Anaplastic lymphoma kinase (ALK) is an established therapeutic target in non-small cell lung cancer (NSCLC), predominantly identified in adenocarcinomas. However, ALK rearrangements also occur in de novo squamous and adenosquamous NSCLCs and their clinicogenomic features remain poorly defined.

The RAS signaling pathway is a fundamental regulator of cellular growth, proliferation, and survival. Dysregulation of this pathway is strongly implicated in cancer development, yet systematic strategies for identifying which pathway proteins represent the most promising therapeutic targets remain limited. The rationale of this study was to investigate the diversity of central proteins within the RAS signaling pathway and assess their functional significance in cancer biology. To achieve this, we modeled the human protein-protein interaction network as a metric space using a graph-theoretical framework. Shortest-path distances were computed to identify the most central proteins, which were then classified into functional zones. Proteins located in zone 1, representing the most connected zone, were cross-referenced with curated RAS pathway datasets. Functional enrichment analysis, oncogene/tumor suppressor evaluation, and cancer genome data integration were used to interpret biological roles and therapeutic potential. The results revealed that 95.2% of central RAS proteins are involved in signaling, with 59.5% classified as essential. Key proteins such as BCL2L1, RAF1, RHOA, MAP2K1, EGFR, CDC42, and ANGPT1 were identified as central players in processes including apoptosis resistance, metastasis, angiogenesis, and tumor progression. Several of these proteins also showed strong associations with established oncogenes and successful therapeutic targets. In conclusion, this study demonstrates that central proteins in the RAS signaling pathway exhibit functional diversity that underpins their importance in cancer progression. These findings provide a reproducible network-based workflow for identifying pathway-relevant molecular candidates and contribute to the development of more precise, pathway-oriented cancer therapies.

This graphical abstract presents findings from a simulation study examining the impact of within-patient correlation on statistical inference in analyses of repeated binary clinical outcomes. Under conditions of strong intracluster correlation (200 patients, 10 observations per patient, 1000 simulated data sets), naive logistic regression that assumed independence substantially underestimated standard errors and led to marked inflation of the type I error rate (30.5%). In contrast, generalized estimating equations (GEE), which appropriately account for within-patient clustering, preserved nominal error control (5.7%). These results underscore the importance of using correlation-adjusted analytic approaches to ensure valid inference when evaluating patient-level exposures in longitudinal or clustered oncology data.

In this study, we assess the activation of autophagy and its impact on cytotoxicity following [HuArgI (Co)-PEG5000]-induced arginine deprivation in AML cells. We have previously shown that arginine deprivation is selectively cytotoxic to AML cells and that cell death is caspase independent and non-apoptotic, hence the mechanism of cell death remained elusive. We tested a panel of 7 AML cell lines, and we first demonstrated that the cytotoxicity of [HuArgI (Co)-PEG5000] to AML cells is long-term and sustained despite re-expression of overexpression of ASS1 in all cell lines. We also demonstrated that arginine deprivation leads to a prolonged and extensive activation of autophagy starting at 24 and lasting up to 120 h in all cells. Autophagy was shown to induce cell death since its inhibition using chloroquine (CQ) significantly decreased [HuArgI (Co)-PEG5000]-induced cytotoxicity, indicating autophagic cell death in AML cells following arginine deprivation. Moreover, we showed that arginine deprivation leads to ROS accumulation and that neutralizing ROS using N-acetylcysteine (NAC) does not affect the autophagic response but completely reverses the cytotoxicity of arginine deprivation, demonstrating that death by autophagy is dependent on ROS generation in AML cells.

Bladder cancer (BC), a leading urogenital malignancy with high mortality, lacks effective early biomarkers. Connexin 43 (Cx43), encoded by GJA1, regulates tumor growth via protein interactions and phosphorylation. While dysregulated in BC, Cx43's downstream regulatory pathways remain unclear. Elucidating these mechanisms is crucial for identifying novel biomarkers and therapeutic targets. qRT-PCR measured Cx43 expression in bladder cancer tissues and cells. Kaplan-Meier analysis assessed correlation between Cx43 expression and patient overall survival (OS) and progression-free survival (PFS). Using MTT, colony formation, and Transwell assays, we evaluated how silencing Cx43 affects BC cell proliferation, migration, and invasion in vitro. Protein-protein interaction (PPI) analysis predicted potential Cx43 downstream targets. Co-immunoprecipitation (Co-IP) confirmed specific interaction between Cx43 and c-Src proteins. Western blotting (WB) examined effects of Cx43 knockdown on expression of these predicted downstream targets. Finally, in vivo mouse xenografts validated Cx43's role in BC cell tumorigenesis. Cx43 was upregulated in bladder cancer tissues and its elevated expression correlated with poor patient prognosis. Silencing Cx43 significantly suppressed BC cell proliferation, migration, and invasion. Functional rescue experiments implicated the c-Src/PTEN pathway in mediating the oncogenic effects of Cx43. Mechanistically, Cx43 drives BC progression by facilitating c-Src-mediated suppression of the tumor suppressor PTEN and subsequent activation of FAK signaling. This study unveiled a novel regulatory pathway, Cx43 promotes malignant bladder cancer progression by modulating the c-Src/PTEN/p-FAK axis.

Extramedullary leukaemia, also known as myeloid sarcoma, is a rare manifestation of acute myeloid leukaemia (AML) that typically occurs in conjunction with bone marrow involvement. It is characterized by infiltration of leukemic cells into extramedullary tissues, including the skin, soft tissues, and lymph nodes, where it may present as mass-like or nodular lesions. When associated with high-risk cytogenetic abnormalities, extramedullary disease may exhibit particularly aggressive behaviour and pose substantial diagnostic challenges, especially when it precedes or masks systemic manifestations of AML.

Current biomarkers of epithelial ovarian cancer (EOC) lack the required sensitivity and specificity for early detection. MicroRNAs (miRNAs) are implicated in cancer progression, and their serum expression could serve as a non-invasive diagnostic tool. This study focuses on evaluating the expression of serum miR-200a, miR-200b, and miR-200c and their association with clinico-pathological characteristics in EOC patients.

Hepatocellular carcinoma (HCC) is a prevalent and highly aggressive cancer, characterized by elevated morbidity and mortality. Ubiquitin-conjugating enzyme E2 (UBE2) plays a crucial role in regulating HCC development, although the underlying mechanisms remain poorly understood.

MET alterations, including MET fusions and splicing variants (F/SVs), are linked to glioma progression, but the clinical features remain underexplored since the 2021 WHO classification of tumors of the CNS. We aimed to systematically depict the MET F/SVs and patient characteristics in a multicenter cohort focusing on clinical, pathological, and survival features. We studied data from 1,041 patients with MET F/SVs data from the public Chinese Glioma Genome Atlas database and the TruSight Tumor 170 study. Clinical outcomes were evaluated based on the RANO criteria. We used chi-square and Fisher's exact tests for variable analysis. Kaplan-Meier analysis was used to assess survival trends, while univariate and multivariate analyses revealed the prognostic value of MET F/SVs. Immunohistochemical staining was performed to demonstrate the MET expression level. Among the 1,041 patients, 49 patients had F/SVs (4.70%), and 23 had ZM fusion (PTPRZ1-MET fusion gene; 2.21%). Among the 67 recurrent grade 4 astrocytomas, the proportions of F/SVs (11.94%, n = 8) and ZMs (5.97%, n = 4) were the highest. MET F/SVs were significantly associated with malignant clinical outcomes in the IDH-mutant astrocytoma cohort, with a frequency of 5.04% (18/357) across all WHO grades. Multivariate analysis revealed that the MET F/SVs were independently associated with worse survival in astrocytoma patients [overall survival (OS): p = 0.0011; progression-free survival (PFS): p = 0.004]. ZM fusion was associated with a worse prognosis in both astrocytoma (OS p < 0.001, PFS p < 0.001) and glioblastoma (OS, p = 0.252; PFS, p = 0.010) patients. We highlight the utmost relevance of ZM fusion as an adverse prognostic factor in astrocytoma (11/382, 2.88%) and glioblastoma grade 4 (11/401, 2.74%) patients and suggest that the grading of these tumors should be refined.

Glutathione S-transferase omega 1 (GSTO1) is overexpressed in a variety of cancers and plays an important role in the promotion of tumor proliferation and metastasis. Nevertheless, the function of GSTO1 in cervical cancer (CC) is unknown. Immunohistochemistry (IHC) was applied to observe GSTO1 protein levels in CC tissues. Cell proliferation, migration, and invasion capabilities were assessed using CCK8, EdU, plate cloning assays, and Transwell experiments in vitro. Flow cytometry was employed to analyze cell cycle progression and reactive oxygen species (ROS) levels. A subcutaneous xenograft model was utilized to observe cell growth in vivo. Cell stemness was assessed via sphere formation assay. Transcriptome sequencing and enrichment analysis were conducted to explore GSTO1-related signaling pathways. The proteins linked to cell cycle regulation, stemness, epithelial-mesenchymal transition (EMT), and the PI3K/AKT/mTOR signaling pathway were identified through western blotting and IHC. In this study, GSTO1 was highly expressed in CC tissues and associated with poor prognosis of patients. Knockdown of GSTO1 suppressed CC cell proliferation in vivo and in vitro and inhibited the cell cycle, stemness, migration, and EMT as in C1-27 treatment. Conversely, down-regulation of GSTO1 promoted ROS production in CC cells. RNA sequencing indicated that GSTO1 mediated the activation of the PI3K/AKT signaling pathway. In addition, silencing GSTO1 decreased the phosphorylation of PI3K, AKT, and mTOR proteins. Interestingly, 740 Y-P (PI3K activator) reversed the inhibitory effects of GSTO1-induced cell proliferation, cycle, stemness, and EMT via the PI3K/AKT/mTOR signaling axis. GSTO1 was important in CC progression through the PI3K/AKT/mTOR pathway and could serve as a promising therapeutic target.

Hepatocellular carcinoma (HCC) is characterized by pronounced heterogeneity and extensive angiogenesis. However, anti-angiogenic therapies often show limited clinical benefit due to therapeutic resistance. Understanding endothelial cell heterogeneity and identifying key regulators of tumor angiogenesis are therefore essential for improving treatment strategies.

Mismatch repair-proficient (pMMR) or microsatellite stable (MSS) metastatic colorectal cancer (mCRC) remains largely refractory to immunotherapy due to its intrinsically immunologically cold tumor microenvironment. Although frontline chemotherapy combined with immune-induction strategies can improve progression-free survival, these benefits have not translated into overall survival gains. Importantly, late-line trials such as LEAP-017 suggest that biologically meaningful immune activity may be masked by dilution effects in unselected populations. This review advocates a shift from empirical treatment approaches toward mechanism-driven precision stratification in refractory pMMR/MSS mCRC. We highlight two complementary immune activation strategies: tumor microenvironment remodeling via tyrosine kinase inhibitor-mediated vascular normalization, and intensified immune priming through cytotoxic T-lymphocyte-associated protein 4 blockade. To address persistently low response rates, we propose an integrated precision framework incorporating genomic repurposing, anatomical filtering, and multimodal synergy, aiming to translate transient immune activation into durable survival benefit.

Dipeptidyl peptidase 4 (DPP4) plays diverse physiological roles, but its pan-cancer significance and immunomodulatory functions remain poorly characterized.

Codon usage bias is a fundamental feature of the genetic code, yet its impact on messenger RNA translation is incompletely defined. Here, we integrate comparative genomics, human tissue proteomes, large cancer cell line, and patient cancer datasets to reveal a conserved codon-bias axis. Across mammals, we show that GC-biased gene conversion drives human-specific GC3 (third codon nucleotide bias score) drifts, yet the functional dichotomy is maintained: A/T-ending codons associate with proliferation and RNA processing, while G/C-ending (Third nucleotide Guanine or Cytosine) codons associate with differentiation and neuronal functions. At the isoacceptors level, synonymous codons segregate into distinct functional categories. To mechanistically connect codon usage to cancer, we introduce the ANN- and m7G-indices, capturing codons decoded by transfer RNA (tRNA) modifications t6A and m7G. Both indices negatively correlate with GC3 and enrich for pro-oncogenic proliferative pathways. Human tissue proteomes reveal strong codon bias discordance between RNA and protein levels, with nervous system tissues enriched for G/C-ending codons while proliferative organs are A/T-biased. Analysis of 2600 cancer cell lines and 21 cancer types revealed heterogeneous codon preferences in cancer cell lines but a global A/T-ending shift in human cancer-upregulated proteins. These findings establish synonymous codon divergence and tRNA modification indices as key determinants of translational reprogramming in health and cancer.

Unlike normal colon cells with butyrate acid as the main energy source, cancerous colon cells are more inclined to use glucose. However, the mechanisms of the investigation into the modulatory role of butyrate metabolism within the pathophysiology of colorectal cancer (CRC) remains insufficiently explored.

Solid pseudopapillary neoplasms (SPNs) are rare pancreatic tumors that are indolent but occasionally present with metastatic or locally invasive disease. Although recurrent CTNNB1 exon 3 mutations define their molecular background, the clinicopathological and molecular features associated with these less common presentations remain incompletely characterized. This retrospective study included 62 patients diagnosed with SPN between 2000 and 2025. Clinicopathological and immunohistochemical features, including β-catenin, progesterone receptor (PR), androgen receptor (AR), and BAP1, were evaluated. Targeted sequencing was performed in a subset of cases with metastatic or locally invasive disease (n = 5). Patients showed a wide age range (8-71 years), female predominance (54/62, 87.1%), and a mean tumor size of 7.2 cm. Lymphovascular invasion was rare (1/59, 1.7%). Metastatic or locally invasive SPNs (n = 8) more frequently showed higher Ki-67 values (median, 5%; range, 1%-15%), increased mitotic activity (2/8, 25%), and capsular/parenchymal invasion (6/8, 75%), while perineural invasion was absent. All tumors demonstrated nuclear β-catenin expression, with PR and AR positivity (50/59, 84.7% and 47/57, 82.5%, respectively). PR expression was higher in AR-positive cases (43/47, 91.5% vs. 6/10, 60%). BAP1 loss was identified in 13/57 cases (22.8%). Targeted sequencing consistently identified CTNNB1 exon 3 mutations. Additional low-frequency molecular alterations affecting genes involved in cell cycle regulation, chromatin remodeling, and signaling pathways, including CDKN2A and BAP1, were observed. During a mean follow-up of 97.2 months, distant metastasis occurred in 4/62 patients (6.5%) and locally invasive disease in 4/62 (6.5%), with an overall survival rate of 95%. Overall, these findings highlight the biological heterogeneity of SPNs and indicate that, despite a shared molecular background, aggressive behavior is not defined by a single reproducible pathological or molecular feature.

Non-small cell lung cancer (NSCLC) is the predominant lung cancer subtype with high mortality rate. Drug resistance and immune evasion limit its therapeutic outcomes. Specific mechanism of the oncogenic ZFP36L1 in NSCLC remains unclear.

NUT carcinoma is a rare and highly aggressive malignancy characterized by the rearrangement of the NUTM1 gene. It typically arises in midline structures, including the respiratory tract. Due to its rarity and poor prognosis, early diagnosis and effective treatment remain challenging. This report presents two cases of NUT carcinoma occurring in the respiratory tract, additionally, a review of the literature is provided to enhance understanding of this disease. Both patients were young females, one tumor was located in the larynx and the other in the left main bronchus. Endoscopic forceps biopsy samples revealed tumor growth beneath the superficial mucosal epithelium, arranged in sheets, cords, or nests with extensive necrosis. The tumor cells were uniform in size, with eosinophilic cytoplasm, ill-defined borders, and round or oval nuclei showing hyperchromasia and a high nuclear-to-cytoplasmic ratio. One case showed focal areas with squamous differentiation. Immunohistochemically, tumor cells were positive for P40, P63, and NUT, and fluorescence in situ hybridization detected NUT gene rearrangement, confirming the diagnosis of NUT carcinoma. One patient experienced rapid disease progression despite receiving chemotherapy and died within five months. Another patient declined further treatment after diagnosis. NUT carcinoma is a rare and aggressive malignancy of the respiratory tract with a poor prognosis. Early diagnosis through molecular testing is crucial for appropriate management. However, diagnosis is often delayed until advanced stages, contributing to low survival rates. Increased awareness of this tumor among clinicians and pathologists may facilitate earlier detection and potentially improve patient outcomes.

Intrahepatic cholangiocarcinoma (ICC) is a malignant tumour associated with a poor prognosis. Recent studies have suggested that ribonucleotide reductase subunit M2 (RRM2) could promote tumour progression. This study aims to explore the expression, function and mechanism of RRM2 in ICC by regulating ferroptosis through the HIF-1α signalling pathway.

Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most commonly mutated oncogene in solid tumors, detected in up to 30% of lung adenocarcinomas. This study aimed to address gaps in the literature by analyzing KRAS mutations (KRASM) in a large Australian population.