal homeostasis and responding to pathological challenges. The traditional view considered apoptosis, pyroptosis, and necroptosis as independent death pathways. However, recent research has revealed extensive interactions and synergies among these pathways, leading to the emergence of a novel form of cell death termed "PANoptosis." Triggered by specific stimuli, PANoptosis involves the assembly of a large multiprotein complex called the PANoptosome. This complex integrates key molecules and morphological features from apoptosis, pyroptosis, and necroptosis, culminating in a highly efficient and coordinated inflammatory cell death program. Concurrently, non-coding RNAs, as crucial regulators of gene expression, participate extensively in the regulation of cellular fate at the post-transcriptional and epigenetic levels. This review systematically summarizes the molecular mechanisms by which non-coding RNAs regulate the core components of PANoptosis and its upstream signaling pathways. It further delves into the pathological role of this regulatory axis in infectious diseases, cancer, neurodegenerative disorders, and autoimmune diseases. Additionally, the article explores the diagnostic potential of non-coding RNA-based approaches and therapeutic strategies targeting the non-coding RNA-PANoptosis axis, while also addressing current challenges related to mechanistic complexity, delivery technologies, and safety assessment. This review aims to establish a systematic framework for the "non-coding RNA-PANoptosis-disease" regulatory axis, providing a theoretical basis for understanding the interactive logic of cell death networks and for developing precise interventions for related diseases.

The 2021 WHO classification permits diagnosis of glioblastoma in IDH-wildtype diffuse astrocytic tumors with TERT promoter mutation, EGFR amplification, or chromosome 7 gain/10 loss, even without necrosis or microvascular proliferation. The clinical behavior of these molecularly defined glioblastomas (molGBM) remains uncertain.