Despite growing efforts to understand how rurality impacts cancer outcomes, significant gaps remain in understanding its prognostic influence and its interaction with race in patients with gastric adenocarcinoma (GA).

This study aimed to assess the predictive value of CT-FFR on survival in patients with esophageal carcinoma (EC) after esophagectomy.

Many advanced-stage pancreatic cancers are fatal, highlighting the need for solid prognostic indicators. This study evaluates transferrin receptor-1 (TfR1) expression in pancreatic cancer tissues and cell lines for clinical and therapeutic potential.

Lung metastasectomy has been considered the cornerstone of treatment of resectable colorectal cancer pulmonary oligometastases (CRCPOM). However, the role of chemotherapy in the neoadjuvant setting remains unclear. This study aimed to determine whether neoadjuvant therapy (NAT) could further improve survival outcomes of patients with resectable CRCPOM.

Endoscopic submucosal dissection (ESD) is a minimally invasive technique used to treat gastrointestinal neoplasms. Lower incidence of gastric lesions results in fewer studies of gastric ESD in the West. We aimed to show the safety and efficacy of gastric ESD in a non-academic center as compared to the available studies, while adhering to established international guidelines.

Cancer progression is often accompanied by epigenetic silencing of tumor-suppressor microRNAs such asmiR-200c, a key regulator of epithelial-to-mesenchymal transition (EMT) and metastasis. Given the reversible nature of DNA methylation, we employed a CRISPR/dCas9-TET1 system to target the miR-200c promoter and restore its expression in MCF-7 and MDA-MB-231 breast cancer cell lines. Two gRNAs were designed to flank CpG-rich regions of the miR-200c promoter, and their individual or combined delivery enabled site-specific demethylation. Co-transfection with both gRNAs resulted in a synergistic increase in miR-200c expression, likely due to expanded coverage of dCas9-TET1 recruitment. This upregulation led to the downregulation of key EMT-related transcription factors ZEB1, ZEB2, and the oncogene KRAS, as well as increased E-cadherin expression in MDA-MB-231 cells. However, E-cadherin changes in MCF-7 cells were minimal, highlighting the complex and context-dependent nature of epigenetic regulation. Functional assays further confirmed the anti-tumorigenic effects of miR-200c restoration, with reduced cell viability and increased apoptosis, effects more pronounced in MDA-MB-231 cells, which initially exhibited higher miR-200c promoter methylation. Collectively, our findings demonstrate that CRISPR/dCas9-TET1-mediated epigenetic editing effectively reactivates miR-200c, reverses EMT-associated gene expression, and impairs tumor cell aggressiveness, supporting its potential as a targeted therapeutic strategy in breast cancer.

Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor. Current therapies (temozolomide/radiotherapy) often encounter resistance, necessitating novel molecular targets. Bioinformatics analysis was performed for the data obtained from TCGA, COSMIC, cbioPortal, and MethSurv databases. Tools such as GO, KEGG, GSEA, ROC, and protein-protein interactions (PPI) were employed to investigate the role that UPP1 has on GBM. The effects of UPP1 were further validated using RT-PCR and Western blotting(WB). UPP1 overexpression correlated with poor survival (P < 0.05) and immunosuppression, showing positive associations with immune infiltrates (Tregs, DCs, Th1/Th17 cells) and inflammation-related pathway activation. Silencing UPP1 suppressed proliferation (P < 0.001) in glioma cells. Several DNA methylation patterns of UPP1(8 CpG sites, e.g., cg07703017) were identified as having significant prognostic value. UPP1 drives immunosuppression and serves as a dual biomarker: expression levels stratify prognosis, while methylation profiles offer therapeutic insights. Its immunometabolic regulation positions UPP1 as a promising target for GBM precision therapy.

Head and neck cancers (HNC) are a group of heterogeneous tumors frequently associated with high-risk HPV or TP53 mutations. HPV-positive cancers are associated with a better prognosis, whereas TP53-mutated tumors are frequently more aggressive. Effective treatment for advanced-stage and metastatic disease is still unavailable. The role of innate immunity in cancer has not been fully explored, and Toll-like receptor 4 (TLR4) has been demonstrated to be an interesting molecular therapeutic target for several types of cancer. Here, we used four HNC cell lines with different molecular profiles, including mutations in TP53 and HPV infection, and evaluated the effect of the TLR4 pathway on tumorigenesis by modulating its activity via the agonist lipopolysaccharide (LPS) and the inhibitor TAK242. We showed that the induction of the TLR4 pathway increased proliferation in the SCC78 and SCC143 cell lines, whereas the inhibition of TLR4 decreased proliferation, colony formation capacity, and migration in all the cell lines studied. TLR4 inhibition reduced IL-6 mRNA expression in SCC78 and SCC143, and MKI67 in SCC78. Also, TAK242 downregulated p53 pathway in SCC78, a TP53 GOF mutation cell line. In combination with cisplatin, TAK242 demonstrated an additive effect, increased cisplatin sensitivity in SCC154, and altered the death mechanism induced by cisplatin in SCC78 cells. In conclusion, TLR4 inhibition led to antitumor effects independent of HPV infection status or TP53 status, suggesting that TLR4 may be a broad-spectrum target for HNC therapy.

Uterine fibroids, though benign in nature, are burdensome tumors of the myometrium and continue to weigh heavily on the landscape of women's health. They affect millions and yet receive a fraction of the therapeutic innovation afforded to malignant diseases. Despite their prevalence, the molecular underpinnings of fibroid pathogenesis have long been met with a blind eye in drug development. Recent insights, however, reveal G-protein-coupled receptor 10 (GPR10) as a central driver of fibroid growth, promoting cell survival through the PI3K/Akt and MAPK/ERK signaling pathways following REST repression. In this study, we present a rigorous, computationally guided approach to design small interfering RNAs (siRNAs) that silence GPR10 expression at the transcriptomic level. Beginning with a library of 275 siRNA candidates, we undertook a layered in-silico refinement process, combining thermodynamic assessment, secondary structure modeling and off-target filtration, to distill a shortlist of ten high-confidence molecules. These were subjected to structural docking against Argonaute 2, the catalytic engine of the RNA-induced silencing complex, revealing siRNA8 and siRNA12 as lead candidates distinguished by robust binding affinity, high predicted silencing efficacy, which was greater than 93.5%, and precise conformational fit. Subsequent molecular dynamics simulations under CHARMM-GUI/CHARMM36m force field, confirmed the structural stability and sustained silencing potential of the complex. Collectively, these findings identify GPR10 as a therapeutically actionable driver in fibroid biology and lay the groundwork for precision RNAi strategies targeting non-malignant, yet clinically neglected, hormone-dependent disorders.

Epithelial-to-mesenchymal transition (EMT) is a cellular process important for numerous developmental processes, wound healing and cancer progression. In the context of heterogenous nature of cancer, EMT occurs at the forefront of tumor invasion, although the precise molecular mechanisms governing its spatial dynamics remain unclear. This study aimed to explore the diverse responses to EMT in monolayer cell cultures of MCF10A epithelial cell with induction of Zinc-finger E-box binding homeobox 1 (ZEB1), an EMT-inducing transcription factor. ZEB1-induced MCF10A cells exhibited EMT in space- and cell density-dependent manner. The expression of ZEB1 was modulated by the ubiquitin-proteasome pathway. We found that CDK4/6 and USP51 enhanced ZEB1 protein stability via deubiquitination. Moreover, suppressing USP51 and CDK4/6 activity attenuated cell migration, a characteristic of the mesenchymal phenotype, in ZEB1-induced MCF10A cells. Finally, we demonstrated that CDK4/6 kinase activity is important for cell migration as well as stabilizing ZEB1 in the mesenchymal breast cancer cell line MDA-MB-231. These insights could pave the way for developing more targeted and effective therapies targeting at ZEB1 and EMT in advanced cancers.

The TLR4/NLRP3 inflammasome pathway drives lung cancer cell proliferation, migration, and invasiveness. However, no in vivo treatments targeting this pathway in lung cancer exist. Resveratrol, an anti-inflammatory compound, inhibits the NLRP3 inflammasome but requires high doses due to its hydrophobicity and instability. This study aimed to enhance the therapeutic efficacy of resveratrol by encapsulating it in liposomes to effectively target the TLR4/NLRP3 inflammasome pathway in lung cancer. In this study, the efficacy of resveratrol liposome was tested in vitro through cell proliferation and migration assays and gene expression analysis. In vivo effects were evaluated in a lung cancer mouse model using histological and molecular techniques. Resveratrol liposome significantly inhibited lung cancer cell proliferation and migration, and induced apoptosis in orthotopic lung cancer models. Additionally, by suppressing TLR4/NLRP3 inflammasome-related genes, resveratrol liposomes diminished levels of IL-1β and IL-18 both locally at tumor sites and systemically, thus modulating the tumor immune microenvironment by decreasing MDSCs and increasing CD4+ and CD8+ T cells. In conclusion, resveratrol liposome alleviates lung cancer progression by targeting the TLR4/NLRP3 inflammasome pathway and enhancing anti-tumor immune responses, highlighting its potential as a promising therapeutic strategy for lung cancer treatment.

Clinical trials demonstrate that screening can reduce lung cancer mortality by over 20%. However, lung cancer screening effectiveness (reduction in lung cancer specific mortality) may vary by personal risk-factors. Here we evaluate heterogeneity in lung cancer screening effectiveness through traditional sub-group analyses, predictive modelling approaches and machine-learning in individual-level data from the Dutch-Belgian lung cancer screening trial (NELSON; 14,808 participants, 12,429 men, 2377 women, 2 persons with an unknown sex) and the National Lung Screening Trial (NLST; 53,405 participants, 31,501 men, 21,904 women). We find that screening effectiveness varies by pack-years (screening effectiveness ranges across trials: lowest groups = 26.8-50.9%, highest groups = 5.5-9.5%), smoking status (screening effectiveness ranges across trials: former smokers = 37.8-39.1%, current smokers = 16.1-22.7%) and sex (screening effectiveness ranges across trials: women = 24.6-25.3%; men = 8.3-24.9%). Furthermore, screening effectiveness varies by histology (screening effectiveness ranges across trials: adenocarcinoma = 17.8-23.0%, other lung cancers = 24.5-35.5%, small-cell carcinoma = 9.7%-11.3%). Screening is ineffective for squamous-cell carcinoma in NLST (screening effectiveness = 27.9% (95% confidence interval: 69.8% increase to 4.5% decrease) mortality increase) but effective in NELSON (screening effectiveness = 52.2% (95% confidence interval: 25.7-69.1% decrease) mortality reduction). We find that variations in screening effectiveness across pack-years, smoking status, and sex are primarily explained by a greater prevalence of histologies with favourable screening effectiveness in these groups. Our study shows that heterogeneity in lung screening effectiveness is primarily driven by histology and that relaxing smoking-related screening eligibility criteria may enhance screening effectiveness.

Viral infections and cancers are driven by evolution of populations of highly mutable genomic variants. A key evolutionary process in these populations is their migration or spread via transmission or metastasis. Understanding this process is crucial for research, clinical practice, and public health, yet tracing spread pathways is challenging. Phylogenetics offers the main methodological framework for this problem, with challenges including determining the conditions when a phylogenetic tree reflects the underlying migration tree structure, and balancing computational efficiency, flexibility, and biological realism. We tackle these challenges using the powerful machinery of graph homomorphisms, a mathematical concept describing how one graph can be mapped onto another while preserving its structure. We focus on metastatic migrations and viral host-to-host transmissions in outbreak settings. We investigate how structural constraints on migration patterns influence the relationship between phylogenetic and migration trees and propose algorithms to evaluate trees consistency under varying conditions. Leveraging our findings, we introduce a framework for inferring transmission/migration trees by sampling potential solutions from a prior random tree distribution and identifying a subsample consistent with a given phylogeny. By varying the prior distribution, this approach generalizes several existing models, offering a versatile strategy applicable in diverse settings.

The unfolded protein response pathway is an evolutionarily conserved cytoprotective signaling cascade, essential for cell function and survival. Unfolded protein response signaling is tightly integrated with bone cell differentiation and function, and chronic unfolded protein response activation has been identified in bone disease. The unfolded protein response has been found to promote oncogenesis and drug resistance, raising the possibility that unfolded protein response modulators may have activity as anti-cancer agents. Cancer-associated bone disease remains a major cause of morbidity for patients with multiple myeloma or bone-metastatic disease. Understanding the critical role of unfolded protein response signaling in cancer development and metastasis, as well as its role in bone homeostasis, may lead to novel mechanisms by which to target cancer-associated bone disease. In this review, we summarize the current research delineating the roles of the unfolded protein response in bone biology and pathophysiology, and furthermore, review unfolded protein response modulating agents in the contexts of cancer and cancer-associated bone disease.

Osteosarcoma (OS), with a high tendency for recurrence and metastasis, is associated with severe impairment of bone regeneration. The inherent temperature-sensitive property of tumors positions magnetic hyperthermia (MH) as an increasingly significant area in non-pharmacological cancer treatments. However, the temperature threshold for tumor ablation often causes tissue damage and bone homeostasis imbalance. Therefore, development of moderate MH for OS, capable of achieving tumor ablation while concurrently restoring bone homeostasis, offers significant potential for addressing this challenge. This study integrates magnetothermal nanoparticles with defined temperature thresholds and borosilicate bioactive glass (BSG) to create an injectable magnetothermal bioactive system that allows for regulation of MH temperature. The ionic and alkaline microenvironment from BSG degradation primarily impairs the malignant behavior of OS cells by activating the TNF signaling pathway. This sickening effect diminishes the hyperthermia tolerance of OS cells, thereby boosting apoptosis of OS cells, even in the presence of the limited anti-tumor effects of moderate MH. Furthermore, the combination of moderate MH and BSG also promotes optimal bone formation by stimulating human bone marrow mesenchymal stem cells (hBMSCs) via calcium and JAK-STAT3 signaling pathways. Collectively, this flourishes the therapeutic approaches and theories for the prevention and management of clinically refractory bone tumors.

DDB1- and CUL4-associated factor 7 (DCAF7) has recently been identified as a critical regulator of tumorigenesis and a potential modulator of ferroptosis. However, the precise function of DCAF7 in regulating the progression of hepatocellular carcinoma (HCC) ferroptosis remains elusive. In this study, we demonstrate that DCAF7 and the deubiquitinase USP2 are highly expressed in HCC. Genetic ablation of DCAF7 or pharmacological inhibition of USP2 sensitizes HCC to ferroptosis and inhibits HCC progression both in vitro and in vivo. Mechanistically, DCAF7 recruits USP2 to inhibit clockophagy (the selective autophagic degradation of core clock protein BMAL1 mediated through p62/SQSTM1) by reducing BMAL1 K63-linked polyubiquitination. Targeting either DCAF7 or USP2 triggers clockophagy-induced ferroptosis through the HIF1α-SLC7A11 axis in HCC cells. Collectively, our study establishes DCAF7 and USP2 as novel suppressors of clockophagy-induced ferroptosis and reveals the potential therapeutic targets for HCC treatment.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death. Currently, molecular targeted therapy remains a crucial approach to the treatment of NSCLC. However, the development of acquired drug resistance poses significant challenges for subsequent treatment. Identifying new therapeutic targets is of great significance for improving the prognosis of patients with NSCLC. Here, we verify synoviolin-1 (SYVN1) as a potential new therapeutic target for NSCLC. SYVN1 is highly expressed in NSCLC, and its upregulation is associated with poor prognosis. We show that the N-terminus (1-290 aa) of SYVN1 directly interacts with the intracellular domain of the epidermal growth factor receptor (EGFR) and activates EGFR signaling, promoting NSCLC growth in vitro and in vivo. Specifically, SYVN1 facilitates Lys 63-linked ubiquitination of EGFR and inhibits proteasome-mediated EGFR degradation. Moreover, we found that SYVN1 inhibits EGFR endocytosis, thereby increasing the amount of EGFR on the cell membrane. Furthermore, we confirmed that LS-102, an enzyme activity inhibitor of SYVN1, inhibits cell proliferation induced by SYVN1. Significantly, LS-102 in combination with the EGFR-TKI AZD9291 exhibits strong inhibitory effects on NSCLC growth and reverses the resistance of NSCLC to AZD9291. Together, our study demonstrates that the SYVN1-EGFR axis plays a critical role in NSCLC development and suggests that targeting the SYVN1-EGFR axis to destabilize EGFR may represent a putative therapeutic strategy for TKI-resistant NSCLC.

ACTL6A, a subunit of the SWI/SNF and INO80 chromatin remodeling complexes, is frequently overexpressed in various cancers, and its depletion attenuates cell proliferation in colorectal cancer (CRC). However, the epigenetic mechanisms underlying ACTL6A function remain poorly understood. Here, we aimed to elucidate how ACTL6A regulates chromatin accessibility and gene expression in CRC. Integrated multi-omics analyses revealed that ACTL6A deficiency alters chromatin accessibility and upregulates P53 pathway-related genes, accompanied by the recruitment of SWI/SNF and INO80 complexes. Mechanistically, ACTL6A depletion enhances KLF4 binding at newly accessible regions, where it cooperates with these chromatin remodeling complexes to activate P53 pathway-related genes and induce apoptosis. ACTL6A contributes to CRC cell proliferation by inhibiting the KLF4-mediated transcriptional activation of tumor-suppressive genes. Thus, our findings highlight that targeting ACTL6A may serve as a promising therapeutic strategy in CRC.

Recognizing the predictive factors of response to chemoradiation is of utmost importance in patients with locally advanced rectal cancer (LARC). The study is designed to explore the correlation between post-neoadjuvant chemoradiation (nCRT) pathologic and MR-based tumor staging in LARC.

Postpartum placental choriocarcinoma is a rare gestational trophoblastic tumor, with an incidence of approximately one in 50 000. Patients often present with persistent postpartum hemorrhage, which can lead to delayed diagnosis, hematogenous metastasis, and ultimately, a poor prognosis.