The coronary slow flow phenomenon (CSFP) is characterized by delayed progression of the injected contrast medium through the coronary tree during coronary angiography due to unknown mechanisms. Here, a human induced pluripotent stem cell (iPSC) line (SYSUi002-A) was established using the Sendai-virus delivery system from dermal fibroblasts of a CSFP patient. This cell line may represent a valuable tool for investigating the pathogenesis and therapeutic strategies of CSFP.
Limited data are available for the combination regimen of anti-programmed cell death protein 1 (PD-1) inhibitor and anti-angiogenic agents as second-line therapy for the treatment of patients with advanced non-small cell lung cancer (NSCLC), especially in patients with squamous NSCLC. This study assessed the efficacy and safety of camrelizumab plus apatinib (a vascular endothelial growth factor receptor 2 inhibitor) as second-line treatment in patients with advanced squamous NSCLC.In the Cohort 3 from a phase II dose-expansion trial, patients with advanced non-central squamous NSCLC who were immunotherapy naïve and had failed prior first-line platinum-based chemotherapy received 200 mg of camrelizumab intravenously every 2 weeks plus oral apatinib at the recommended dose of 250 mg once daily. The primary endpoint was objective response rate (ORR) assessed by the investigators as per the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1.Cohort 3 was prematurely terminated because of slow accrual after 25 patients with advanced squamous NSCLC had been enrolled between 10 October 2018, and 3 March 2019. At the data cutoff date of 12 June 2020, the median follow-up was 13.3 (range, 1.6 to 19.2) months. Among all 25 participants, the ORR was 32.0% (95% CI: 14.9% to 53.5%), the clinical benefit rate was 44.0% (95% CI: 24.4% to 65.1%), and the disease control rate (DCR) was 84.0% (95% CI: 63.9% to 95.5%). Median progression-free survival (PFS) was 6.0 (95% CI: 3.5 to 8.1) months, and median overall survival (OS) was 13.3 (95% CI: 6.4 to 18.8) months. Furthermore, clinical benefits from this combination regimen were evident across all tumor PD ligand 1 (PD-L1) expression subgroups. The most common treatment-related adverse events (TRAEs) of grade 3 or higher were hypertension (44.0%) and palmar-plantar erythrodysesthesia (16.0%). As reported by the investigators, 3 participants (12.0%) died due to TRAEs (interstitial pneumonia, hemorrhage, and unknown reason; n=1 each, 4%).Camrelizumab plus apatinib as second-line therapy showed satisfactory antitumor activity in patients with non-central squamous NSCLC, regardless of tumor PD-L1 expression. Camrelizumab plus apatinib had a manageable safety profile in this patient population, and the toxic reactions observed were generally consistent with those in previously reported studies. Interstitial pneumonia and hemorrhage are important risks requiring careful monitoring and prompt intervention.
e21651 Background: Anti PD-1 antibodies, nivolumab or pembrolizumab, have been approved for the treatment of a variety of malignant tumors including melanoma and non-small cell lung cancer (NSCLC). Pneumonitis has been described as a major adverse effect related with these agents, although the overall incidence and risk remain unclear. We performed a meta-analysis to characterize the overall incidence and risk of pneumonitis in cancer patients treated with these agents and to describe the relative risk compared with control. Methods: The electronic databases PubMed, Embase, Web of Science, Cochrane databases, and ASCO (American Society of Clinical Oncology) abstracts were searched for studies to include in the meta-analysis. Eligible studies were prospective phase II and III clinical trials of nivolumab or pembrolizumab with adequate safety data. Summary incidences, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed or random effect models depending on the heterogeneity of the included studies. Results: A total of 5005 patients with a variety of malignant tumors from 15 prospective clinical trials were included for the meta-analysis. The overall incidence of all-grade and high-grade pneumonitis due to anti PD-1 antibodies was 2.9% (95% CI: 2.4 – 3.6%) and 1.8% (95% CI: 1.6 – 2.1%), respectively. Compared with control, the RR of pneumonitis of anti PD-1 antibodies was increased for all-grade (RR = 3.42, 95% CI: 1.83 – 6.43, P < 0.001) but not high-grade (RR = 2.21, 95% CI: 0.87 – 5.62, P= 0.10) pneumonitis, respectively. The incidence of all-grade and high-grade pneumonitis in the nivolumab group was comparable to the pembrolizumab group. Subgroup analysis showed the incidence of all-grade and high-grade pneumotitis in non-melanoma patients was higher than melanoma patients. Conclusions: Treatment with anti PD-1 antibodies, nivolumab and pembrolizumab is associated with a significant increase in the all-grade risk of pneumonitis in patients with malignant tumors. Close monitoring for pneumonitis is critical for patients during their treatment with anti PD-1 antibodies.
e20074 Background: It is unclear about the clinical outcome of the combination of icotinib and rh-endostatin (Endostar) in treating advanced non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) activating mutations. This single-arm pilot study aims to investigate the preliminary efficacy and safety of the combination therapy for those patients. Methods: Patients with histologically confirmed nonsquamous advanced NSCLC who had exon 19 exon del or L858R were included. All patients received icotinib (125 mg po TID) plus rh-endostatin (15 mg civ for ten days, every 3 weeks) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) at 24 weeks, and secondary endpoint is safety profile. In addition, exploratory evaluation was performed using dynamic contrast enhanced MRI (DCE-MRI) to analyse the tumor vascular permeability parameter, Ktrans. Results: 10 patients have been enrolled. The median age was 60 years old, with 7 female and 3 male patients. There were 6 patients with exon 19 del, 3 patients with L858R mutation, and 1 patient with L858R and S768I muation. The preliminary results showed the clinical ORR at 24 weeks was 60% (1 complete resonse, 5 partial responses, and 4 stable diseases) and a mean reduction in tumor size of 32.5%. Compared with baseline, there was 52.4% and 7.5% increase in patients who obtained ORR and SD as their best response with mean Ktrans of 0.22 and 0.40, respectively. The dynamic changes of Ktrans were consistent with clinical outcome of tumor responses. In ORR group, the tumor Ktransdropped as early as seven days after the therapy, while it remained stable in SD group. The overall tolerability of the combination was good, as there were no toxicities of CTC-AE 4.0 grade 3 or greater. Conclusions: The combination of icotinib and rh-endostatin was effective and safe. Serial Ktrans derived from DCE-MRI could be used as a non-invasive imaging biomarker to prodict the tumor response after treatment, optimize the regimen and facilitate the identification of the best patient population who may potentially benefit from this combination regimen. Clinical trial information: NCT02375022.
Purpose: The aim of this study was to compare the pharmacokinetics and safety between two vinorelbine formulations [a new oil-in-water emulsion formulation (ANX) versus a previously marketed solution formulation (Navelbine)] in Chinese patients with advanced non-small cell lung cancer (NSCLC). Method: This was a single-center, randomized, open-label study. Eligible patients aged 18-70 years who had histologically or cytologically confirmed NSCLC were enrolled. In cycle 1, the patients alternatively received the two formulations (30 mg/m2, given as a 10-min infusion) with a 7-day interval. Samples for pharmacokinetic analysis were taken during cycle 1. For all subsequent 21-day cycles (maximum four cycles), ANX was administered on days 1 and day 8. Bioequivalence analysis was performed on Cmax, AUClast, and AUCinf. The safety profiles and anti-tumor effects were also determined. Results: From March 2013 to January 2015, 24 patients were enrolled and 20 were eligible for pharmacokinetic evaluation. The 20 subjects in the pharmacokinetic analysis set had a median age of 61 years (range, 37-70 years), and 15 patients were male (75%). Mean vinorelbine Cmax values for ANX and Navelbine were 1,317.40 and 1,446.30 ng/mL, respectively. Corresponding AUClast values were 797.08 and 924.26 ng·h/mL, respectively. AUCinf values were 830.14 and 957.16 ng·h/mL, respectively. Treatment ratios of the geometric means were 90.00% (90% CI, 83.22-99.07%) for Cmax, 86.92% (90% CI, 80.91-93.37%) for AUClast, and 87.44% (90% CI, 82.08-93.16%) for AUCinf. These results met the required 80-125% bioequivalence criteria. The most frequently reported adverse events after vinorelbine administration were neutropenia, leucopenia, neutropenic fever, and constipation. Conclusion: At therapeutic dosage levels, pharmacokinetic behavior and safety profiles were similar for both formulations. Chinese National Registry Code: ChiCTR-IPR-15005856.
Inflammasome, a multiprotein complex that regulates interleukin (IL)‑1β secretion and pyroptosis, participates in numerous inflammatory diseases, including sepsis, atherosclerosis and type‑2 diabetes. Investigating the inflammasome regulation is therefore crucial to understand the inflammasome activation and develop treatment for the related diseases. In addition, it remains unknown how the inflammasome is naturally suppressed during the inflammatory process. The present study aimed to investigate the role of resolvin D2 (RvD2), an innate suppressor of inflammation produced from essential ω3‑polyunsaturated fatty acids, in the activation of the inflammasome via in vitro and in vivo experiments. The effects of RvD2 on the cytokine production of inflammasome‑related peritonitis were determined, and the NLRP3 inflammasome activation was investigated in the presence of RvD2. Moreover, the potential mechanisms underlying RvD2 in NLRP3 inflammasome regulation through autophagy and proteasome were investigated. The results of the present study demonstrated that RvD2 suppressed inflammasome‑mediated peritonitis in vivo and regulated the NLR family pyrin domain containing 3 (NLRP3) inflammasome, but not in absent in melanoma 2 (AIM2), NLR family CARD domain containing 4 (NLRC4) inflammasomes. Mechanistically, RvD2 was found to promote the degradation of NLRP3 through autophagy, and the inhibition of autophagy could reverse the RvD2‑mediated suppression of NLRP3 inflammasome in vitro and partially reverse the inflammasome‑mediated peritonitis in vivo. In summary, the present study reported the negative regulation of NLRP3 inflammasome activation by RvD2. The findings from this study may extend the knowledge of the innate regulation of inflammasome and highlight a possible target for inflammasome‑related diseases.
Abstract Animal studies have indicated that SOX10 is one of the key transcription factors regulating the proliferation, migration and differentiation of multipotent neural crest (NC), and mutation of SOX10 in humans may lead to type 4 Waardenburg syndrome (WS). However, the exact role of SOX10 in human NC development and the underlying molecular mechanisms of SOX10-related human diseases remain poorly understood due to the lack of appropriate human model systems. In this study, we successfully generated SOX10-knockout human induced pluripotent stem cells (SOX10 −/− hiPSCs) by the CRISPR-Cas9 gene editing tool. We found that loss of SOX10 significantly inhibited the generation of p75 high HNK1 + /CD49D + postmigratory neural crest stem cells (NCSCs) and upregulated the cell apoptosis rate during NC commitment from hiPSCs. Moreover, we discovered that both the neuronal and glial differentiation capacities of SOX10 −/− NCSCs were severely compromised. Intriguingly, we showed that SOX10 −/− hiPSCs generated markedly more TFAP2C + nonneural ectoderm cells (NNE) than control hiPSCs during neural crest differentiation. Our results indicate that SOX10 is crucial for the transition of premigratory cells to migrating NC and is vital for NC survival. Taken together, these results provide new insights into the function of SOX10 in human NC development, and the SOX10-knockout hiPSC lines may serve as a valuable cell model to study the pathogenesis of SOX10-related human neurocristopathies.
To observe the inhibitory effect of mizolastine on substance P(SP)-induced production of leukotriene B(4) (LTB(4)) and interleukin 5 (IL-5) in mouse skin.Mice were fed with different doses of mizolastine or other control drugs, 30 min after administration animals were injected intradermally with SP on the back. The treated skin samples were taken and competitive enzyme-link immunoassay (ELISA) method was applied to detect LTB (4) and IL-5 in the skin samples.The LTB(4) and IL-5 levels in 10 mg/kg mizolastine group were (1.23 +/-0.29)pg/ml and (34.28 +/-11.00)pg/ml, respectively, which were lower than those in saline control group [(5.52+/-1.88)pg/ml and (179.62 +/-46.25)pg/ml respectively] or loratadine group [(3.89+/-1.27)pg/ml and (127.74 +/-43.27)pg/ml respectively]. No significant difference was found between 10 mg/kg mizolastine group and dexamethasone group (P=0.161 and P=0.508).Mizolastine might inhibit the production of LTB(4) and IL-5 induced by substance P in mouse skin, suggesting that anti-inflammatory effect and the blockade of histamine H1 receptors might be involved in its anti-pruritic mechanisms.
Piwi-interacting RNAs (piRNAs or piRs) are a novel class of non-coding RNAs that participate in germline development by silencing transposable elements and regulating gene expression. To date, the association between piRNAs and non‑small cell lung carcinoma (NSCLC) has not yet been elucidated. In the present study, we have demonstrated that a significant increase in piR-651 expression occurs in NSCLC. Furthermore, the abnormal expression of piR-651 was associated with cancer progression in the patients with NSCLC. The upregulation of piR-651 in A549 cells caused a significant increase in cell viability and metastasis. The percentage of arrested cells in the G0/G1 phase was lower after piR-651 overexpression compared with the controls. We also examined the expression of oncogenes and cancer suppressor genes following piR-651 overexpression in NSCLC cells. Only the expression levels of cyclin D1 and CDK4 significantly correlated with piR-651 expression both in vivo and in vitro. Furthermore, by injecting nude mice with A549 cells transfected with piR-651 plasmids to establish a xenograft model, we demonstrated that there was a correlation between piR-651 overexpression and tumor growth, which was mediated by cyclin D1 and CDK4. These findings strongly support the notion that piR-651 induces NSCLC progression through the cyclin D1 and CDK4 pathway and it may have applications as a potential diagnostic indicator and therapeutic target in the management of NSCLC.
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