Tusamitamab ravtansine demonstrated antitumor activity in the Phase 1/1b study of advanced non-squamous non-small cell lung cancer with high (HE, ≥2+ intensity in ≥50 % of tumor cells) or moderate (ME, ≥2+ intensity in ≥1 % to <50 % of tumor cells) carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) expression. Tumor CEACAM5 expression, biomarker associations and whether biomarkers predict objective response rate (ORR) were explored.

This study aims to develop and validate a CT-based radiomics model for predicting the prognosis of head and neck cancer patients, particularly those with nasopharyngeal carcinoma (NPC), following intensity-modulated radiation therapy (IMRT).

Pancreatic ductal adenocarcinoma (PDAC) exhibits profound chemoresistance and metastasis, driving its dismal prognosis. Gemcitabine (GEM) resistance remains a critical barrier, necessitating exploration of metabolic regulators like choline phosphotransferase 1 (CHPT1) and ferroptosis in PDAC therapy.

Non-alcoholic fatty liver disease (NAFLD) is involved in non-alcoholic steatohepatitis (NASH), liver cirrhosis (LC), and even hepatocellular carcinoma (HCC). Hence, this study was to elucidate nuanced key mechanism(s), target(s), and Natural Indole-Derived Molecules (NIDMs) against NAFLD-derived HCC.

The preference of cancer cells to generate energy from glycolysis for rapid cell proliferation is called the Warburg effect. Poly(ADP-ribose) polymerase 1 (PARP1) performs various cellular functions, including poly-ADP-ribosylation and DNA repair. In the present study, we investigated the novel effects and mechanisms of PARP1 inhibition on glucose metabolism in colorectal cancer cells under hypoxia. We subjected Caco-2 and LoVo cancer cell lines to a concentration gradient of PARP1 inhibitor in a hypoxic environment induced with a tri-gas incubator (5 % CO, 1 % O, 94 % N). Inhibiting PARP1 activation attenuated Poly-ADP-ribosylation, increasing the NAD/NADH ratio. High concentrations of PARP1 significantly reduced the glucose consumption rate of the treated cells, while PARP1 inhibition depressed cell progression in a concentration-dependent manner. The expression of hypoxia-inducible factor-1α (HIF-1α), hexokinase 2 (HK2), and glucose transporter 1 (GLUT-1), critical for the Warburg effect and glucose metabolism, was considerably reduced after the inhibitor treatments. Moreover, inhibiting PARP1 activation reduced phosphorylated AKT (p-AKT) and mTOR (p-mTOR) levels. In conclusion, our study revealed that PARP1 inhibition decelerates the Warburg effect in colorectal cancer cells, likely through the AKT/mTOR/HIF-1α pathway.

The success of cancer immunotherapy is hampered by the lack of dynamic models that can predict patient-specific responses and guide the development of novel treatments. Static biomarkers, such as PD-L1 expression and tumor mutational burden, often fail to capture the complexity of the tumor-immune dialogue. Patient-derived tumor organoids (PDTOs) have emerged as a revolutionary ex vivo platform that bridges this gap. This review outlines the evolution of PDTOs from simple epithelial cultures to sophisticated, immune-competent "avatars" that faithfully recapitulate the patient's tumor microenvironment (TME). We critically discuss the key methodologies for reconstructing the TME, including "add-in" co-culture systems with diverse immune and stromal cells (e.g., T-cells, MDSCs, CAFs, neutrophils) and "all-in-one" approaches that preserve the native immune ecosystem. Furthermore, we highlight the expanding role of these advanced models beyond predicting checkpoint inhibitor efficacy. We showcase their groundbreaking applications as core development platforms for next-generation immunotherapies, including CAR-T cell therapy and the validation of personalized neoantigen-based vaccines. While acknowledging the significant translational challenges that remain, we conclude that immune-competent PDTOs represent an indispensable tool poised to accelerate the new era of precision immuno-oncology.

Gastric cancer (GC) remains a major cause of cancer-related mortality globally, largely due to the absence of reliable non-invasive biomarkers for early detection. Circular RNAs (circRNAs), characterized by covalently closed-loop structures, stability, and detectability in circulation, have emerged as promising liquid biopsy candidates.

Mutations in nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2) occur in 10-22 % of esophageal squamous cell carcinoma (ESCC) cases and result in NRF2 activation, promoting tumor progression, and therapeutic resistance. Although previous studies suggested a link between NRF2 and kinases, specific kinases responsive to NRF2 activation remain to be fully identified. Using protein phosphorylation profiling and kinase activity profiling, we identified phosphatidylinositol 3-kinase (PI3K) pathway as a downstream effector in NRF2-KYSE70 cells compared to isogenic NRF2-KYSE70 cells. AREG, pEGFR, PIK3CA, pAKT, p-S6, and p-PTEN were downregulated in NRF2 deficient cells. Notably, NRF2 deficiency sensitized ESCC cells to EGFR, PIK3CA, and AKT inhibitors. Co-treatment with Alpelisib (a PIK3CA inhibitor) and Pyrimethamine (an NRF2 inhibitor) synergistically suppressed the growth of NRF2-KYSE70 and NRF2-KYSE180 cells. In vivo, NRF2 activation in the esophageal epithelium of Keap1 and Sox2CreER;LSL-Nrf2 mice resulted in upregulation of pAKT, p-mTOR, and pS6. In human ESCC tissues, expression of pNRF2 (an active form of NRF2) was positively associated with that of pAKT and p-mTOR. Furthermore, co-treatment with Pyrimethamine and Alpelisib significantly inhibited hyperproliferation and hyperkeratinization in the esophageal epithelium of Sox2CreER;LSL-Nrf2mice. Together, our data demonstrates the PI3K pathway as a downstream effector of NRF2 activation in the esophagus, and co-targeting of NRF2 and the PI3K pathway may offer a promising therapeutic strategy for NRF2 ESCC.

Piwi-interacting RNAs (piRNAs), while crucial for genomic integrity in germline cells, remain poorly characterized in somatic cancers. This study identifies piR-43452 as a significantly downregulated piRNA in bladder cancer (BCa), with loss of expression correlating clinically with muscle invasion and lymph node metastasis. Through assays in vitro and in vivo, we demonstrate that piR-43452 acts as a potent tumor suppressor, inhibiting BCa cell proliferation, migration, and xenograft growth while promoting apoptosis. Mechanistically, we identified that piR-43452 directly binds the 3'UTR of LRP1 mRNA and recruits the GTSF1/PIWIL4 complex, which enhances target cleavage through GTSF1-dependent conformational activation. This post-transcriptional regulation led to significant LRP1 suppression, subsequently inhibiting proliferation and restoring chemosensitivity. Our findings establish a novel piRNA-guided mechanism for overcoming chemoresistance and suggest that targeting the piR-43452/GTSF1/PIWIL4/LRP1 axis may provide therapeutic benefit in gemcitabine-resistant BCa.

To investigate whether β-Sitosterol (SIT) enhanced the anticarcinogenic effects of sorafenib on HCC.

Cancer stem cells (CSC) drive therapeutic resistance and recurrence in head and neck squamous cell carcinoma (HNSCC). We and others have shown that treatment with cytotoxic chemotherapy agents (e.g. Cisplatin, Carboplatin) induce Bmi-1 expression and increase the fraction of highly tumorigenic CSC in HNSCC. Notably, Bmi-1 is a master regulator of stem cell self-renewal and DNA repair. The purpose of this work was to test whether therapeutic inhibition of Bmi-1 sensitizes HNSCC cancer stem cells to chemotherapy. HNSCC cells (UM-SCC-1,-22A,-22B) were treated with Cisplatin or Carboplatin and subjected to stemness analyses to evaluate the impact of Bmi-1 on chemoresistance. We observed that both, shRNA-mediated Bmi-1 silencing or pharmacologic inhibition of Bmi-1 with the small molecule inhibitor PTC596, blocked chemotherapy-induced cancer stemness (i.e. increase in the fraction of ALDHCD44 cells), CSC self-renewal (i.e. orosphere formation) and inhibited protective DNA damage responses in HNSCC. Further, it is known that high IL-6 serum levels correlate with poor HNSCC patient survival, and that platinum-based therapies induce IL-6 signaling. Here, we observed that Bmi-1 silencing (or PTC596 treatment) inhibited the IL-6R/STAT3 signaling pathway even in presence of platinum-based cytotoxic agents (i.e. Cisplatin, Carboplatin). In vivo, Bmi-1 inhibition with PTC596 suppressed Cisplatin-mediated increase in the fraction of ALDHCD44 cells (cancer stemness). Collectively, these preclinical results demonstrate that Bmi-1 is a key mediator of head and neck cancer stemness and suggest that HNSCC patients might benefit from treatment with a Bmi-1 inhibitor combined with a conventional chemotherapeutic agent.

Overcoming osimertinib resistance in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) is challenging due to unclear mechanisms. We previously reported a NSCLC case with EGFR mutations progressed on osimertinib therapy, revealing a novel NOTCH2-NTRK1 fusion gene in the plasma and tumor tissue. Although the NTRK gene fusion has been identified in NSCLC and a range of tumor types, the role of NOTCH2-NTRK1 in osimertinib resistance is unclear.

There is an urgent need to identify novel therapeutic targets for papillary thyroid carcinoma (PTC). APOC1 (Apolipoprotein C1) has emerged as a candidate: it is overexpressed in several cancers and its high expression often associates with worse clinical outcomes. Using bioinformatic analysis of TCGA-THCA RNA-seq data, we found that APOC1 is highly expressed in PTC and that elevated APOC1 correlates with poorer patient prognosis and with signatures of immune-evasion. We validated these observations in PTC cell lines. Immunofluorescence, colony-formation assays, CCK-8 proliferation measurements, and flow-cytometry apoptosis analysis all indicate that APOC1 promotes proliferation, enhances colony survival, and confers resistance to apoptosis. To identify candidate therapeutics that target APOC1-related pathways, we queried the Connectivity Map using shared differentially expressed genes (DEGs) and nominated cyclopamine as the top small-molecule hit. Cyclopamine reduces PTC cell proliferation and induces apoptosis in vitro; APOC1 depletion further sensitizes cells to cyclopamine, producing greater inhibition of proliferation and increased cell death. Finally, cyclopamine suppresses tumor growth in a PTC mouse model. Together, these results implicate APOC1 as a driver of PTC progression and immune evasion and identify cyclopamine as a promising therapeutic that acts, at least in part, through APOC1-related signaling. Our study thus provides a rationale for targeting APOC1 as a novel treatment strategy for papillary thyroid carcinoma.

Burkitt lymphoma (BL) is an aggressive B-cell non-Hodgkin lymphoma, historically classified into three subtypes; endemic, sporadic and immunodeficiency associated BL. Accumulating evidence suggests that Epstein-Barr virus (EBV)-positive and EBV-negative BL represent biologically distinct entities. In this review, we aim to compare the clinicopathological and molecular differences in BL in the context of EBV status and chronic malaria infection. From our review, clinical features of BL vary by both EBV status and geographical region, reflecting underlying epidemiological differences. The cell of origin may also differ between EBV-positive and EBV-negative cases. At a molecular level, differences based on EBV status include variations in the immunoglobulin (IG)::MYC translocation breakpoints, mutations in the inhibitor of DNA binding 3 (ID3)/ transcription factor 3 (TCF3)/ cyclin D3 (CCND3) signalling axis, the anti-apoptotic effects of EBV latency gene products, differences in the alternative reading frame (ARF)/ mouse double minute 2 (MDM2)/p53 and ataxia-telangiectasia mutated (ATM)/ ATM and RAD3-related (ATR) pathways, and deregulation of B-cell leukemia/lymphoma 2 (BCL-2) family proteins. We further discuss the theory that aberrant activation-induced cytidine deaminase (AID) expression, in the setting of EBV infection and chronic malaria exposure, is the most likely aetiology of endemic BL. This review provides a comprehensive summary of key molecular differences between EBV-positive and EBV-negative BL, that may guide the development of future targeted therapeutic strategies.

To identify molecular determinants of tumor aggressiveness in TETs and to elucidate their functional roles and underlying mechanisms in tumor progression.

As a subgroup of AGC kinases, serine/threonine kinase 32 family (STK32, also known as Yet Another Novel Kinases family) consists of three members: STK32A, STK32B and STK32C. Recently, emerging evidences have implicated the aberrant expression and dysregulated functions of STK32 kinases in human malignancies. However, there is a lack of systematic review on this topic. Here, we aim to detailly examine the expression and functional features of STK32 family kinases within the context of present reports and public datasets related, and outline current understanding on the multifunctional roles and up-stream regulatory mechanisms and down-stream effectors of STK32 kinases to highlight key research focus for future exploration and provide rationale for developing STK32-targeted therapeutics in cancer.

This study aims to investigate the heterogeneity of cancer-associated fibroblasts (CAFs) and smooth muscle cells (SMCs) and their interactions with malignant epithelium in gastric cancer (GC), with the goal of identifying potential therapeutic targets.

This study aimed to elucidate the novel effects and underlying mechanisms of L-theanine on colorectal cancer (CRC) in a rat model. Specifically, it focused on how L-theanine uniquely impacts cell proliferation, apoptosis, epithelial-mesenchymal transition (EMT), oxidative stress, inflammation, intestinal microbiota, and short-chain fatty acids in rat CRC compared to existing studies. In the 1,2-dimethylhydrazine (DMH) group, serum levels of CRP, AFP, CEA, and CA199 were elevated compared to controls, but L-theanine treatment reduced these levels. IHC analysis showed a significant decrease in Ki67-positive cells in colon tissues with L-theanine. HE staining indicated improved colon pathology, and TUNEL assays revealed increased apoptosis. Western blotting demonstrated up-regulation of caspase-3, cleaved caspase-3, and Bax, and down-regulation of Bcl-2 with L-theanine. It also corrected abnormal expressions of tumor and EMT markers. L-theanine reduced oxidative stress and inflammation by boosting CAT activity, SOD, and GSH levels, while decreasing MDA content and ROS intensity in CRC rats. It decreased pro-inflammatory cytokines IL-1β, TNF-α, and IL-6, increased anti-inflammatory IL-10, and reduced COX2, NF-κB p65, and NLRP3 protein levels. L-theanine altered the gut microbiota composition in CRC rat models, resulting in 379 new strains and reduced levels of genera like Kineothrix and Parasutterella. Immunohistochemical analysis showed increased GPR41 expression in the DMH group versus controls. These novel findings suggest L-theanine's potential as a distinct chemopreventive agent for CRC due to its beneficial and unique effects.

This study aims to evaluate the prognostic value of tumor macroscopic morphology in colorectal cancer (CRC) and understand the molecular mechanism behind different tumor morphologies.

The role of pyroptosis in pancreatic cancer remains controversial. Using two-sample Mendelian randomization (MR) integrating GWAS data from FinnGen (314,193 controls, 731 cases), pQTL data from Iceland, and the UK Biobank, we systematically investigated causal links between pyroptosis genes and pancreatic cancer. We found that Beta-2-microglobulin (B2M) indirectly increases pancreatic cancer risk by upregulating Neutrophil Elastase (ELANE)-to our knowledge, this is the first study to establish a causal, mediation-based genetic link between B2M and ELANE in the context of pancreatic cancer. Mediation analysis revealed ELANE accounts for 20.572 % [15.32%-25.81 %] of this effect. Sensitivity analyses confirmed robustness without significant pleiotropy, and bioinformatics validation supported our MR findings. Drug sensitivity analysis further identified potential therapeutic agents. The findings support B2M as a diagnostic biomarker for pancreatic cancer, given its significant overexpression in tumors and high diagnostic accuracy (AUC = 0.976, 95 % CI: 0.958-0.993), and highlight the B2M-ELANE axis-identified through a data-driven MR mediation framework-as a promising therapeutic target.

PARP inhibitors have revolutionized ovarian cancer treatment, with benefits strongly linked to the presence of Homologous Recombination Deficiency (HRD). Although HRD testing was originally conducted on centralized platforms, there is growing demand for scalable, accessible, and robust solutions capable of supporting expanded clinical utilization. In the present study, a decentralized NGS-based assay was compared for its ability to effectively identify HRD positive patients when compared to the reference assay as well as other testing platforms. Eighty-two cases of ovarian cancer patients previously tested using the reference HRD assay (Myriad MyChoice® CDx assay) were evaluated by an NGS based HRD assay, the 1021-HRD assay (GenePlus), that provides genomic instability (GI) analysis along with tumor molecular profiling. HRD status, GI status (referred to as HRD-score), and even BRCA1/2 mutation detection were assessed for concordance with the reference test and the analytical accuracy of the assay was calculated. Additionally, GI alignment across alternative HRD testing platforms was examined. Finally, the association between key tumor alterations and the HRD status was evaluated. The 1021-HRD assay demonstrated an overall HRD classification agreement of approximately 92.68 % (κ = 0.841) in comparison to the reference method, as evidenced by the results, with 81.25 % specificity and 100 % sensitivity. These features generally suggest consistent performance, with only minor discrepancies observed. The BRCA1/2 alterations detected were 97.56 % in agreement with the approved assay. The Pearson r value of 0.878 indicates a strong correlation between the GI values obtained. The assay's capacity to detect non-BRCA1/2 HRD phenotypes was verified by the observation that 55.56 % of BRCA-wildtype malignancies were HRD-positive. Of particular interest, combining molecular profiling with GI analysis, the assay identified additional actionable alterations in 65 % of the cases, revealing clinically relevant biomarkers beyond the homologous recombination pathway. This wide-ranging approach may provide more diagnostic and therapeutic insight than HRD testing alone. In conclusion, the 1021-HRD assay is a dependable, decentralized alternative for HRD testing. It can provide a more comprehensive genomic characterization and exhibits remarkable analytical concordance with current standards. Its combined format and accessibility render it well-suited for real-world use in personalized ovarian cancer care. Its additional capacity to reveal more extensive tumor genomic alterations improves clinical decision-making and underscores the importance of integrating HRD scoring with comprehensive molecular profiling in personalized oncology.