Cucurbitacin B targets STAT3 to induce ferroptosis in non-small cell lung cancer.

Cucurbitacin B (CuB) is a compound found in plants like Cucurbitaceae that has shown promise in fighting cancer, particularly in lung cancer. However, the specific impact of CuB on ferroptosis and how it works in lung cancer cells has not been fully understood. Our research has discovered that CuB can effectively slow down the growth of non-small cell lung cancer (NSCLC) cells. Even in small amounts, it was able to inhibit the growth of various NSCLC cell lines. This inhibitory effect was reversed when ferroptosis inhibitors DFO, Lip-1 and Fer-1 were introduced. CuB was found to increase the levels of reactive oxygen species (ROS), lipid ROS, MDA, and ferrous ions within H358 lung cancer cells, leading to a decrease in GSH, mitochondrial membrane potential (MMP) and changes in ferroptosis-related proteins in a dose-dependent manner. These findings were also confirmed in A549 lung cancer cells. In A549 cells, different concentrations of CuB induced the accumulation of intracellular lipid ROS, ferrous ions and changes in ferroptosis-related indicators in a concentration-dependent manner. Meanwhile, the cytotoxic effect induced by CuB in A549 cells was counteracted by ferroptosis inhibitors DFO and Fer-1. Through network pharmacology, we identified potential targets related to ferroptosis in NSCLC cells treated with CuB, with STAT3 targets showing high scores. Further experiments using molecular docking and cell thermal shift assay (CETSA) revealed that CuB interacts with the STAT3 protein. Western blot and immunofluorescence staining demonstrated that CuB inhibits the phosphorylation of STAT3 (P-STAT3) in H358 cells. Silencing STAT3 enhanced CuB-induced accumulation of lipid ROS and iron ions, as well as the expression of ferroptosis-related proteins. On the other hand, overexpression of STAT3 reversed the effects of CuB-induced ferroptosis. The results indicate that CuB has the capability to suppress STAT3 activation, resulting in ferroptosis, and could be a promising treatment choice for NSCLC.

Bimin Kang ameliorates the minimal persistent inflammation in allergic rhinitis by reducing BCL11B expression and regulating ILC2 plasticity.

ETHNOPHARMACOLOGICAL RELEVANCE: Minimal persistent inflammation (MPI) is a major contributor to the recurrence of allergic rhinitis (AR). The traditional Chinese herbal medicine known as Bimin Kang Mixture (BMK) have been used in clinics for decades to treat AR, which can relieve AR symptoms, reduce inflammatory response and improve immune function. However, its mechanism in controlling MPI is still unclear. AIM OF THE STUDY: This study aims to assess the therapeutic effect of BMK on MPI, and elaborate the mechanism involved in BMK intervention in BCL11B regulation of type 2 innate lymphoid cell (ILC2) plasticity in the treatment of MPI. MATERIAL AND METHODS: The effect of BMK (9.1 ml/kg) and Loratadine (15.15 mg/kg) on MPI was evaluated based on symptoms, pathological staining, and ELISA assays. RT-qPCR and flow cytometry were also employed to assess the expression of BCL11B, IL-12/IL-12Rß2, and IL-18/IL-18Rα signaling pathways associated with ILC2 plasticity in the airway tissues of MPI mice following BMK intervention. RESULTS: BMK restored the airway epithelial barrier, and markedly reduced inflammatory cells (eosinophils, neutrophils) infiltration (P < 0.01) and goblet cells hyperplasia (P < 0.05). BCL11B expression positively correlated with the ILC2 proportion in the lungs and nasal mucosa of AR and MPI mice (P < 0.01). BMK downregulated BCL11B expression (P < 0.05) and reduced the proportion of ILC2, ILC3 and ILC3-like ILC2 subsets (P < 0.05). Moreover, BMK promoted the conversion of ILC2 into an ILC1-like phenotype through IL-12/IL-12Rß2 and IL-18/IL-18Rα signaling pathways in MPI mice. CONCLUSION: By downregulating BCL11B expression, BMK regulates ILC2 plasticity and decreases the proportion of ILC2, ILC3, and ILC3-like ILC2 subsets, promoting the conversion of ILC2 to ILC1, thus restoring balance of ILC subsets in airway tissues and control MPI.

Protective Effects and Mechanisms of Esculetin against H2O2-Induced Oxidative Stress, Apoptosis, and Pyroptosis in Human Hepatoma HepG2 Cells.

Oxidative stress plays a crucial role in the pathogenesis of many diseases. Esculetin is a natural coumarin compound with good antioxidant and anti-inflammatory properties. However, whether esculetin can protect HepG2 cells through inhibiting H2O2-induced apoptosis and pyroptosis is still ambiguous. Therefore, this study aimed to investigate the protective effects and mechanisms of esculetin against oxidative stress-induced cell damage in HepG2 cells. The results of this study demonstrate that pretreatment with esculetin could significantly improve the decrease in cell viability induced by H2O2 and reduce intracellular ROS levels. Esculetin not only apparently reduced the apoptotic rates and prevented MMP loss, but also markedly decreased cleaved-Caspase-3, cleaved-PARP, pro-apoptotic protein (Bax), and MMP-related protein (Cyt-c) expression, and increased anti-apoptotic protein (Bcl-2) expression in H2O2-induced HepG2 cells. Meanwhile, esculetin also remarkably reduced the level of LDH and decreased the expression of the pyroptosis-related proteins NLRP3, cleaved-Caspase-1, Il-1ß, and GSDMD-N. Furthermore, esculetin pretreatment evidently downregulated the protein expression of p-JNK, p-c-Fos, and p-c-Jun. Additionally, anisomycin, a specific activator of JNK, blocked the protection of esculetin against H2O2-induced HepG2 cells apoptosis and pyroptosis. In conclusion, esculetin can protect HepG2 cells against H2O2-induced oxidative stress, apoptosis, and pyroptosis via inhibiting the JNK signaling pathway. These findings indicate that esculetin has the potential to be used as an antioxidant that improves oxidative stress-related diseases.

Efficacy and safety analysis of immunotherapy in non-small cell lung cancer patients with MET alterations.

BACKGROUND: Mesenchymal epithelial transition factor (MET) is a rare oncologic driver gene, and information on immunotherapy for non-small cell lung cancer (NSCLC) patients with this driver gene is limited. Here we evaluate the efficacy and safety of immune checkpoint inhibitors (ICI) under different therapeutic regimen for NSCLC patients with MET alterations. METHODS: From June 2019 to December 2023, we assessed the efficacy and toxicity of ICIs in 42 NSCLC patients with MET alterations. Survival curves were plotted using the Kaplan-Meier method and the Cox proportional hazards model applied for univariate and multivariate analyses. We assessed the size of target lesion according to RECIST v1.1, and objective response rate (ORR) was defined as the sum of complete response (CR) and partial response (PR), disease control rate (DCR) as the sum of CR, PR, and disease stable. RESULTS: A total of 42 NSCLC patients with MET alterations were included in this retrospective study, 10 was MET 14 skipping mutation and 32 was MET amplification. The ORR for ICI treatment was 30.95% and the DCR was 71.43%. Median progression-free survival (mPFS) and median overall survival (OS) were 4.40 and 13.97 months, respectively. There exists statistical differences between the mPFS of ICI monotherapy and combine ICI therapy (2.8 vs 7.8 months, p = 0.022). The incidence of drug-related adverse reactions was 47.62%, mainly bone marrow suppression (14.28%), immune-related pneumonia (7.14%), and liver function impairment (7.14%), and six patients (14.28%) experiencing grade 3 or above adverse events. CONCLUSION: NSCLC patients with MET alterations can benefit from immunotherapy, especially the patients treated by combined ICI therapy. However, special attention should be paid to the occurrence of grade 3/4 adverse reactions while using the combined ICI therapy.

Honokiol suppress the PD-L1 expression to improve anti-tumor immunity in lung cancer.

Lung cancer is a serious health issue globally, and current treatments have proven to be inadequate. Therefore, immune checkpoint inhibitors (ICIs) that target the PD-1/PD-L1 pathway have become a viable treatment option in lun cancer. Honokiol, a lignan derived from Magnolia officinalis, has been found to possess anti-inflammatory, antioxidant, and antitumor properties. Our research found that honokiol can effectively regulate PD-L1 through network pharmacology and transcriptome analysis. Cell experiments showed that honokiol can significantly reduce PD-L1 expression in cells with high PD-L1 expression. Molecular docking, cellular thermal shift assay (CETSA) and Bio-Layer Interferometry (BLI)indicated that Honokiol can bind to PD-L1. Co-culture experiments on lung cancer cells and T cells demonstrated that honokiol mediates PD-L1 degradation, stimulates T cell activation, and facilitates T cell killing of tumor cells. Moreover, honokiol activates CD4 + and CD8 + T cell infiltration in vivo, thus suppressing tumor growth in C57BL/6 mice. In conclusion, this study has demonstrated that honokiol can inhibit the growth of lung cancer by targeting tumor cell PD-L1, suppressing PD-L1 expression, blocking the PD-1/PD-L1 pathway, and enhancing anti-tumor immunity.

Edoxaban for stroke prevention in atrial fibrillation and factors associated with dosing: patient characteristics from the prospective observational ETNA-AF-China registry.

Real-world data on effectiveness and safety of a single non-vitamin K antagonist oral anticoagulant in the Chinese population with atrial fibrillation (AF) are limited. This study reports characteristics of patients treated with edoxaban and factors associated with dosing patterns from routine care in China. ETNA-AF-China (NCT04747496) is a multicentre, prospective, observational study enrolling edoxaban-treated patients from four economic regions with a targeted 2-year follow-up. Of the 4930 patients with AF (mean age: 70.2 ± 9.5 years; male, 57.1%), the mean creatinine clearance (CrCl), CHA2DS2-VASc, and HAS-BLED scores were 71.2 mL/min, 2.9, and 1.6. Overall, 6.4% of patients were perceived as frail by investigators. Available label dose reduction criteria (N = 4232) revealed that 3278 (77.5%) patients received recommended doses and 954 (22.5%) non-recommended doses. Northeast (53.0%) and West (43.1%) regions had the highest prescriptions of 60 mg and 30 mg recommended doses, respectively. Non-recommended 30 mg doses were more frequently prescribed in patients with antiplatelet use and history of heart failure than recommended 60 mg. Multivariate analysis identified advanced age as the strongest associated factor with non-recommended doses. Frailty had the strongest association with 30 mg except for age, and history of TIA was the most relevant factor associated with 60 mg. In conclusion, patients in the ETNA-AF-China study were predominantly aged 65 years and older, had mild-to-moderate renal impairment and good label adherence. Advanced age was associated with non-recommended doses, with frailty most common for non-recommended 30 mg and a history of TIA for the non-recommended 60 mg dose.

PVB exerts anti-inflammatory effects by inhibiting the activation of MAPK and NF-κB signaling pathways and ROS generation in neutrophils.

Pinaverium bromide (PVB) has been shown to protect mice against sepsis, which is predominantly attributed to PVB-mediated anti-inflammatory effects by inhibiting primed neutrophils to produce proinflammatory cytokines. However, the underlying mechanism(s) by which PVB affects neutrophils remains unknown. In this study, we report that treatment with PVB either before or after LPS stimulation attenuated IL-1ß and TNF-α expression at both mRNA and protein levels in LPS-activated murine neutrophils. Further experiments revealed that PVB inhibited the phosphorylation of ERK, JNK, and IκBα in LPS-stimulated murine neutrophils. Moreover, PVB reduced reactive oxygen species (ROS) levels via regulating NADPH oxidase 2 (NOX2) activity, as represented by inhibiting p47phox translocation from the cytoplasm to the cellular membrane. Importantly, PVB significantly attenuated IL-1ß, TNF-α, IL-6, CXCL1 production in both LPS-stimulated low density neutrophils (LDNs) and normal density neutrophils (NDNs) isolated from septic patients. Collectively, we demonstrated that PVB exerts anti-inflammatory effect by attenuating ROS generation and suppressing the activation of MAPK and NF-κB signaling pathways, suggesting that PVB may act as a potential therapeutic agent for sepsis by inhibiting neutrophil priming and activation.

Ursolic acid induces apoptosis and pyroptosis in Reh cells by upregulating of the JNK signalling pathway based on network pharmacology and experimental validation.

Objective: To explore the mechanism of ursolic acid (UA) against acute B lymphoblastic leukaemia (B-ALL) based on network pharmacological analysis, molecular docking and experimental verification. Methods: The core targets, functional processes, and biological pathways of UA in B-ALL were predicted by network pharmacology and molecular docking. The efficacy and mechanism of UA against B-ALL were verified through in vitro experiments such as cell viability assays, CCK-8 assays, LDH assays, AO/EB staining, flow cytometry, and Western blot assays. Results: Network pharmacology analysis of the core targets indicated that the effects of UA on B-ALL were related to programmed cell death (apoptosis and pyroptosis). Molecular docking results showed that FOS, CASP8, MAPK8, IL-1ß and JUN were the key targets of UA against B-ALL. The MTS assay showed that UA decreased the viability of Reh cells in a concentration- and time-dependent manner. Cellular and Western blot experiments found that UA induced Reh cell apoptosis and pyroptosis by upregulating the JNK signalling pathway. Conclusions: Our findings demonstrated that UA could induce Reh cell apoptosis and pyroptosis by activating the JNK signalling pathway to exert anti-B-ALL effects. This indicates that UA may become a potential drug for the effective treatment of B-ALL.

Clinical characteristics and treatment efficacy of immune checkpoint inhibitors (ICIs) in patients with ICIs-induced Adrenal insufficiency.

BACKGROUND: Adrenal insufficiency (AI) caused by immune checkpoint inhibitors (ICIs) is an extremely rare immune-related adverse event (irAE). The detailed clinical characteristics and outcomes of patients with ICI-induced AI are unavailable. This study aimed to explore the clinical characteristics and efficacy of treatment in patients with ICI-induced AI. METHODS: We retrospectively collected information on patients diagnosed with AI caused by ICIs at LiShui Municipal Central Hospital and Zhejiang Cancer Hospital, including baseline characteristics, laboratory results, symptoms, treatment outcomes of AI, and hormone use. Survival outcomes were calculated using the Kaplan-Meier method and stratified according to the different situations. RESULTS: From December 2020 to February 2023, among 1014 patients treated with ICI therapy, a total of twenty patients were diagnosed with ICI-induced AI. Most of the patients were men (80%, n = 16), with a performance status (PS) of 0 - 1 (95%, n = 19). The median (range) age was 65.9 (49-80) years and 14 patients (70%) were treated with ICIs as first-line therapy. The majority of the patients (70%, n = 14) experienced grade 3 - 4 AI. All patients received corticosteroid replacement therapy, and only 7 patients recovered. The median time to the diagnosis of AI after starting ICI therapy was 5.2 (3.0 - 7.5) months. The objective response rate was 70% and  median progression-free survival in these patients was 16.0 months (95% confidence interval: 11.7 - 20.3 months). CONCLUSIONS: ICI-induced AI is a rare irAE, and close monitoring of cortisol levels is important. Patients diagnosed with AI after receiving immunotherapy seem to have a favorable outcome.

SGK3 overexpression correlates with a poor prognosis in endoscopically resected superficial esophageal squamous cell neoplasia: A long-term study.

BACKGROUND: The expression status of serum and glucocorticoid-induced protein kinase 3 (SGK3) in superficial esophageal squamous cell neoplasia (ESCN) remains unknown. AIM: To evaluate the SGK3 overexpression rate in ESCN and its influence on the prognosis and outcomes of patients with endoscopic resection. METHODS: A total of 92 patients who had undergone endoscopic resection for ESCN with more than 8 years of follow-up were enrolled. Immunohistochemistry was used to evaluate SGK3 expression. RESULTS: SGK3 was overexpressed in 55 (59.8%) patients with ESCN. SGK3 overexpression showed a significant correlation with death (P = 0.031). Overall survival and disease-free survival rates were higher in the normal SGK3 expression group than in the SGK3 overexpression group (P = 0.013 and P = 0.004, respectively). Cox regression analysis models demonstrated that SGK3 overexpression was an independent predictor of poor prognosis in ESCN patients (hazard ratio 4.729; 95% confidence interval: 1.042-21.458). CONCLUSION: SGK3 overexpression was detected in the majority of patients with endoscopically resected ESCN and was significantly associated with shortened survival. Thus, it might be a new prognostic factor for ESCN.

The impact of ABCB1, CYP3A4/5 and ABCG2 gene polymorphisms on rivaroxaban trough concentrations and bleeding events in patients with non-valvular atrial fibrillation.

BACKGROUND: The influence of genetic factors on the pharmacokinetics and clinical outcomes of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF) is poorly understood. This study aimed to explore the effects of CYP3A4/5, ABCB1, and ABCG2 gene polymorphisms on the trough concentrations and the bleeding risk of rivaroxaban in NVAF patients. PATIENTS AND METHODS: This study is a prospective multicenter study. The patient's blood samples were collected to detect the steady-state trough concentrations of rivaroxaban and gene polymorphisms. We visited the patients regularly at month 1, 3, 6, and 12 to record bleeding events and medications. RESULTS: A total of 95 patients were enrolled in this study, and 9 gene loci were detected. For the dose-adjusted trough concentration ratio (Ctrough/D) of rivaroxaban, the homozygous mutant type was significantly lower than wild type at ABCB1 rs4148738 locus (TT vs. CC, P = 0.033), and the mutant type was significantly lower than the wild type at ABCB1 rs4728709 locus (AA + GA vs. GG, P = 0.008). ABCB1 (rs1045642, rs1128503), CYP3A4 (rs2242480, rs4646437), CYP3A5 (rs776746), and ABCG2 (rs2231137, rs2231142) gene polymorphisms had no significant effect on the Ctrough/D of rivaroxaban. For the bleeding events, we found that there were no significant differences among genotypes of all gene loci. CONCLUSION: This study found for the first time that ABCB1 rs4148738 and rs4728709 gene polymorphisms had a significant impact on the Ctrough/D of rivaroxaban in NVAF patients. CYP3A4/5, ABCB1, and ABCG2 gene polymorphisms were not associated with the bleeding risk of rivaroxaban.

Objective quantification of posterior capsule opacification after cataract surgery with swept-source optical coherence tomography.

PURPOSE: To evaluate the application of swept-source optical coherence tomography (SS-OCT) and pentacam scheimpflug tomography in posterior capsule opacification (PCO) severity assessment. METHODS: The posterior capsule image region segmentation and adaptive threshold algorithm are used to process the SS-OCT scanned image to obtain the posterior capsule thickness (PCT). Scheimpflug tomography reconstructed and analysized by image J software can obtain the average gray value and evaluate the effectiveness with the two methods. RESULT: One hundred sixty-two IOL eyes of 101 patients were divided into two groups, laser group (65 eyes) with the mean PCT was 8.0 ± 2.7 pixel unit and the mean gray value of the eyes was 66 ± 33 pixel unit. However, these figures in the control group (97 eyes) were 5.0 ± 0.9 and 11 ± 17. The sensitivity, specificity and area under curve(AUC) of SS-OCT PCT were 85%, 74% and 0.942,the sensitivity, specificity and AUC of Pentacam gray value were 91%, 76% and 0.947, respectively. After using the multivariable model of generalized estimation equation to corrected the dependence of subjects' eyes, it was found that SS-OCT PCT, Pentacam gray value, low vision quality of life questionnaire (LVQ questionnaire) for distance vision, and mobility and lighting dimension were significantly correlated with the PCO score (P = 0.012, P = 0.001, P = 0.005, respectively). CONCLUSION: The region segmentation and adaptive threshold algorithm of posterior capsule image will accurately quantify the posterior capsule. Computer aided quantifications of posterior capsule are of great significance in the early surgical decision-making of PCO. The average occurrence time of most PCO was around 34 months, and the severity of PCO worsened with increasing postoperative time.

Discovery of novel arylamide derivatives containing piperazine moiety as inhibitors of tubulin polymerisation with potent liver cancer inhibitory activity.

In this work, a series of novel arylamide derivatives containing piperazine moiety were designed and synthesised as tubulin polymerisation inhibitors. Among 25 target compounds, compound 16f (MY-1121) exhibited low nanomolar IC50 values ranging from 0.089 to 0.238 µM against nine human cancer cells. Its inhibitory effects on liver cancer cells were particularly evident with IC50 values of 89.42 and 91.62 nM for SMMC-7721 and HuH-7 cells, respectively. Further mechanism studies demonstrated that compound 16f (MY-1121) could bind to the colchicine binding site of ß-tubulin and directly act on ß-tubulin, thus inhibiting tubulin polymerisation. Additionally, compound 16f (MY-1121) could inhibit colony forming ability, cause morphological changes, block cell cycle arrest at the G2 phase, induce cell apoptosis, and regulate the expression of cell cycle and cell apoptosis related proteins in liver cancer cells. Overall, the promising bioactivities of compound 16f (MY-1121) make the novel arylamide derivatives have the value for further development as tubulin polymerisation inhibitors with potent anticancer activities.

Boron-peptide conjugates with angiopep-2 for boron neutron capture therapy.

Boron neutron capture therapy (BNCT) induces intracellular nuclear reaction to destroy cancer cells during thermal neutron irradiation. To selectively eliminate cancer cells but avoid harmful effects on normal tissues, novel boron-peptide conjugates with angiopep-2, namely ANG-B, were constructed and evaluated in preclinical settings. Boron-peptide conjugates were synthesized using solid-phase peptide synthesis, and the molecular mass was validated by mass spectrometry afterwards. Boron concentrations in 6 cancer cell lines and an intracranial glioma mouse model after treatments were analyzed by inductively coupled plasma atomic emission spectroscopy (ICP-AES). Phenylalanine (BPA) was tested in parallel for comparison. In vitro treatment with boron delivery peptides significantly increased boron uptake in cancer cells. BNCT with 5 mM ANG-B caused 86.5% ± 5.3% of clonogenic cell death, while BPA at the same concentration caused 73.3% ± 6.0% clonogenic cell death. The in vivo effect of ANG-B in an intracranial glioma mouse model was evaluated by PET/CT imaging at 31 days after BNCT. The mouse glioma tumours in the ANG-B-treated group were shrunk by 62.9% on average, while the BPA-treated tumours shrank by only 23.0%. Therefore, ANG-B is an efficient boron delivery agent, which has low cytotoxicity and high tumour-to-blood ratio. Based on these experimental results, we expected that ANG-B may leverage BNCT performance in clinical applications in future.

Niclosamide exposure disrupts antioxidant defense, histology, and the liver and gut transcriptome of Chinese soft-shelled turtle (Pelodiscus sinensis).

Niclosamide (NIC) is the only commercially available molluscicide for controlling schistosomiasis, and its negative effects on aquatic animals had been frequently reported in recent years. However, the toxicity mechanism of NIC on the Chinese soft-shelled turtle (Pelodiscus sinensis) have not yet been investigated. Therefore, juvenile turtles were exposed to 0 (control group), 10 (low NIC, L), and 50 (high NIC, H) µg/L NIC for 120 h and our results demonstrated that NIC exposure induced severe pathological changes in the liver of P. sinensis. And the typical symptom included edema, nuclear migration and deformation, and vacuolization. Compared with the liver, the NIC exposure did not cause significant damage in the gut tissue. In addition, the DHE staining demonstrated that the ROS production of liver and gut increased with the increase in concentration of NIC. The activities of antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) was inhibited with increased malondialdehyde (MDA) content, indicating that the antioxidant defense was significantly perturbed. Further, the transcriptome sequencing and was applied to evaluate the underlying toxicity mechanisms of NIC exposure in liver and gut of P. sinensis. Pathway enrichment showed that the disorder of lipid metabolism and innate immune regulation, including Toll-like receptors (TLRs), tumor necrosis factor (TNF), lectins, and complement and coagulation cascades, were toxicological properties of NIC on P. sinensis. Overall, the current study provides valuable information to understand the toxic effect of NIC on Chinese soft-shelled turtle.

The combination of etoposide and platinum for the treatment of thymic neuroendocrine neoplasms: A retrospective analysis.

BACKGROUND: To provide real-world outcomes for the combination of etoposide and platinum as a first-line treatment for advanced thymic neuroendocrine neoplasms (TNENs). METHODS: Retrospective analysis was performed on patients with advanced TNENs confirmed by pathology who received etoposide combined with platinum as a first-line chemotherapy in our institution between 2010 and 2022. RESULTS: A total of 16 patients were included in this study. Twelve patients (75%) received etoposide combined with cisplatin, and four patients (25%) received etoposide combined with carboplatin. Efficacy was evaluated in all patients, with an objective response rate of 31.3%. One patient achieved a complete response, four achieved a partial response, and in eight patients the disease remained stable; the disease control rate was 81.3%. The median progression-free survival (PFS) was 7.2 months with a 95% confidence interval (CI) of 2.1-12.3 months. The median overall survival (OS) was 50.4 months with a 95% CI of 32.1-68.8 months. No significant difference in efficacy was observed between the treatment groups with regards to PFS (p = 0.095) and OS (p = 0.061). Treatment-related adverse events were observed in all 12 patients when evaluated for toxicity, manifesting as hematologic toxicity. Grade 3-4 bone marrow suppression occurred in six patients (50%). No treatment-related deaths were recorded. CONCLUSION: This retrospective analysis, conducted in a real-life setting, suggests that the combination of etoposide and platinum has a promising anti-tumor activity in advanced TNENs, with a clinically significant overall response rate.

TXNL4B regulates radioresistance by controlling the PRP3-mediated alternative splicing of FANCI.

Ionizing radiation (IR) has been extensively used for cancer therapy, but the radioresistance hinders and undermines the radiotherapy efficacy in clinics greatly. Here, we reported that the spliceosomal protein thioredoxin-like 4B (TXNL4B) is highly expressed in lung tissues from lung cancer patients with radiotherapy. Lung cancer cells with TXNL4B knockdown illustrate increased sensitivity to IR. Mechanistically, TXNL4B interacts with RNA processing factor 3 (PRP3) and co-localizes in the nucleus post-IR. Nuclear localization of PRP3 promotes the alternative splicing of the Fanconi anemia group I protein (FANCI) transcript variants, FANCI-12 and FANCI-13. PRP3 regulates alternative splicing of FANCI toward the two variants, FANCI-12 and FANCI-13. Radioresistance was greatly enhanced through the combination of PRP31 and PRP8, the critical components of core spliceosome promoted by PRP3. Notably, the inhibition of PRP3 to suppress the production of FANCI-12 would deprive PRP31 and PRP8 of such interaction. As a result, cell cycle G2/M arrest was induced, DNA damage repair was delayed, and radiosensitivity was improved. Collectively, our study highlights potential novel underlying mechanisms of the involvement of TXNL4B and alternative splicing in radioresistance. The results would benefit potential cancer radiotherapy.

Clinical outcomes of immune checkpoint inhibitors to treat non-small cell lung cancer patients harboring epidermal growth factor receptor mutations.

BACKGROUND: We aimed to determine the clinical. outcomes of various immune checkpoint inhibitor (ICI) combinations for the treatment of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. The results predicted the treatment efficacy of these combinations. METHODS: From July 15, 2016 to March 22, 2022, 85 NSCLC patients with EGFR mutations, enrolled at the Zhejiang Cancer Hospital, received ICI combinations after resistance to prior EGFR-tyrosine kinase inhibitors (EGFR-TKIs). These patients were diagnosed with EGFR mutations using an amplification refractory mutation system PCR (ARMS-PCR) and next-generation sequencing (NGS). Survival times were analyzed using the Kaplan-Meier method and log-rank test. RESULTS: Patients who received ICIs combined with anti-angiogenic therapy had longer progression-free survival (PFS) and overall survival (OS) than patients who received ICIs combined with chemotherapy. There was no significant difference in survival time between patients who received ICIs combined with chemotherapy and anti-angiogenic therapy and patients who received ICIs combined with anti-angiogenic therapy or ICIs combined with chemotherapy, which was due to the limitation sample size of patients who received ICIs combined with chemotherapy and anti-angiogenic therapy. Patients with L858R mutations had a longer PFS and OS than patients with exon 19 deletions. T790M negative patients benefited more from ICI combinations, compared with T790M positive patients. In addition, there was no significant difference in PFS and OS between patients with TP53 co-mutations and patients without a TP53 co-mutation. We also found that patients with prior first-generation EGFR-TKI resistance had longer PFS and OS than prior third-generation EGFR-TKI resistance patients. There was no new adverse event in this study. CONCLUSIONS: EGFR-mutated patients who received ICIs combined with anti-angiogenic therapy had longer PFS and OS than patients with ICIs combined with chemotherapy. Patients with L858R or without T790M mutation benefited more from ICI combinations. Besides, patients with prior first-generation EGFR-TKI resistance could benefit more from ICIs combinations than prior third-generation EGFR-TKI resistance patients.

Discovery of a novel Coumarin-Dihydroquinoxalone derivative MY-673 as a tubulin polymerization inhibitor capable of inhibiting the ERK pathway with potent anti-gastric cancer activities.

As a class of microtubule targeting agents, colchicine binding site inhibitors (CBSIs) are considered as promising drug candidates for cancer therapy. However, due to adverse reactions, there are currently no CBSIs approved by FDA for cancer treatment. Therefore, extensive efforts are still encouraged to find novel CBSIs with different chemical structures and better anticancer efficacies. In this work, we designed and synthesized a new coumarin-dihydroquinoxalone derivative, MY-673, and evaluated its anticancer potency in vitro and in vivo. We confirmed that MY-673 was a potent CBSI that it not only inhibited tubulin polymerization, but also exhibited significant inhibitory potency on the growth of 13 cancer cells with IC50 values from 11.7 nM to 395.9 nM. Based on the results of kinase panel screening, MY-673 could inhibit ERK (extracellular regulated protein kinases) pathways-related kinases. We further confirmed that MY-673 could inhibit ERK signaling pathway in MGC-803 and HGC-27 cells, and then affected the expression level of SMAD4 protein in TGF-ß (transforming growth factor ß) /SMAD (small mother against decapentaplegic) signaling pathway using the western blotting assay. In addition, compound MY-673 could effectively inhibit cell proliferation, migration and induce cell apoptosis. We also further confirmed the in vivo efficacy of MY-673 in inhibiting tumor growth using the MGC-803 xenograft tumor model. At 20 mg/kg, the TGI rate was 85.9%, and it did not cause obvious toxicity to the main organs of mice. Together, the results we report here indicated that MY-673 was a promising CBSI for cancer treatment, which was capable of inhibiting the ERK pathway with potent antiproliferative activities in vitro and in vivo.

Efficacy and safety of immune checkpoint inhibitors (ICIs) combined with antiangiogenic therapy for thymic epithelial tumors (TETs): a retrospective study.

Background: Immune checkpoint inhibitors (ICIs) combined with antiangiogenic therapy have shown promising antitumor activity against a range of advanced cancers. However, evidence is lacking as to whether this combination therapy could benefit thymic epithelial tumors (TETs). We aimed to explore the efficacy and safety of this combination therapy in advanced TETs. Methods: Ten patients with pathologically proven advanced TETs who received ICIs combined with an antiangiogenic agent from 2020 to 2022 at Zhejiang Cancer Hospital were included in the study. The Kaplan-Meier method was used to compare the treatment efficacy and survival outcomes. Results: Of the cohort of ten patients who received immunotherapy combined with antiangiogenic targeting drugs, two patients achieved a partial response (PR) with an objective response rate of 20% and seven patients achieved stable disease (SD) with a disease control rate (DCR) of 90%. The median progression-free survival (PFS) was 6.7 months [95% confidence interval (CI): 3.35-8.515] and the median overall survival (OS) was 45.6 months (95% CI: 3.265-88.001). Grade 3 treatment-related adverse events (TRAEs) were only detected in one patient. No grade 4 or above TRAEs were observed. Conclusions: ICIs in combination with antiangiogenic targeted drugs may be a promising treatment for advanced TETs.