Reversing MET-Mediated Resistance in Oncogene-Driven NSCLC by MET-Activated Wnt Condensative Prodrug.

The amplification of MET is a major cause of acquired resistance to targeted therapy in EGFR-mutant non-small-cell lung cancer (NSCLC), only to be temporarily restrained by the partial efficacy of MET inhibitors. This study reveals that the MET inhibitor has unexpectedly limited efficacy due to amplified MET triggering a strong positive feedback loop in the Wnt/ß-catenin signaling pathway, allowing optimal functionality even when the MET pathway is suppressed again. To test this conjecture and specifically target the Wnt/ß-catenin pathway, a cleverly designed Wnt condensative pro drug called WntSI is developed using reversible supramolecular self-assembly driven by liquidliquid phase separation (LLPS). This process involves a MET/pH-responsive peptide (Tyr-Pep) and a potent Wnt inhibitor known as CA. Upon recognition and phosphorylation of Tyr-Pep by over expressed MET in cells, it disrupts LLPS propensity and facilitates the disintegration of WntSI. Consequently,this enables it to suppress the carcinogenic effect mediated by ß-catenin,effectively overcoming acquired resistance to EGFR-TKIs caused by MET amplification in both cell line-derived and patient-derived tumor xenograft (PDX) mouse models while maintaining exceptional biosecurity. This effective strategy not only suppresses the Wnt/ß-catenin signaling pathway selectively, but also serves as an innovative example for pro-drug development through biologically responsive LLPS.

SENP1 knockdown potentiates the apoptosis, cell cycle arrest, and reduces cisplatin resistance of diffuse large B cell lymphoma cells via inducing ferroptosis.

Ferroptosis has been regarded as a critical event in the process of diffuse large B cell lymphoma (DLBCL). Sentrin-specific protease 1 (SENP1) has emerged as an oncogene in multiple human malignancies. The present work was to investigate the effects of SENP1 on the progression of DLBCL and the possible regulatory mechanism involving ferroptosis. SENP1 expression in DLBCL tissues, parental and cisplatin-resistant DLBCL cells were, respectively, tested by GEPIA database, RT-qPCR, and Western blot. Cell viability was estimated via CCK-8 assay. Flow cytometry analysis estimated cell apoptosis and cycle. Western blot examined the expression of apoptosis-, cell cycle-, and ferroptosis-associated proteins. TBARS assay and BODIPY 581/591 C11 probe measured lipid peroxidation. Related assay kit assessed total iron levels. CCK-8 and flow cytometry evaluated cisplatin resistance. SENP1 expression was raised in DLBCL tissues and cells. SENP1 knockdown reduced cell viability, boosted cell apoptosis, cell cycle arrest, and elevated cisplatin sensitivity in DLBCL. SENP1 depletion drove the ferroptosis of both parental and cisplatin-resistant DLBCL cells and ferroptosis inhibitor Fer-1 reversed the influences of SENP1 inhibition on cell viability, apoptosis, cell cycle, and cisplatin resistance in DLBCL. Anyway, SENP1 absence might facilitate ferroptosis to obstruct the development of DLBCL and cisplatin resistance.

[Clinical Analysis of PEG-rhG-CSF in Mobilization of Autologous Hematopoietic Stem Cells in Hematological Tumors].

OBJECTIVE: To investigate the efficiency and optimal time of stem cell apheresis mobilized by pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) in autologous stem cell transplantation (ASCT) for hematological malignancies without monitoring pre-collection CD34+ cells. METHODS: Forty-six patients underwent stem cell mobilization were retrospectively analyzed between August 2017 and January 2022 at the First Affiliated Hospital of Fujian Medical University. 27 patients using high dose chemotherapy combined with PEG-rhG-CSF mobilization were enrolled in the PEG-rhG-CSF group, and other 19 patients mobilized with recombinant human granulocyte colony stimulating factor (G-CSF) were enrolled in G-CSF group. The mobilization and collection effects of the patients in two groups were compared. RESULTS: A total of 46 patients underwent 86 apheresis procedures, the median amount of mononuclear cell (MNC) in the PEG-rhG-CSF group and G-CSF group was 6.54（3.85-12.61）×108/kg and 6.15（1.13-11.58）×108/kg, respectively (P >0.05), the total CD34+ cells of the grafts were 11.44(1.33-65.02)×106/kg and 4.95(0.30-24.02)×106/kg (P < 0.05), with harvest timing of 14(10-20) days and 14(4-22) days, respectively (P >0.05). In the PEG-rhG-CSF group, there was a significant difference between the number of CD34+ cells collected when white blood cells (WBC) ≥10×109/L and WBC<10×109 /L, 19.04(2.85-65.02)×106/kg and 6.22(0.81-34.86)×106/kg, respectively (P < 0.05). CONCLUSION: Stem cells mobilization with PEG-rhG-CSF was highly efficient with a median mobilization time of 14 days. In the absence of peripheral blood CD34 monitoring, peripheral blood WBC≥10×109/L can be considered as a threshold for a single stem cell apheresis to collect sufficient stem cells.

Platinum-based neoadjuvant chemotherapy upregulates STING/IFN pathway expression and promotes TILs infiltration in NSCLC.

Objectives: To evaluate the effects of platinum-based neoadjuvant chemotherapy (NACT) on the STING/IFN pathway and tumor-infiltrating lymphocytes (TILs) in non-small cell lung cancer (NSCLC), as well as clinicopathological factors affecting patient survival. Materials and methods: A total of 68 patients aged 34-77 years with NSCLC who received neoadjuvant chemotherapy and surgical treatment from March 2012 to February 2019 were reviewed, and the clinical pathological data and paired tissue specimens before and after NACT were collected. Immunohistochemistry and immunofluorescence were used to detect the protein levels of STING, PD-L1 and IFN-ß, and the infiltration density of CD3+ TILs and CD8+TILs. The correlation between the expression of STING, PD-L1, IFN-ß and the infiltration density of CD3+ TILs and CD8+ TILs as well as the clinicopathological characteristics before and after NACT was analyzed. The relationship between the related indexes, clinicopathological features and prognosis was also discussed. Results: NACT increased the expression of STING, IFN-ß and PD-L1 in tumor cells, and the infiltration of CD3+ and CD8+ TILs. In addition, ypTNM stage, ypN stage, changes in CD3+ TILs and in PD-L1 were associated with DFS (disease-free survival). CD3+ TILs changes and ypN stage were associated with OS (overall survival). Notably, ypN stage and CD3+ TILs changes were independent prognostic factors for DFS and OS. Conclusion: NACT stimulates STING/IFN-ß pathway, promotes infiltration of CD3+ and CD8+ TILs, triggers innate and adaptive immunity, and also upregulates PD-L1, which complemented the rationale for neoadjuvant chemotherapy in combination with immunotherapy. In addition, DFS was longer in patients with ypTNM I, ypN0-1, and elevated CD3+TILs after NACT. Patients with ypN0 and elevated CD3+ TILs after NACT had better OS benefits.

Advancing the Boundaries of Immunotherapy in Lung Adenocarcinoma with Idiopathic Pulmonary Fibrosis by a Biomimetic Proteinoid Enabling Selective Endocytosis.

The coexistence of lung adenocarcinoma (LUAD) with idiopathic pulmonary fibrosis (IPF), which has been extensively documented as a prominent risk factor for checkpoint inhibitor-related pneumonitis (CIP) in patients undergoing immunotherapy, has long been considered a restricted domain for the use of immune checkpoint inhibitors (ICIs). To overcome it, an approach was employed herein to specifically target PD-L1 within the cellular interior, surpassing the conventional focus solely on the cytomembrane, thereby facilitating the development of ICIs capable of distinguishing between LUAD cells and noncancerous cells based on their distinctive endocytic propensities. By exploiting the aurophilicity-driven self-assembly of a PD-L1 binding peptide (PDBP) and subsequently encapsulating it within erythrocyte membranes (EM), the resulting biomimetic ICIs protein EMS-PDBP exhibited extraordinary selectivity in internalizing LUAD cells, effectively targeting PD-L1 within cancer cells while hindering its membrane translocation. The EMS-PDBP treatment not only reactivated the antitumor immune response in the LUAD orthotopic allograft mouse model but also demonstrated a favorable safety profile by effectively eliminating any immune-related adverse events (irAEs). Most significantly, EMS-PDBP successfully and safely restored the antitumor immune response in a mouse model of LUAD with coexistent IPF, thus shattering the confines of ICIs immunotherapy. The reported EMS-PDBP collectively offers a potential strategy for immune reactivation to overcome the limitations of immunotherapy in LUAD coexisting with IPF.

Modulating ß-catenin/BCL9 interaction with cell-membrane-camouflaged carnosic acid to inhibit Wnt pathway and enhance tumor immune response.

Introduction: Lung adenocarcinoma (LUAD) therapies are plagued by insufficient immune infiltration and suboptimal immune responses in patients, which are closely associated with the hyperactive Wnt/ß-catenin pathway. Suppressing this signaling holds considerable promise as a potential tumor therapy for LUAD, but Wnt suppressor development is hindered by concerns regarding toxicity and adverse effects due to insufficient targeting of tumors. Methods: We have synthesized a tumor-specific biomimetic Wnt pathway suppressor, namely CM-CA, by encapsulating carnosic acid within Lewis lung carcinoma (LLC) cell membranes. It possesses nano-size, allowing for a straightforward preparation process, and exhibits the ability to selectively target the Wnt/ß-catenin pathway in lung adenocarcinoma cells. To evaluate its in vivo efficacy, we utilized the LLC Lewis homograft model, and further validated its mechanism of action through immunohistochemistry staining and transcriptome sequencing analyses. Results: The findings from the animal experiments demonstrated that CM-CA effectively suppressed the Wnt/ß-catenin signaling pathway and impeded cellular proliferation, leading to notable tumor growth inhibition in a biologically benign manner. Transcriptome sequencing analyses revealed that CM-CA promoted T cell infiltration and bolstered the immune response within tumor tissues. Conclusion: The utilization of CM-CA presents a novel and auspicious approach to achieve tumor suppression and augment the therapeutic response rate in LUAD, while also offering a strategy for the development of Wnt/ß-catenin inhibitors with biosafety profile.

A de novo dual-targeting supramolecular self-assembly peptide against pulmonary metastasis of melanoma.

Despite recent advances in treatment, overall survival rates for metastatic melanoma, especially those that invade the lungs, continue to be low, with 5-year survival rates of only 3% to 5%. It was recently discovered that Wnt/ß-catenin signaling pathways and MAPK/ERK signaling pathways are involved in melanoma metastasis. Methods: Herein, a bifunctional supramolecular peptide termed HBBplus@CA was constructed by a self-assembling RGD-modified MAPK/ERK peptide inhibitor (HBBplus) and a small molecule catenin inhibitor (carnosic acid (CA)). Results: Expectedly, the HBBplus@CA could internalize melanoma cells, accumulate in the tumor-bearing lung, and be biosafe. As designed, HBBplus@CA simultaneously suppressed both Wnt/ß-catenin and MAPK/ERK signaling pathways and suppressed melanoma cell proliferation, migration, and invasion in more action than CA or HBBplus monotherapy. More importantly, HBBplus@CA demonstrated potent inhibition of lung metastasis in mice bearing metastatic melanoma of B16F10 and significantly prolonged their survival. Conclusion: In summary, a supramolecular peptide-based strategy was not only developed to suppress pulmonary metastasis of melanoma, but it also renewed efforts to identify cocktail drugs that act on intracellular targets in various human diseases, including cancer.

Cost-effectiveness of the combination of immunotherapy and chemotherapy for extensive-stage small-cell lung cancer: a systematic review.

BACKGROUND: The combination of immunotherapy and chemotherapy for extensive-stage small-cell lung cancer (ES-SCLC) was primarily carried out with a combination of immune checkpoint inhibitors (ICIs) and platinum-etoposide (EP). It is likely to be more effective in treating ES-SCLC than EP alone, but could result in high healthcare costs. The study aimed to investigate the cost-effectiveness of this combination therapy for ES-SCLC. METHODS: We searched literature from the following databases: PubMed, Embase, Cochrane Library, and Web of Science for studies on cost-effectiveness of immunotherapy combined with chemotherapy for ES-SCLC. The literature search period was up to April 20, 2023. The quality of the studies was evaluated using the Cochrane Collaboration's tool and Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. RESULTS: A total of 16 eligible studies were included in the review. All studies met CHEERS recommendations, and all randomized controlled trials (RCTs) in these studies were rated as having low risk of bias using the Cochrane Collaboration's tool. The treatment regimens compared were ICIs plus EP or EP alone. All studies mainly used incremental quality-adjusted life year and incremental cost-effectiveness ratio as outcomes. Most ICIs plus EP treatment regimens were not cost-effective based on corresponding willingness-to-pay thresholds. CONCLUSIONS: Adebrelimab plus EP and serplulimab plus EP were probably cost-effective for ES-SCLC in China, and serplulimab plus EP was probably cost-effective for ES-SCLC in the U.S. Lowering the price of ICIs and selecting ES-SCLC patients who were sensitive to ICIs could improve the cost-effectiveness of the ICIs-combined treatment.

Patient-derived xenografts or organoids in the discovery of traditional and self-assembled drug for tumor immunotherapy.

In addition to the rapid development of immune checkpoint inhibitors, there has also been a surge in the development of self-assembly immunotherapy drugs. Based on the immune target, traditional tumor immunotherapy drugs are classified into five categories, namely immune checkpoint inhibitors, direct immune modulators, adoptive cell therapy, oncolytic viruses, and cancer vaccines. Additionally, the emergence of self-assembled drugs with improved precision and environmental sensitivity offers a promising innovation approach to tumor immunotherapy. Despite rapid advances in tumor immunotherapy drug development, all candidate drugs require preclinical evaluation for safety and efficacy, and conventional evaluations are primarily conducted using two-dimensional cell lines and animal models, an approach that may be unsuitable for immunotherapy drugs. The patient-derived xenograft and organoids models, however, maintain the heterogeneity and immunity of the pathological tumor heterogeneity.

Retrospective Analysis of the Expression of CD56 in Multiple Myeloma with Bone-Related Extramedullary Diseases.

OBJECTIVE: To identify the clinical characteristics and tissue CD56 expression pattern in patients with multiple myeloma (MM) with bone-related extramedullary disease (b-EMD), not connected to or isolated from the bone marrow. METHODS: We reviewed consecutive patients with MM hospitalised at the First Affiliated Hospital of Fujian Medical University between 2016 and 2019. Patients with b-EMD were identified, and the clinical and laboratory features of patients with and without b-EMD were compared. Immunohistochemistry of extramedullary lesions was performed based on b-EMD histology. RESULTS: Ninety-one patients were included in the study. Among them, 19 (20.9%) were found to have b-EMD at initial diagnosis. Median age was 61 years (range, 42-80 years), with a female/male ratio of 6/13. The most common site of b-EMD was the paravertebral space (11/19; 57.9%). Compared to those without b-EMD, patients with b-EMD had lower levels of serum ß2-microglobulin and similar levels of lactate dehydrogenase. Immunophenotype analysis based on histopathology showed that CD56 was expressed in 9/10 (90.0%) patients with b-EMD. CONCLUSION: A considerable number of MM patients presented with b-EMD at the time of initial diagnosis, and most patients with b-EMD exhibited CD56 expression, highlighting a potential new therapeutic target in the future.

Association of socioeconomic status with cardiovascular disease and cardiovascular risk factors: a systematic review and meta-analysis.

Aim: Cardiovascular disease (CVD) remains one of the leading causes of mortality worldwide, and several studies have indicated the association between socioeconomic status (SES) with CVD and cardiovascular risk factors (CVRFs). It is necessary to elucidate the association of SES and CVRFs with CVD. Subject and methods: We searched PubMed, Embase, Web of Science, and the Cochrane Library for publications, using "socioeconomic status," "cardiovascular disease," and corresponding synonyms to obtain literature. The quality of studies was evaluated using the National Institutes of Health Quality Assessment Tool (NIH-QAT). All analyses were performed using Stata V.12.0. Results: There were 31 eligible studies included in this meta-analysis. All studies presented a low risk of bias via NIH-QAT assessment. As for CVD incidence/mortality, pooled hazard ratios (HR) of low and middle vs. high income were [HR = 1.22 (1.17-1.28); HR = 1.12 (1.09-1.16)] and [HR = 1.37 (1.21-1.56); HR = 1.19 (1.06-1.34)]. The HR of education were [HR = 1.44 (1.28-1.63); HR = 1.2 (1.11-1.3)] and [HR = 1.5 (1.22-1.83); HR = 1.13 (1.05-1.22)]. The HR of deprivation were [HR = 1.28 (1.16-1.41); HR = 1.07 (1.03-1.11)] and [HR = 1.19 (1.11-1.29); HR = 1.1 (1.02-1.17)]. SES was negatively correlated with CVD outcomes. A subgroup analysis of gender and national income level also yielded a negative correlation, and additional details were also obtained. Conclusions: SES is inversely correlated with CVD outcomes and the prevalence of CVRFs. As for CVD incidence, women may be more sensitive to income and education. In terms of CVD mortality, men may be more sensitive to income and education, and people from low- and middle-income countries are sensitive to income and education. Supplementary Information: The online version contains supplementary material available at 10.1007/s10389-023-01825-4.

Modification and evaluation of diatrizoate sodium containing polymethyl methacrylate bone cement.

Polymethyl methacrylate (PMMA) bone cement is now widely used in percutaneous vertebro plasty (PVP) and percutaneous kyphoplasty (PKP). However, studies showed that the radiopacifiers (zirconia, barium sulfate, etc.) added to PMMA will have a negative impact on its use, e.g. barium sulfate will weaken the mechanical properties of bone cement and lead to bone absorption and aseptic loosening. Iodine is an element existing in the human body and has good imaging performance. Iodine contrast agent has been used in clinic for many years and has abundant clinical data. Therefore, using iodine instead of barium sulfate may be a promising choice. In this paper, the effect of different content of diatrizoate sodium (DTA, C11H8I3N2NaO4) on the properties of PMMA was studied and compared with the traditional PMMA bone cement containing 30 wt% barium sulfate. The mechanical properties, setting properties, radiopacity, and biocompatibility of bone cement were evaluated. The compressive strength of PMMA bone cement with 20 wt% DTA can reach 76.38 MPa. DTA released from bone cement up to 14 days accounted for only 2.3% of its dosage. The water contact angle was 62.3°. The contrast of bone cement on X-ray film was comparable to that of bone cement containing 30 wt% barium. The hemolysis rate was lower than 4%, and there was no obvious hemolysis. PMMA with 20 wt% DTA can maintain the relative growth rate of MC3T3-E1 and L929 cells above 80%. The results show that adding 20 wt% DTA into PMMA can obtain good radiopacity while maintaining its mechanical properties, setting properties, and biocompatibility. DTA can be used as a promising candidate material for PMMA bone cement radiopacifier.

The role of PD-1/PD-L1 axis in idiopathic pulmonary fibrosis: Friend or foe?

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease with a bleak prognosis. Mounting evidence suggests that IPF shares bio-molecular similarities with lung cancer. Given the deep understanding of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway in cancer immunity and the successful application of immune checkpoint inhibitors (ICIs) in lung cancer, recent studies have noticed the role of the PD-1/PD-L1 axis in IPF. However, the conclusions are ambiguous, and the latent mechanisms remain unclear. In this review, we will summarize the role of the PD-1/PD-L1 axis in IPF based on current murine models and clinical studies. We found that the PD-1/PD-L1 pathway plays a more predominant profibrotic role than its immunomodulatory role in IPF by interacting with multiple cell types and pathways. Most preclinical studies also indicated that blockade of the PD-1/PD-L1 pathway could attenuate the severity of pulmonary fibrosis in mice models. This review will bring significant insights into understanding the role of the PD-1/PD-L1 pathway in IPF and identifying new therapeutic targets.

The efficacy and safety of anlotinib combined with platinum-etoposide chemotherapy as first-line treatment for extensive-stage small cell lung cancer: A Chinese multicenter real-world study.

Background: Patients with extensive-stage small-cell lung cancer (ES-SCLC) have high recurrence rates and bleak prognosis. This multicenter real-world study aimed to explore the efficacy and safety of anlotinib combined with platinum-etoposide chemotherapy as the first-line treatment of ES-SCLC. Methods: Pathologically confirmed ES-SCLC patients receiving anlotinib plus platinum-etoposide chemotherapy as the first-line treatment were enrolled in this retrospective study. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse reactions. The Cox regression analyses were employed to investigate the independent prognostic factors for OS and PFS of these individuals. Results: In total, 58 patients were included in this study. The median PFS was 6.0 months [95% confidence interval (CI): 3.5-8.5], and the median OS was 10.5 months (95%CI 8.7-12.3). Thirty-four patients achieved partial response (PR), 18 patients achieved stable disease (SD), and 6 patients achieved progressive disease (PD). The ORR and DCR were 58.6% and 89.6%. The main treatment-related adverse reactions were generally tolerated. Myelosuppression (44.8%) was the most common adverse reaction, followed by hypertension (41.4%), fatigue (34.5%), gastrointestinal reaction (32.7%), and hand-foot syndrome (24.1%). Multivariate analysis showed that post-medication hand-foot syndrome [PFS 8.5 vs. 5.5 months, Hazards Ratio (HR)=0.23, 95%CI 0.07-0.72, P =0.012] was the independent predictor of PFS, and hypertension (OS 15.9 vs. 8.3 months, HR=0.18, 95%CI 0.05-0.58, P =0.005) was the independent predictor of OS. Conclusion: Anlotinib combined with platinum-etoposide chemotherapy as the first-line treatment for ES-SCLC appears to be effective and well-tolerated in the real-world. Well-designed large-scale prospective studies are urgently needed in the future to verify our findings.

Nanomedicines Targeting Metabolism in the Tumor Microenvironment.

Cancer cells reprogram their metabolism to meet their growing demand for bioenergy and biosynthesis. The metabolic profile of cancer cells usually includes dysregulation of main nutritional metabolic pathways and the production of metabolites, which leads to a tumor microenvironment (TME) having the characteristics of acidity, hypoxic, and/or nutrient depletion. Therapies targeting metabolism have become an active and revolutionary research topic for anti-cancer drug development. The differential metabolic vulnerabilities between tumor cells and other cells within TME provide nanotechnology a therapeutic window of anti-cancer. In this review, we present the metabolic characteristics of intrinsic cancer cells and TME and summarize representative strategies of nanoparticles in metabolism-regulating anti-cancer therapy. Then, we put forward the challenges and opportunities of using nanoparticles in this emerging field.

The Efficacy and Safety of Anlotinib in Extensive-Stage Small Cell Lung Cancer: A Multicenter Real-World Study.

Purpose: Anlotinib, an antiangiogenic multi-target tyrosine kinase inhibitor (TKI), has shown favorable anticancer efficacy and acceptable safety in treating extensive-stage small cell lung cancer (ES-SCLC) in some clinical studies. This research aimed to explore the real-world efficacy and safety of anlotinib in ES-SCLC. Methods: Pathologically confirmed ES-SCLC patients receiving anlotinib were enrolled for this retrospective study. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse reactions. Results: In total, 202 patients were included in this study. The median PFS of all patients was 4.8 months [95% confidence interval (CI): 3.9-5.7], and the median OS was 7.6 months (95% CI 6.5-8.7). Respectively, the overall ORR and DCR were 30.2% and 87.1%. The univariate and multivariate Cox regression analyses revealed that patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1, plus chemotherapy or immunotherapy, plus radiotherapy, and post-medication hypertension might have longer PFS and OS. The PFS and OS were significantly prolonged in combination group than that in monotherapy group [PFS 6.0 vs 3.6 months, hazards ratio (HR)=0.49, 95% CI 0.34-0.70, P < 0.001; OS 9.2 vs 4.8 months, HR = 0.48, 95% CI 0.32-0.72, P < 0.001]. The main treatment-related adverse reactions were generally tolerated. The incidence of adverse reactions in combination group was higher than that in monotherapy group (75.0% vs 52.6%, P = 0.001). The most common adverse reaction was hypertension, followed by hand-foot syndrome and fatigue, regardless of monotherapy or combination group. Conclusion: Anlotinib is effective and well tolerated in patients with ES-SCLC in the real-world. The clinical efficacy of anlotinib combined with chemotherapy or immunotherapy is better than that of monotherapy. Further investigations are needed for prospective studies with larger sample size.

hsa-miR-34a-5p Ameliorates Hepatic Ischemia/Reperfusion Injury Via Targeting HNF4α.

BACKGROUND: To investigate the relationship between the expression level of hsa-miR-34a-5p and liver injury and to further explore its regulatory signaling pathways Methods: Liver tissue and blood were collected from 60 patients undergoing hepatectomy. We constructed a rat HIRI model and treated it with an intraperitoneal injection of agomir-miR-34a-5p or agomir-normal control (NC) for 7 days after the surgery. The pathological changes of agomir-miR-34a-5p or agomir-normal control (NC) groups were compared. 7702 and AML12 cells were transfected with mimics NC or miR-34a-5p mimics and then treated with H2O2 for 6 hours. Cell apoptosis was detected by flow cytometry, Western blot, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, respectively. Furthermore, the target genes of miR- 34a-5p were identified by luciferase reporter gene assay and were verified in vitro. RESULTS: The relatively high miR-34a-5p expression group revealed a lower level of alanine aminotransferase and aspartate aminotrans- ferase compared with the relatively low miR-34a-5p expression group. HIRI+agomir-miR-34a-5p rats exhibited significantly higher miR-34a-5p expression, lower serum alanine aminotransferase, aspartate aminotransferase, alleviated hepatic necrosis, reduced hepa- tocyte apoptosis, and decreased expression of apoptosis-related proteins, when compared with HIRI+agomir-NC rats (P < .05). After hydrogen peroxide treatment, alpha mouse liver-12 cell (AML-12) and normal liver cell line LO2 (LO2) cells transfected with miR-34a-5p mimics had significantly lower apoptosis rate compared with miR-34a-5p mimics NC group (P < .05). Hepatocyte nuclear factor 4α was identified as a miR-34a-5p target gene. Hepatocyte nuclear factor 4α expression was significantly downregulated in AML12 and HL-7702 (7702) cells transfected with miR-34a-5p (P < .05). Moreover, AML12 and 7702 cells transfected with miR-34a-5p signifi- cantly showed higher c-Jun N-terminal kinase (JNK), P38, cleavage cas-3, and BCL2 associated X (Bax) protein levels compared with AML12 and 7702 cells transfected with agomir-NC. CONCLUSION: miR-34a-5p possibly protected the liver from I/R injury through downregulating Hepatocyte nuclear factor 4α to inhibit the JNK/P38 signaling pathway.

Assembling p53 Activating Peptide With CeO2 Nanoparticle to Construct a Metallo-Organic Supermolecule Toward the Synergistic Ferroptosis of Tumor.

Inducing lipid peroxidation and subsequent ferroptosis in cancer cells provides a potential approach for anticancer therapy. However, the clinical translation of such therapeutic agents is often hampered by ferroptosis resistance and acquired drug tolerance in host cells. Emerging nanoplatform-based cascade engineering and ferroptosis sensitization by p53 provides a viable rescue strategy. Herein, a metallo-organic supramolecular (Nano-PMI@CeO2) toward p53 restoration and subsequent synergistic ferroptosis is constructed, in which the radical generating module-CeO2 nanoparticles act as the core, and p53-activator peptide (PMI)-gold precursor polymer is in situ reduced and assembled on the CeO2 surface as the shell. As expected, Nano-PMI@CeO2 effectively reactivated the p53 signaling pathway in vitro and in vivo, thereby downregulating its downstream gene GPX4. As a result, Nano-PMI@CeO2 significantly inhibited tumor progression in the lung cancer allograft model through p53 restoration and sensitized ferroptosis, while maintaining favorable biosafety. Collectively, this work develops a tumor therapeutic with dual functions of inducing ferroptosis and activating p53, demonstrating a potentially viable therapeutic paradigm for sensitizing ferroptosis via p53 activation. It also suggests that metallo-organic supramolecule holds great promise in transforming nanomedicine and treating human diseases.

Immune Checkpoint Inhibitor-Associated Cardiotoxicity in Solid Tumors: Real-World Incidence, Risk Factors, and Prognostic Analysis.

Background: Immune checkpoint inhibitors (ICIs) have achieved acknowledged progress in cancer therapy. However, ICI-associated cardiotoxicity as one of the most severe adverse events is potentially life-threatening, with limited real-world studies reporting its predictive factors and prognosis. This study aimed to investigate the real-world incidence, risk factors, and prognosis of ICI-related cardiotoxicity in patients with advanced solid tumors. Methods: Electronic medical records from patients with advanced solid tumors receiving ICIs in the First Affiliated Hospital of Xi'an Jiaotong University were retrospectively reviewed. All patients were divided into the cardiotoxicity group and control group, with logistic regression analysis being implemented to identify potential risk factors of ICI-related cardiotoxicity. Furthermore, survival analysis was also performed to investigate the prognosis of patients with ICI-related cardiotoxicity. Results: A total of 1,047 participants were enrolled in this retrospective study. The incidence of ICI-related cardiotoxicity in our hospital is 7.0%, while grade 3 and above cardiotoxicity was 2.4%. The logistic regression analysis revealed that diabetes mellitus [odds ratio (OR):1.96, 95% confidence Interval (CI): 1.05-3.65, p = 0.034] was an independent risk factor, whereas baseline lymphocyte/monocyte ratio (LMR) (OR: 0.59, 95% CI: 0.36-0.97, p = 0.037) was the protective factor of ICI-related cardiotoxicity. Survival analysis indicated that severe cardiotoxicity (≥grade 3) was significantly correlated with bleak overall survival (OS) than mild cardiotoxicity (≤grade 2) (8.3 months vs. not reached, p = 0.001). Patients with ICI-related overlap syndrome had poorer overall survival than patients with mere cardiotoxicity (9.4 vs. 24.7 months, p = 0.033). However, the occurrence of ICI-related cardiotoxicity was not significantly associated with the OS of overall population with solid tumors. Subgroup analysis showed that lung cancer and PD-L1 usage were significantly correlated with a higher incidence of severe cases. Conclusion: Immune checkpoint inhibitor-related cardiotoxicity is more common in the real-world setting than the previously published studies. Diabetes mellitus and baseline LMR are the potential predictive biomarkers of ICI-related cardiotoxicity. Although ICI-related cardiotoxicity is not correlated with the prognosis of these patients in our cohort, a systematic and comprehensive baseline examination and evaluation should be performed to avoid its occurrence.

Turing milk into pro-apoptotic oral nanotherapeutic: De novo bionic chiral-peptide supramolecule for cancer targeted and immunological therapy.

Chirality in biomolecules is ubiquitous in our world, but oral nanomedicines constructed from chiral peptides are extremely rare, principally because of the immature nanofabrication and inadequate bioavailability of chiral nanostructures. Methods: To realize the oral administration of chiral peptides and break through their forbidden zone in intracellular space, a chiral-peptide supramolecular (DPAICP) camouflaging with the membrane from milk-derived extracellular vesicles (ME) was developed herein through an aqueous-based growth method of chiral peptide Au(I) infinite covalent polymer (DPAICP) involving in organothiol D-peptides and Au3+, and a feasible camouflage technology using ME. Results: DPAICP@ME possessed favorable pharmaceutical properties to remain stable during the gastrointestinal absorption and blood circulation, and showed the satisfactory tumor accumulation through oral medication. Expectedly, oral DPAICP@ME played its predetermined role in vivo to restore p53 signaling pathway for cancer therapy in B16F10 homograft malignant melanoma model, LLC Lewis orthotopic transplantation model of lung cancer and patient-derived orthotopic xenograft (PDOX) mice model of colon cancer. Moreover, oral DPAICP@ME augmented the action of immunotherapy by Anti-PD1 through the further T-cell activation. Conclusion: The de novo design of the bionic chiral-peptide supramolecule provides a practicable strategy for the construction of biomimetic chiral peptide-derived nanostructures that can be taken orally, and likely boosts chiral nanomedicine discovery efforts for a wider range of diseases including cancer.