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Leucine rich repeat containing 15 (LRRC15) is recognized for its intimate association with the extracellular matrix, where it modulates fibroblast function and shapes the immune landscape within the tumour microenvironment. The specific expression patterns and molecular contributions of LRRC15 in triple-negative breast cancer(TNBC) have not been fully elucidated. This study aimed to delineate the clinical relevance and biological implications of LRRC15 in TNBC, and to assess its potential as a novel therapeutic target for this disease. Our findings revealed robust overexpression of LRRC15 in TNBC tumour tissues and cell lines, which was inversely correlated with patient survival outcomes. Notably, the suppression of LRRC15 expression led to pronounced inhibition of TNBC cell proliferation, invasion, and migration both in vitro and in vivo. Mechanistically, we established that LRRC15 interacts with Integrin Beta 1(ITGB1), facilitating the phosphorylation of the T788/T789 residues on ITGB1 and recruiting focal adhesion kinase (FAK) to the site of integrin aggregation. This recruitment promotes the downstream phosphorylation of PI3K and AKT, suggesting that LRRC15 is a key activator of the ITGB1/FAK/PI3K signalling pathway. Collectively, our data indicate that LRRC15 is a critical promoter of TNBC cell proliferation and metastasis through the activation of this signalling pathway, identifying LRRC15 as a promising candidate for therapeutic intervention in TNBC.

Multi-functional DEAD-box helicase 5 (DDX5), which is important in transcriptional regulation, is hijacked by diverse viruses to facilitate viral replication. However, its regulatory effect in antiviral innate immunity remains unclear. We found that DDX5 interacts with the N 6 -methyladenosine (m6A) writer METTL3 to regulate methylation of mRNA through affecting the m6A writer METTL3–METTL14 heterodimer complex. Meanwhile, DDX5 promoted the m6A modification and nuclear export of transcripts DHX58, p65, and IKKγ by binding conserved UGCUGCAG element in innate response after viral infection. Stable IKKγ and p65 transcripts underwent YTHDF2-dependent mRNA decay, whereas DHX58 translation was promoted, resulting in inhibited antiviral innate response by DDX5 via blocking the p65 pathway and activating the DHX58-TBK1 pathway after infection with RNA virus. Furthermore, we found that DDX5 suppresses antiviral innate immunity in vivo. Our findings reveal that DDX5 serves as a negative regulator of innate immunity by promoting RNA methylation of antiviral transcripts and consequently facilitating viral propagation.

Patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations often benefit from third-generation tyrosine kinase inhibitors (TKIs), such as aumolertinib (AUM). However, the development of drug resistance significantly limits the clinical efficacy of AUM. To address this, we established an in vitro model of AUM-resistant cell lines and performed RNA sequencing to identify resistance-associated differentially expressed genes. Using machine learning, we constructed an AUM resistance-related prognostic signature (ARRPS). Our results demonstrated that ARRPS effectively predicts the prognostic risk of patients. Notably, for patients with high ARRPS scores, the addition of CD-437 or TPCA-1 to conventional AUM treatment may help overcome drug resistance. These findings suggest that ARRPS serves as both a prognostic tool and a guide for personalized treatment strategies, potentially optimizing the clinical management of NSCLC patients.

Endoplasmic reticulum (ER) stress is widely involved in the drug resistance of hepatocellular carcinoma (HCC), but the mechanism of ER stress-induced drug resistance involves multiple signaling pathways that cannot be fully explained. Exploring genes associated with ER stress could yield a novel therapeutic target for ER stress-induced drug resistance. By analyzing RNA-sequencing, ATAC-sequencing, and Chip-sequencing data of Tunicamycin (TM)-treated or untreated HCC cells, we found that Rho guanine nucleotide exchange factor 2 (ARHGEF2) is upregulated in HCC cells with ER stress. ARHGEF2 plays an active role in tumor malignant progression. Notwithstanding, no research has been done on the link between ER stress and ARHGEF2. The function of ARHGEF2 as a novel downstream effector of ER stress in the angiogenesis and treatment resistance of HCC was revealed in this work. ARHGEF2 overexpression was linked to malignant development and a poor prognosis in HCC. ER stress stimulates the expression of ARHGEF2 through upregulation of ZNF263. Elevated ARHGEF2 accelerates HCC angiogenesis via the EDN1 pathway, enhances HCC cell proliferation and tumor growth both in vitro and in vivo, and contributes to ER stress-related treatment resistance. HCC cell growth was more inhibited when ARHGEF2 knockdown was paired with targeted medicines. Collectively, we uncovered a previously hidden mechanism where ARHGEF2/EDN1 pathway promotes angiogenesis and participates in ER stress-related drug resistance in HCC.

Background Transforming growth factor-β (TGF-β) is a cytokine with multiple functions, including cell growth regulation, extracellular matrix production, angiogenesis homeostasis adjustment and et al. TGF-β pathway activation promotes tumor metastasis/progression and mediates epithelial-mesenchymal transmission suppressing immunosurveillance in advanced tumors. GFH018, a small molecule inhibitor blocking TGF-β signal transduction, inhibits the progression and/or metastasis of advanced cancers. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of GFH018 monotherapy in patients with advanced solid tumors. Methods This phase I, open-label, multicenter study used a modified 3+3 dose escalation and expansion design. Adult patients with advanced solid tumors failing the standard of care were enrolled. Starting at 5 mg, eight dose levels up to 85 mg were evaluated. Patients received GFH018 BID (14d-on/14d-off) starting on the 4th day after a single dose on cycle 1, day 1. Subsequent cycles were defined as 28 days. The study also explored the safety of 85 mg BID 7d-on/7d-off. Adverse events were graded using NCI criteria for adverse events (NCI-CTCAE v5.0). PK was analyzed using a noncompartmental method. Efficacy was evaluated using RECIST 1.1. Blood samples were collected for biomarker analysis. Results Fifty patients were enrolled and received at least one dose of GFH018. No dose-limiting toxicity occurred, and the maximum tolerated dose was not reached. Forty-three patients (86.0%) had at least one treatment-related adverse event (TRAE), and three patients (6.0%) had ≥ G3 TRAEs. The most common TRAEs (any grade/grade ≥3) were AST increased (18%/0%), proteinuria (14%/2%), anemia (14%/2%), and ALT increased (12%/0%). No significant cardiotoxicity or bleeding was observed. GFH018 PK was linear and dose-independent, with a mean half-life of 2.25–8.60 h from 5 – 85 mg. Nine patients (18.0%) achieved stable disease, and one patient with thymic carcinoma achieved tumor shrinkage, with the maximum target lesion decreased by 18.4%. Serum TGF-β1 levels were not associated with clinical responses. The comprehensive recommended dose for Phase II was defined as 85 mg BID 14d-on/14d-off. Conclusions GFH018 monotherapy presented a favorable safety profile without cardiac toxicity or bleeding. Modest efficacy warrants further studies, including combination strategies. Trial registration ClinicalTrial. gov ( https://www.clinicaltrials.gov/ ), NCT05051241. Registered on 2021-09-02.

Background Emerging evidence demonstrates that microRNAs (miRNAs) play an important role in regulation of cell growth, invasion and metastasis through inhibiting the expression of their targets. It has been reported that miR-130a-3p controls cell growth, migration and invasion in a variety of cancer cells. However, it is unclear whether miR-130a-3p regulates epithelial-mesenchymal transition (EMT) in drug resistant cancer cells. Therefore, in the current study, we explore the role and molecular mechanisms of miR-130a-3p in gemcitabine resistant (GR) hepatocellular carcinoma (HCC) cells. Methods The real-time RT-PCR was used to measure the miR-130a-3p expression in GR HCC cells compared with their parental cells. The wound healing assay was conducted to determine the cell migratory activity in GR HCC cells treated with miR-130a-3p mimics. The migration and invasion assays were also performed to explore the role of miR-130a-3p in GR HCC cells. Western blotting analysis was used to measure the expression of Smad4, E-cadherin, Vimentin, and MMP-2 in GR HCC cells after depletion of Smad4. The luciferase assay was conducted to validate whether Smad4 is a target of miR-130a-3p. The student t -test was used to analyze our data. Results We found the down-regulation of miR-130a-3p in GR HCC cells. Moreover, we validate the Smad4 as a potential target of miR-130a-3p. Furthermore, overexpression of miR-130a-3p suppressed Smad4 expression, whereas inhibition of miR-130a-3p increased Smad4 expression. Consistently, overexpression of miR-130a-3p or down-regulation of Smad4 suppressed the cell detachment, attachment, migration, and invasion in GR HCC cells. Conclusions Our findings provide a molecular insight on understanding drug resistance in HCC cells. Therefore, activation of miR-130a-3p or inactivation of Smad4 could be a novel approach for the treatment of HCC.

Background and aims This individual patient data pooled analysis aimed to evaluate the effectiveness, safety, and patterns of use of camrelizumab in a large cohort of advanced esophageal cancer (AEC) patients. Approach and results Adult patients (≥ 18 years) who had received camrelizumab as part of AEC treatment were pooled from three independent, prospective observational cohort studies (NCT04616040, ChiCTR1900027275, and ChiCTR2000039499). The main outcomes were patterns of camrelizumab use, progression-free survival (PFS), overall survival (OS), and safety in the overall population and specific subgroups of underrepresented patients. Among 987 patients, 450 (45.6%) received camrelizumab in the first line, 398 (40.3%) in the second line, and 139 (14.1%) in the third line or later. Most (69.7%) patients received camrelizumab plus chemotherapy regardless of treatment lines. The median PFS was 9.9 (95% CI 7.4, 14.4), 6.6 (95% CI 5.1, 8.8), and 5.7 (95% CI 3.1, 9.6) months in the first line, second line, and third line or later, respectively. The corresponding median OS was 15.5 (95% CI 12.6, 18.4), 12.1 (95% CI 10.0, 14.7), and 10.9 (95% CI 8.1, 14.5) months. Patients with poor performance status (ECOG PS ≥ 2) and with camrelizumab in the second line or later, but not patients with older age (≥ 75 years), were associated with poor survival. Adverse events occurred in 721 (73.0%) patients, with no new safety signals. Conclusions This study provides an overview of camrelizumab use in unselected AEC patients. The real-world effectiveness and safety of camrelizumab are generally consistent with those observed in pivotal trials.

Manufacturing molecule-based functional elements directly at device interfaces is a frontier in bottom-up materials engineering. A longstanding challenge in the field is the covalent stabilization of pre-assembled molecular architectures to afford nanodevice components. Here, we employ the controlled supramolecular self-assembly of anthracene derivatives on a hexagonal boron nitride sheet, to generate nanographene wires through photo-crosslinking and thermal annealing. Specifically, we demonstrate µm-long nanowires with an average width of 200 nm, electrical conductivities of 10 6  S m −1 and breakdown current densities of 10 11  A m −2 . Joint experiments and simulations reveal that hierarchical self-assembly promotes their formation and functional properties. Our approach demonstrates the feasibility of combined bottom-up supramolecular templating and top-down manufacturing protocols for graphene nanomaterials and interconnects, towards integrated carbon nanodevices. The bottom-up fabrication of structures with robust performance in the nm-to-μm scale usable for integrated carbon nanodevices is challenging. Here the authors report micrometer-long, highly conducting nanographene wires following self-assembly, photo-crosslinking and thermal annealing of anthracene derivatives on hexagonal boron nitride sheets.

Berberine (BBR), an isoquinoline alkaloid extracted from Coptis chinensis , is clinically used to treat chronic colitis, diabetes, and other diseases. Although BBR has antitumor effects, it is unclear whether it can inhibit hepatocellular carcinoma (HCC) by modulating the tumor inflammatory microenvironment. In this study, we demonstrated that BBR inhibits HCC development in mice by suppressing the M2 polarization of macrophages. Using an H22 tumor-bearing xenograft mouse model, we found that BBR significantly inhibited H22 tumor growth. Analysis of scRNA-seq results revealed reduced M2 macrophage infiltration and polarization in BBR-treated HCC tissues. Pharmacodynamic studies showed that BBR treatment markedly increased CD8 + T cell infiltration and attenuated M2 polarization. In vitro , BBR suppressed IL-4 or tumor cell supernatant-induced M2 polarization, as evidenced by decreased expression of M2 polarization marker genes (Arg 1 , Retnla , etc.) and reduced JAK1/STAT6 phosphorylation levels. Molecular docking and protein stability assays revealed that BBR directly binds to JAK1’s FERM domain, stabilizing it. Combination therapy with BBR and anti-PD-L1 antibody synergistically inhibited H22 tumor growth. These findings suggest that BBR can reduce the M2 polarization of tumor-associated macrophages (TAMs) by targeting the IL-4-JAK1-STAT6 axis, and combining with anti-PD-L1 antibody may represent a promising therapeutic strategy to enhance BBR’s antitumor efficacy.

Purpose A novel paclitaxel delivery system has the potential to avoid the side effects associated with Cremophor EL and thus enhance therapeutic efficacy. Here, we report the results of a preclinical and phase I clinical study investigating ZSYY001, a nanoparticle formulation of polymeric micellar paclitaxel (PM‐paclitaxel). Methods In preclinical studies, A549, MDA‐MB‐231, and SKOV3 xenograft tumor models were developed. Various concentrations of ZSYY001 were administered, and tumor growth and body weight were measured. Sprague–Dawley (SD) rats and Beagle dogs were used to evaluate the toxicity. In the phase I study, a dose‐escalation study using a 3 + 3 design was conducted in patients with solid tumors. The PM‐paclitaxel dose was escalated from 175 mg/m2 to 390 mg/m2. PM‐paclitaxel was intravenously administered over 3 h every 21 days without any premedication. This study was registered with number CTR20210347. Results Preclinical studies showed that ZSYY001 significantly inhibited tumor growth without causing weight loss. In the phase I study, all patients were evaluable for toxicity and pharmacokinetic analysis, and 18 patients were evaluable for tumor response. Acute hypersensitivity reactions were not observed. Anemia and hair loss were the most common toxicities. Dose‐limiting toxicity events were not observed at any dose levels. Dose escalation to 390 mg/m2 did not identify a maximum‐tolerated dose. There were two partial responses (11.11%) and seven cases of stable disease (38.89%) among the 18 patients, five of whom had prior exposure to paclitaxel chemotherapy. The paclitaxel area under the curve and peak paclitaxel concentration suggest that PM‐paclitaxel does not exhibit linear pharmacokinetics. Conclusions ZSYY001 was safe and well tolerated without additional toxicity and exhibited desirable antitumor activity, making it a promising treatment. Trial Registration CTR20210347