Precise segmentation of brain tumors is essential for efficient diagnosis and therapy planning. While current automated methods frequently fail to capture complicated tumor shapes, traditional manual methods are laborious, subjective, and unpredictable. These issues are addressed by the suggested Attention-based Convolutional U-Net (ACU-Net) model, which incorporates attention processes into the U-Net architecture. The objective is to enhance the degree of precision and dependability of the tumor's edge delineation by proposing and testing the ACU-Net model-based brain tumor segmentation on MRI data. The research framework consists of data acquisition from the BraTS 2018 MRI data set. The first processing steps carried out in this study were the normalization of acquired data, spatial resolution, and augmentation of the obtained data. ACU-Net is a model developed with the use of attention gates and has been trained with dice and cross-entropy losses. Precision, recall, dice similarity coefficient (DSC), and intersection over union (IoU) are the performance measures used in the proposed ACU-Net and compared with the basic benchmark models, including U-Nets and convolutional neural networks (CNNs). The model of ACU-Net was shown to be most effective in brain tumor segmentation, and the dice scores were 94.04% for Whole Tumor (WT), 98. 63% for Tumor Core (TC) and 98.77% for Enhancing Tumor (ET). The proposed ACU-Net performed better than baseline models, showing the high capacity of the current approach to segment various classes of tumors. The model ACU-Net enhances brain tumor segmentation, acting as a reliable tool for clinical applications. These findings confirm that attention mechanisms improve the accuracy and robustness of medical image segmentation.

Targeting cancer cell plasticity through chromatin organization is an emerging research area, yet the molecular mechanisms that govern chromatin loop formation remain unclear. Here, we develop a CRISPR screen based on our engineered live-cell CTCF-cohesin contact reporters to identify regulators of chromatin loops. Our findings reveal that tousled-like kinase 2 (TLK2) functions as a key regulator of chromatin loop formation during the cancer stemness transition. Mechanistically, TLK2 phosphorylates DYNLL1, enhancing its interaction with CTCF to promote CTCF-cohesin hub formation at the KLF4 locus. Suppressing TLK2 impairs cancer stemness plasticity, sensitizes cancer cells to cytotoxic stress in vitro, and reduces lung metastases and enhances immunotherapy response in breast cancer mouse models. Clinically, elevated TLK2 expression correlates with poor prognosis in breast cancer patients. Collectively, these findings identify TLK2 as a potential therapeutic target for mitigating cancer stemness plasticity, highlighting chromatin loop-targeting therapy as a promising strategy to eradicate cancer stem cells.

Curcumin, a pharmacological agent found in turmeric's rhizome, has been studied for its various therapeutic properties. However, its clinical development is hindered by its instability and low solubility in water, resulting in inadequate oral bioavailability. Two potential curcumin analogs, 2,5-bis(4'-hydroxy-3',5'-dimethoxybenylidene)cyclopentanone (PGV-5) and 2,6-bis(4'-hydroxy-3',5'-dimethoxybenylidene)cyclohexanone (HGV-5), are being developed to address this issue and enhance their therapeutic efficacy. The study aims to screen novel curcumin analog compounds by integrating in silico assessment of ADME properties, acute toxicity studies, and computational analysis. PGV-5 and HGV-5 are classified as Global Harmonized System of Classification and Labeling of Chemicals (GHS) class 4 and class 5, respectively, in acute toxicity assessment, as they cause histopathological changes in the heart and lungs. Their ADME profile indicates they serve as effective P-glycoprotein (P-gp) inhibitors, making them potential candidates for development as anti-multidrug resistance agents, particularly in cancer cells. Molecular docking on P-gp revealed significant inhibitory capability relative to curcumin, exhibiting comparable binding characteristics to the native ligand, as evidenced by superior docking scores. Subsequent molecular dynamics simulations confirmed the stable interaction of both compounds with P-gp, with HGV-5 showing the most favorable binding free energy. Target gene mapping revealed several pivotal targets including AKT1, STAT3, EGFR, and NF-κB1. These findings suggest that PGV-5 and HGV-5 merit further research as agents against multidrug-resistant in cancer, regardless of their toxicity profiles. Further confirmation of their effects requires more laboratory studies and clinical trials.

Aberrant metabolic enzymes drive glucose metabolism reprogramming, which plays a crucial role in tumor malignancy and metastasis. Protein acetylation is one of the key regulatory mechanisms of metabolic enzyme function, yet its precise role requires further clarification. In the present study, we reported that the deacetylation and low expression of transaldolase 1 (TALDO1) mediated by HDAC6 weakened the inhibitory effect of TALDO1 on tumor proliferation and metastasis in nasopharyngeal carcinoma (NPC). Mechanistically, highly expressed HDAC6 induced lysine 7 (K7) deacetylation of TALDO1, which could inhibit SMURF1-mediated K63-linked ubiquitination, thus reducing the protein stability of TALDO1. Notably, TALDO1 deacetylation inhibited its nuclear translocation and interaction with BRCA1, thereby reducing the inhibition of c-Myc transcriptional activation, promoting the expression of HK2/LDHA/PDK1, and further enhancing glycolysis independent of TALDO1 enzyme activity. This research elucidated the regulatory mechanism of TALDO1 from the perspective of acetylation modification, clarified the moonlighting functions of TALDO1 in metabolic reprogramming, and provided novel biomarkers and intervention strategies, such as HDAC inhibitors, for the clinical treatment of NPC.

Radiation resistance in glioblastoma (GBM) poses a persistent clinical hurdle, driven in part by hyperactivated EGFR and NF-κB signaling. To recapitulate post-radiation tumor recurrence, we engineered radioresistant glioblastoma stem cells (GSCs) from U87-derived GSCs via 13 cycles of 5Gy irradiation (IR), yielding differentiated radioresistant progeny cells (Diff) that mimic the aggressive phenotype of recurrent GBM. Integrative analysis of RNA sequencing data from parental U87 cells, GSCs, and Diff cells-along with the TCGA database-identified coordinated EGFR and NF-κB (RelA/p65) signaling as central mediators of therapeutic resistance. Leveraging this insight, we designed iRGD-modified liposomes (iRGD-OB-LP) for targeted co-delivery of Osimertinib (EGFR inhibitor) and Bortezomib (NF-κB suppressor). These liposomes exhibited enhanced tumor penetration, sustained release kinetics, and dual pathway inhibition, which collectively prolonged radiation-induced DNA damage, attenuated cancer stemness, and amplified apoptotic cell death. In vivo, iRGD-OB-LP achieved tumor-specific biodistribution, synergized with radiotherapy to suppress tumor progression, and extended survival without systemic toxicity. By bridging a radioresistant GBM model with mechanism-driven nanotherapy, this work provides a translatable blueprint for dismantling therapeutic resistance in GBM through precision multi-targeting.

The ubiquitin-proteasome system plays a crucial role in neuroblastoma progression, yet the regulation of key degradation targets remains incompletely understood. By integrating transcriptomic and proteomic data, we identified nine candidate proteins, including CELF6, whose degradation is potentially mediated by ubiquitination. Survival analyses revealed that high CELF6 expression correlated with a favorable prognosis. Functional assays demonstrated that CELF6 suppresses neuroblastoma cell proliferation without affecting apoptosis. Mechanistically, the E3 ubiquitin ligase MDM2 directly interacts with CELF6, promoting its degradation via K48-linked ubiquitination. MDM2 overexpression accelerates CELF6 degradation, while its inhibition stabilizes CELF6 protein levels, an effect reversed by proteasome inhibitors. Furthermore, MDM2-driven neuroblastoma cell proliferation is dependent on CELF6 depletion. These findings establish MDM2 as a key regulator of CELF6 stability and highlight the MDM2-CELF6 axis as a potential therapeutic target in neuroblastoma.

The regulatory mechanisms governing transcriptional programs in the cancer genome remain elusive, particularly those concerning cell-type specificity. We carefully curated single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) data from eight distinct carcinoma tissues, including breast, skin, colon, endometrium, lung, ovary, liver, and kidney. Using single-cell multi-omics analysis, we identified extensive open chromatin regions and constructed peak-gene link networks, which can reveal distinct cancer gene regulation and genetic risks. We further explored conserved epigenetic regulation across cell types within cancer and elucidated their functional implications. Moreover, we identified cell-type-associated transcription factors (TFs) that regulate key cellular functions, such as the TEAD family of TFs, which widely control cancer-related signaling pathways in tumor cells. In colon cancer, we further identified tumor-specific TFs that are more highly activated in tumor cells than in normal epithelial cells, including CEBPG, LEF1, SOX4, TCF7, and TEAD4, which are pivotal in driving malignant transcriptional programs and represent potential therapeutic targets, as corroborated by single-cell sequencing data from multiple sources and in vitro experiments. Our findings provide a comprehensive understanding of the regulatory dynamics underlying carcinomas and offer valuable insights into potential therapeutic interventions.

Radiotherapy (RT) is a crucial treatment for hepatocellular carcinoma (HCC); however, resistance to radiation remains a major challenge to its effectiveness. Circular RNAs (circRNAs), traditionally considered stable non-coding RNAs, have recently gained attention for their potential to encode proteins or peptides that play crucial roles in HCC radioresistance. In this study, circSNX25 (has_circ_0004874) was identified as a novel circRNA with coding potential related to radiation resistance in HCC through circRNA sequencing, Northern blotting, and mass spectrometry (MS). We demonstrated that SNX25-215, a novel protein encoded by circSNX25, rather than the parental circSNX25 itself, promotes resistance to radiotherapy in HCC cells both in vitro and in vivo. Co-immunoprecipitation (co-IP) and molecular docking revealed that amino acids H207 and E214 of SNX25-215 are critical for binding to Golgi to ER traffic protein 4 homolog (GET4). This interaction inhibits the binding of BCL2-associated athanogene 6 (BAG6) to GET4, thereby exposing the nuclear localization sequence (NLS) of BAG6 and facilitating its nuclear translocation. This, in turn, enhances DNA damage repair, ultimately increasing resistance to ionizing radiation (IR) in HCC cells. Importantly, elevated levels of SNX25-215 lead to nuclear localization of BAG6, endowing HCC cells with radioresistant activity, which is further supported by clinical evidence. Our findings highlight the potential of circSNX25 as a prognostic biomarker and a therapeutic target for overcoming radioresistance in HCC. This study provides deeper insights into the roles that circRNA-encoded proteins play in HCC radioresistance.

Replication protein A1 (RPA1) is a crucial regulator of homologous recombination (HR) repair and DNA end resection. Studies have demonstrated that the expression and activity of RPA1 are regulated through posttranslational modifications. However, the exact molecular mechanism through which RPA1 activity is regulated remains unclear. Here, we discovered that RNF213 interacts directly with and ubiquitinates RPA1, thereby inhibiting HR repair and DNA end resection. Furthermore, RNF213 is phosphorylated by ATM at Ser217 following DNA damage, which increases the catalytic activity of RNF213. In addition, RNF213 overexpression sensitizes triple-negative breast cancer (TNBC) cells to PARP inhibitor (PARPi) treatment in an RPA1-dependent manner both in vitro and in vivo. Taken together, our findings reveal that RNF213 modulates the response of TNBC cells to PARPi treatment by regulating the ubiquitination of RPA1 and inhibiting HR repair.

Most clinicians have limited experience with rare diseases, making diagnosis and treatment challenging. Large real-world data sources, such as electronic health records (EHRs), provide a massive amount of information that can potentially be leveraged to determine the patterns of diagnoses and treatments for rare tumors that can serve as clinical decision aids.

We aimed to discover signature disease trajectories of 3 rare cancer types: pancreatic cancer, STS of the trunk and extremity (STS-TE), and STS of the abdomen and retroperitoneum (STS-AR).

Leveraging IQVIA Oncology Electronic Medical Record, we identified significant diagnosis pairs across 3 years in patients with these cancers through matched cohort sampling, statistical computation, right-tailed binomial hypothesis test, and then visualized trajectories up to 3 progressions. We further conducted systematic validation for the discovered trajectories with the UTHealth Electronic Health Records (EHR).

Results included 266 significant diagnosis pairs for pancreatic cancer, 130 for STS-TE, and 118 for STS-AR. We further found 44 2-hop (i.e., 2-progression) and 136 3-hop trajectories before pancreatic cancer, 36 2-hop and 37 3-hop trajectories before STS-TE, and 17 2-hop and 5 3-hop trajectories before STS-AR. Meanwhile, we found 54 2-hop and 129 3-hop trajectories following pancreatic cancer, 11 2-hop and 17 3-hop trajectories following STS-TE, 5 2-hop and 0 3-hop trajectories following STS-AR. For example, pain in joint and gastro-oesophageal reflux disease occurred before pancreatic cancer in 64 (0.5%) patients, pain in joint and "pain in limb, hand, foot, fingers and toes" occurred before STS-TE in 40 (0.9%) patients, agranulocytosis secondary to cancer chemotherapy and neoplasm related pain occurred after pancreatic cancer in 256 (1.9%) patients. Systematic validation using the UTHealth EHR confirmed the validity of the discovered trajectories.

We identified signature disease trajectories for the studied rare cancers by leveraging large-scale EHR data and trajectory mining approaches. These disease trajectories could serve as potential resources for clinicians to deepen their understanding of the temporal progression of conditions preceding and following these rare cancers, further informing patient-care decisions.