Lung squamous cell carcinoma (LUSC) is a major subtype of non-small cell lung cancer (NSCLC) with limited therapeutic targets and poor prognosis. Zinc finger CCHC-type RNA-binding protein 1 (ZCRB1) has been implicated in RNA metabolism, yet its role in LUSC remains largely unexplored. In this study, we found that ZCRB1 was significantly overexpressed in NSCLC tissues, particularly in LUSC, and high ZCRB1 expression was associated with poorer overall and disease-free survival. ZCRB1 knockdown markedly suppressed LUSC cell proliferation, migration, and invasion in vitro and inhibited tumor growth and pulmonary metastasis in vivo. Bioinformatic and experimental analyses identified DSG3 as a key downstream target positively correlated with ZCRB1 expression in LUSC tissues. Mechanistically, ZCRB1 directly bound to DSG3 mRNA and enhanced its stability. Importantly, DSG3 overexpression partially reversed the inhibitory effects of ZCRB1 knockdown on LUSC cell malignant phenotypes both in vitro and in vivo. In conclusion, ZCRB1 functions as an oncogenic RNA-binding protein in LUSC by promoting tumor growth and metastasis through stabilization of DSG3 mRNA. Targeting the ZCRB1-DSG3 axis may represent a novel therapeutic strategy for lung squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy characterized by dismal outcomes, but its molecular pathogenesis remains incompletely understood. To uncover critical driver genes in ESCC, we conducted a functional screen using a CRISPR/Cas9 sgRNA library targeting 406 copy-number alteration (CNA)-related genes. Among the candidates, gap junction protein beta 6 (GJB6), a major connexin family member, emerged as a tumor suppressor that inhibits malignant phenotypes. Clinically, reduced GJB6 expression significantly correlates with ESCC development and predicts unfavorable outcomes. Mechanistically, we delineated a reciprocal regulation between GJB6 and its downstream gene GRHL3: GJB6 enhances GRHL3 expression via Ca²⁺-dependent signaling, while GRHL3 transcriptionally upregulates GJB6, thereby forming a positive feedback circuit to exert their tumor-suppressive functions. Disruption of the GJB6/GRHL3 reciprocal regulatory axis activates AKT signaling, thereby driving ESCC pathogenesis. Notably, the oncogenic effects of GJB6 ablation could be pharmacologically reversed by the AKT inhibitor capivasertib, suggesting a potential therapeutic strategy for GJB6-deficient ESCC patients. Collectively, our findings establish GJB6 as both a critical suppressor and a clinically actionable prognostic biomarker, highlighting the potential of drug repurposing approaches for ESCC treatment.

The STING pathway holds immunotherapeutic promise but faces challenges in tumor-specific delivery and systemic toxicity. A lung-targeting peptide (APWHLSAQYSRT)-modified lipid nanoparticle (LNP) system (LT-STING-LNPs) is developed to deliver STING mRNA for non-small cell lung cancer (NSCLC) treatment. These spherical, stable LNPs exhibited high mRNA encapsulation efficiency. In vitro, LT-STING-LNPs induced potent STING overexpression in lung cells, inhibiting NSCLC cell proliferation, migration, and invasion. In vivo, LNPs demonstrated superior lung tropism, enabling targeted STING activation in pulmonary tissue without systemic distribution. In murine lung metastasis models, treatment drastically reduced metastatic burden, suppressed tumor proliferation (Ki-67), and inhibited epithelial-mesenchymal transition (Vimentin). Notably, the platform shows excellent safety with no organ toxicity. LT-STING-LNPs synergized robustly with anti-PD1 therapy, achieving near-complete metastasis inhibition. Mechanistically, this is driven by STING-TBK1-IRF3 signaling activation, inflammatory cytokine (IFN-α, IL-1β, CXCL10) production, and immune microenvironment remodeling, including increased CD8+ T cell and M1 macrophage infiltration. This targeted, safe, and highly effective immunotherapy strategy represents a promising advancement for NSCLC, leveraging synergistic STING pathway activation and immune checkpoint blockade.

Long non-coding RNAs (lncRNAs) have emerged as crucial regulators of cancer development and progression. Among them, Differentiation Antagonizing Non-Protein Coding RNA (DANCR) has been implicated in various malignancies, including esophageal squamous cell carcinoma (ESCC). This study explores the clinical characteristics, prognostic implications, functional roles, and molecular mechanisms of DANCR in ESCC. Our results demonstrate that DANCR is highly expressed in ESCC, and acts as an oncogene in ESCC both in vitro and in vivo. Through bioinformatics analysis and experimental validation, we revealed that DANCR promotes ESCC progression by sponging miR-3193 and regulating its target gene DDIT3 expression. These findings highlight the critical role of DANCR in the development of ESCC and suggest its potential as a prognostic predictor and drug therapeutic target.

Interstitial cystitis/bladder pain syndrome (IC/BPS) plagues patients and clinicians with its unclear etiology and pathogenesis, and ineffective treatments. Destruction of epithelial tissue and proliferation of interstitial tissue are typical pathological features of IC/BPS, in which epithelial-mesenchymal transition (EMT) may play an important role. Both the increased urination frequency observed in mice with acute cystitis induced by cyclophosphamide (CYP) and the disruption of the anti-leakage barrier in urothelial cells induced by LPS are associated with the occurrence of EMT. The expression of heparanase 1 (HPSE) and syndecan-2 (SDC-2) is up-regulated in the bladder mucosa of patients with IC, and both of them can promote the development of EMT. Improvement of lower urinary tract symptoms and restoration of the uroepithelial cell anti-leakage barrier in mice with CYP-induced cystitis after treatment with the HPSE inhibitor OGT2115 and inhibited the development of EMT. We then verified that HPSE binds to SDC-2 and that SDC-2 is a key intermediate protein in the pro-EMT role of HPSE, and that EMT was inhibited by knockdown of SDC-2. SDC-2 exerts its biological function by inhibiting the ubiquitinated degradation of TGF-βR1. Here we identified a novel mechanism by which the HPSE/ SDC-2 axis promotes EMT development and thus causes epithelial dysfunction and altered voiding behavior, providing a new direction for the treatment of IC/BPS.

Esophageal cancer (ESCA) is a lethal malignancy with limited therapeutic options and poor survival outcomes. Here, we identify RBM39 as a novel oncoprotein that drives ESCA progression through post-transcriptional stabilization of Fanconi anemia, complementation group D2 (FANCD2) mRNA. RNA-binding motif protein 39 (RBM39) is significantly upregulated in ESCA tissues and cell lines, and its high expression correlates with poor overall survival (OS) and disease-free survival (DFS) in clinical cohorts. Functional studies demonstrate that RBM39 knockdown suppresses proliferation, migration, and invasion in ESCA cells (TE-1, TE-12) in vitro and impairs tumor growth and pulmonary metastasis in xenograft models. Mechanistically, RBM39 directly binds the 3' untranslated regions (3'-UTR) of FANCD2 mRNA (validated by RIP-qPCR and motif mutagenesis), extending its half-life (actinomycin D assay). ESCA transcriptomic profiling of TCGA database links RBM39 to the Fanconi anemia DNA repair pathway, with FANCD2 as its top target. Critically, FANCD2 overexpression rescues oncogenic phenotypes upon RBM39 silencing, restoring tumorigenesis in vivo. These findings establish the RBM39-FANCD2 axis as a therapeutic vulnerability, where targeting the RBM39-FANCD2 axis may offer a promising therapeutic strategy for the ESCA clinical treatment.

Lung adenocarcinoma (LUAD), the predominant subtype of lung cancer, has a high incidence and annual mortality worldwide. Members of the cadherin-related (CDHR) family are associated with many malignant tumor types. However, their role and clinical significance in LUAD have not been clarified. We analyzed the association of CDHRs mRNA expression profiles with prognostic significance, immune infiltration, and potential biological functional signatures in several public databases. We constructed a co-expressed mRNA network, and performed an intrinsic molecular structure and function enrichment analysis. Our results showed that CDHR2 mRNA expression was upregulated in LUAD, whereas CDHR1, CDHR3, CDHR4, and CDHR5 mRNAs were downregulated. Upregulation of CDHR2 mRNA is associated with a poor prognosis in patients with LUAD. Next, the correlation between CDHR family members and immune infiltration was observed. A receiver operating characteristic curve showed that the CDHR family is valuable for diagnosing LUAD. In this study, we found that CDHR2 mRNA expression was upregulated in LUAD. Upregulation of CDHR2 mRNA was associated with a poor prognosis in patients with LUAD.

Background and aims The treatment of esophageal squamous cell carcinoma is still controversial, and neoadjuvant chemotherapy combined with immunotherapy is a hot topic of current research. We investigated the recent efficacy and surgical safety of patients with III–IVA esophageal squamous cell carcinoma after neoadjuvant regimen of paclitaxel + cisplatin/nedaplatin/carboplatin + sindilizumab, to provide a theoretical basis for evaluating the feasibility of surgery after neoadjuvant therapy. Methods The clinical data of patients with stage III–IVA esophageal squamous cell carcinoma admitted from January 2022 to April 2023 at our hospital were collected for retrospective analysis. The patients were divided into the neoadjuvant combination surgery group (34 patients with the regimen of paclitaxel + cisplatin/nedaplatin/carboplatin + sintilimab two/three cycles of preoperative neoadjuvant therapy) and surgery-only group (36 patients). Statistical analysis was performed to compare the differences between both groups particularly for intraoperative bleeding, operative time, incidence of postoperative pulmonary complications, laryngeal recurrent nerve injury, thoracic duct injury, anastomotic fistula, and postoperative hospital days. Additionally, the pCR/MPR rates of the neoadjuvant group were analysed. Results Significant differences were present in the clinical and pathological staging before and after neoadjuvant treatment ( P ≤ 0.001). The neoadjuvant group had a pCR rate of 26.47% and an ORR rate of 88.23%. No significant differences were discovered in R0 resection rate between both groups, as well as intraoperative bleeding, operative time, intraoperative laryngeal recurrent nerve injury rate, thoracic duct injury rate, postoperative anastomosis incidence, postoperative hospital days, and postoperative lung infection incidence ( P > 0.05). Conclusions The neoadjuvant immune combination chemotherapy regimen had considerable tumor regression and pathological remission benefits, without reducing the safety of surgery, possibly presenting as a new treatment plan.

Non-small cell lung cancer (NSCLC) is a prevalent form of lung cancer. Patients with advanced NSCLC are currently being treated with various therapies, including traditional radiotherapy, chemotherapy, molecular targeted therapies and immunotherapy. However, a considerable proportion of advance patients who cannot benefit from them. Consequently, it is essential to identify a novel research target that offers an encouraging perspective. The stimulator of interferon genes (STING) has emerged as such a target. At present, it is confirmed that activating STING in NSCLC tumor cells can impede the proliferation and metastasis of dormant tumor cells. This review focuses on the role of STING in NSCLC treatment and the factors influencing its activation. Additionally, it explores the correlation between STING activation and diverse therapy modalities for NSCLC, such as radiotherapy, chemotherapy, molecular targeted therapies and immunotherapy. Furthermore, it proposes the prospect of innovative therapy methods involving nanoparticles, with the aim of using the features of STING to develop more strategies for NSCLC therapy.

ObjectivesTo synthesize qualitative evidence on the experience of lay responders performing cardiopulmonary resuscitation (CPR).MethodsQualitative evidence synthesis was performed using the Thomas and Harden method. The PubMed, Cochrane Library, Web of Science, OVID Medline, Embase, CINAHL, CNKI, and WanFang databases were systematically searched. The quality of the research was assessed by the Critical Assessment Skills Program Tool (CASP).ResultsA total of 5,610 studies were identified, and 9 studies were included in the analysis. Four analytical themes were generated: emotional ambivalence before CPR, psychological tolerance during CPR, perceived experience after CPR, and enhancing psychological resilience.ConclusionLay responders face complicated psychological experience during CPR, which may be susceptible to psychological effects such as “loss aversion,” “bystander effects” and “knowledge curse.” In addition to the timely retraining of CPR, lay responders should be instructed to manage psychological distress and improve psychological resilience. More importantly, the psychological sequelae may be long-lasting, requiring ongoing psychological intervention and follow-up based on valuing transdisciplinarity across endeavours.

Prostate cancer (PCa) is a common malignancy in elderly men. We have applied Traditional Chinese Medicine CFF-1 in clinical treatments for PCa for several years. Here, we aimed to identify the underlying mechanism of CFF-1 on PCa using network pharmacology and experimental validation. Active ingredients, potential targets of CFF-1 were acquired from the public databases. Subsequently, protein-protein interaction (PPI) and the herbs-active ingredients-target network was constructed. A prognostic model for PCa was also constructed based on key targets. In vitro experiments using PCa cell lines CWR22Rv1 and PC-3 were carried out to validate the potential mechanism of CFF-1 on PCa. A total of 112 bioactive compounds and 359 key targets were screened from public databases. PPI and herbs-active ingredients-target network analysis determined 12 genes as the main targets of CFF-1 on PCa. Molecular docking studies indicated that the primary active ingredients of CFF-1 possess strong binding affinity to the top five hub targets. DNMT3B, RXRB and HPRT1 were found to be involved in immune regulation of PCa. In vitro, CFF-1 was found to inhibit PCa cell proliferation, migration, invasion and induce apoptosis via PI3K-Akt, HIF-1, TNF, EGFR-TKI resistance and PD-1 checkpoint signaling pathways. This study comprehensively elucidates the underlying molecular mechanism of CFF-1 against PCa, offering a strong rationale for clinical application of CFF-1 in PCa treatment.

PURPOSE Prehabilitation, which is the process of enhancing functional capacity before undergoing surgery or other treatments, has been shown to improve cancer patients' outcomes. Patient and healthcare provider attitudes and perceptions are essential factors in the successful implementation of prehabilitation. The purpose of this systematic review is to synthesize qualitative evidence and explore the barriers and facilitators to prehabilitation implementation. METHODS From the earliest available date to October 2023, 7 databases (PubMed, Web of Science, Cochrane Library, Embase, CINAHL, PsycINFO, and MEDLINE) were searched for a systematic review. Data were extracted, thematically analysed, and mapped onto the Capability, Opportunity, and Motivation Model of Behaviour (COM-B). The Critical Appraisal Skills Programme (CASP) tool was used to assess the quality of the studies. RESULTS A total of 26 studies were included, involving 377 patients, 51 caregivers, and 156 healthcare providers. 16 factors were identified and mapped onto the COM-B model: reflective/automatic motivation, physical/social opportunity, physical/ psychological capability. CONCLUSIONS Patients and healthcare provides identified a lack of reflective motivation and physical opportunities as the most significant barriers to engagement in prehabilitation. Personalized approaches, social support, and healthcare providers' engagement are key factors for prehabilitation. Future research should focus on developing effective interventions to enhance the uptake and sustainability of prehabilitation.

e14626 Background: More and more studies focus on the neoadjuvant chemotherapy combined with immunotherapy (chemo-immunotherapy) in resectable esophageal squamous carcinoma (ESCC). Herein, we aimed to evaluate the efficacy and safety of neoadjuvant programmed cell death protein 1 inhibitors with chemotherapy and explore tumor microenvironment (TME) profiles. Methods: Patients with previously untreated, resectable, stage III ESCC in the third affiliated hospital of Soochow University were enrolled. Each patient received two-four cycles of neoadjuvant chemo-immunotherapy before surgical resection. The TME profiles of formalin-fixed paraffin-embedded tumor samples at baseline were evaluated by multiplex immunofluorescence to discover novel biomarkers of response to neoadjuvant chemo-immunotherapy. Results: Twenty patients were included, all of whom underwent R0 resection. 85% (17/20) of patients underwent 2 cycles of neoadjuvant therapy. TP53 (13/20,65%) was were high-frequency mutated gene, followed by CDKN2A (5/20,25.0%) and PIK3CA (3/20, 15.0%). PD-L1 positive (TPS≥1%) was found in only 3 patients. Postoperative pathological evaluation showed that 18 patients (90.0%) were major pathologic response (MPR), of which 5 patients (28.0%) achieved pathological complete response (pCR). Neoadjuvant therapy has acceptable side effects. TME profiles at baseline showed no significant correlation between PD-L1 and pathological response. The density of Treg cell in the tumor area was significantly lower in pCR patients than in MPR patients (P=0.0302). Conclusions: Neoadjuvant chemo-immunotherapy was well tolerated and was effective therapy for resectable ESCC. Treg cells may serve as potential predictive biomarkers.

Triple-negative breast cancer (TNBC) is the most lethal and aggressive subtype of breast cancer, and chemoresistance is the major determinant of TNBC treatment failure. This study explores the molecular mechanism of TNBC chemoresistance. The Cancer Genome Atlas, breast cancer integrative platform, and GEPIA databases were used to analyze the expression and correlation of YTHDF1 and seven in absentia homology 2 (SIAH2) in breast cancer. Knockdown of YTHDF1 and SIAH2, or overexpression of SIAH2 in vitro and in vivo, was conducted to evaluate the impact of changes in YTHDF1 and SIAH2 expression on TNBC cell proliferation, apoptosis, stemness, drug resistance, and Hippo pathway gene expression. YTHDF1 and SIAH2 were highly expressed in breast cancer patients and TNBC cells. Knockdown of YTHDF1 and SIAH2 significantly inhibited proliferation and stemness and promoted apoptosis and chemosensitivity of TNBC cells. Mechanistically, the knockdown of YTHDF1 inhibited the expression of SIAH2, thereby downregulating the Hippo pathway, which inhibited proliferation and stemness and promoted apoptosis and chemosensitivity of TNBC cells. The current findings revealed the regulatory mechanism of YTHDF1 in TNBC and clarified the role of the YTHDF1/SIAH2 axis in TNBC drug resistance and stemness. This could provide new insights into the vital role of targeting YTHDF1/SIAH2 to suppress drug resistance and stemness in TNBC cells.

Immunotherapy has revolutionized the treatment landscape of advanced cancer including stage IV small cell lung cancer (SCLC). But few data on stage IV SCLC patients to systemic therapy achieving a clinical downstaging have been reported. The purpose of this study was to evaluate the clinical response and safety of stage IV SCLC patients after treatment with tislelizumab combined with chemotherapy.

Background:Immunotherapy has become the first-line treatment for advanced non-small-cell lung cancer (NSCLC), but most patients still fail to benefit or have disease progression following treatment. M2 phenotype tumor-associated macrophages (M2-TAMs) are important cellular components in the immunosuppressive microenvironment of NSCLC, but how they contribute to immunoresistance remains unclear. This study was conducted to investigate the role and mechanism of M2-TAMs in NSCLC immunoresistance. Methods:We collected postoperative tumor samples for detection of M2-TAMs and other immune cells infiltration by immunofluorescence detection and flow cytometry. We then constructed a non-contact cell co-culture system using Transwell chambers. CCK-8, colony formation, wound healing and invasion assays were performed to evaluated the effect of M2-TAMs on the proliferation, migration and invasion abilities of lung adenocarcinoma (LUAD) cells in vitro. Xenograft model were performed to analysis the effect of M2-TAMs on the tumorigenesis and metastasis of LUAD cells in vivo. Results:M2-TAMs were greatly increased in the tumor tissue of patients with immunoresistant LUAD. They could significantly promote the proliferation, invasion, and migration of LUAD cells, and improve their resistance to cytotoxic T lymphocytes (CTL) cytotoxicity. Further research showed M2-TAMs could considerably enhance the expression of METTL3 and total m6A RNA level in LUAD cells and interfering with METTL3 could significantly reverse the impairment of M2-TAMs on the efficacy of CTL in killing tumor cells. Conclusions:In conclusion, M2-TAMs could promote LUAD immunoresistance by enhancing METTL3-mediated m6A methylation. Our results suggest METTL3 could be a potential therapeutic target for reversing immunoresistance and shed new light on the mechanism of M2-TAMs promoting LUAD immunoresistance.

Background Targeted therapy has revolutionized the treatment of patients with malignancies harboring mutations in driver genes and has brought a favorable survival benefit to the population with actionable oncogenic mutations. In recent years, the MET exon14 skipping mutation has been recognized as a potentially promising therapeutic target in non-small cell lung cancer (NSCLC). These changes are mutually exclusive with molecular drivers such as EGFR, KRAS, HER-2 , BRAF, ALK and ROS1 . The prevalence rate of coexisting MET exon 14 mutations and EGFR sensitive mutations (L858R, exon 19 deletions) in Chinese population was reported to be 0.2% (3/1590). However, the coexistence of MET exon 14 mutations with EGFR exon 20 insertion mutations has never been reported and the management of this subtype is not identified. Case presentation A 69-year-old male with a right lung adenocarcinoma (T4N2M0, IIIB) was confirmed to be positive for MET exon 14 skipping (c.3028_3028+1delGGinsTT, 44.4%), MET amplification (copy number 4.4), and EGFR exon 20 insertion (p. N771_H773dup, 22.1%) mutations. After the progression of one cycle of chemotherapy (Pemetrexed 0.8 g d1), the patient was subsequently accepted treatment with Crizotinib (250 mg twice a day) and achieved an important clinical remission for six months until the development of brain metastases. Then, he was submitted to a cycle of anti-programmed cell death-1 (PD-1) therapy after failure of Crizotinib and eventually acquired resistance despite of the high expression of programmed death ligand-1 (PD-L1) and tumor mutational burden (TMB) status. Conclusion This case report provides treatment strategies for epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)-untreated lung adenocarcinoma patients simultaneously carrying MET alterations and EGFR exon 20 insertion mutations. In addition, the signatures of PD-L1 or TMB expression were not the candidate for predicting the efficacy of immunotherapy in this context.

Palbociclib is the first CDK4/6 inhibitor approved by FDA and has been studied in many types of cancer. However, some studies showed that it could induce epithelial-mesenchymal transition (EMT) of cancer cells. To test the effect of palbociclib on non-small-cell lung cancer (NSCLC) cells, we treated NSCLC cells with different concentrations of palbociclib and detected its effects via MTT, migration and invasion assays, and apoptosis test. Further RNA sequencing was performed in the cells treated with 2 μM palbociclib or control. And Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and protein-protein interaction network (PPI) were analyzed to explore the mechanism of palbociclib. The results showed that palbociclib significantly inhibited the growth of NSCLC cells and promoted apoptosis of cells, however, enhanced the migration and invasion abilities of cancer cells. RNA sequencing showed that cell cycle, inflammation-/immunity-related signaling, cytokine-cytokine receptor interaction, and cell senescence pathways were involved in the process, and CCL5 was one of the significantly differential genes affected by palbociclib. Further experiments showed that blocking CCL5-related pathways could reverse the malignant phenotype induced by palbociclib. Our results revealed that palbociclib-induced invasion and migration might be due to senescence-associated secretory phenotype (SASP) rather than EMT and suggested that SASP could act as a potential target to potentiate the antitumor effects of palbociclib in cancer treatment.

Lung adenocarcinoma (LUAD) is a major subtype of non-small-cell lung cancer, which is the leading cause of cancer death worldwide. The histone H3K36 methyltransferase SETD2 has been reported to be frequently mutated or deleted in types of human cancer. However, the functions of SETD2 in tumor growth and metastasis in LUAD has not been well illustrated. Here, we found that SETD2 was significantly downregulated in human lung cancer and greatly impaired proliferation, migration, and invasion in vitro and in vivo. Furthermore, we found that SETD2 overexpression significantly attenuated the epithelial-mesenchymal transition (EMT) of LUAD cells. RNA-seq analysis identified differentially expressed transcripts that showed an elevated level of interleukin 8 (IL-8) in STED2-knockdown LUAD cells, which was further verified using qPCR, western blot, and promoter luciferase report assay. Mechanically, SETD2-mediated H3K36me3 prevented assembly of Stat1 on the IL-8 promoter and contributed to the inhibition of tumorigenesis in LUAD. Our findings highlight the suppressive role of SETD2/H3K36me3 in cell proliferation, migration, invasion, and EMT during LUAD carcinogenesis, via regulation of the STAT1-IL-8 signaling pathway. Therefore, our studies on the molecular mechanism of SETD2 will advance our understanding of epigenetic dysregulation at LUAD progression.