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Background: Anlotinib is a new multi-target tyrosine kinase inhibitor (TKI) and has been shown to have antitumor effects and synergistic antitumor effects with immunotherapy only in animal studies and in the 2nd-line treatment in small clinical trials. A real-world study with large sample to compare the efficacy and safety of anlotinib plus immune checkpoint inhibitors (ICIs) with ICIs alone in the multiline treatment of advanced non-small cell lung cancer (NSCLC) was urgently needed. Methods: The data of 535 advanced NSCLC patients were collected from January 1, 2018, to December 31, 2021. The patients were divided into 2 groups: (I) ICI monotherapy (230 patients); (II) ICI + anlotinib (305 patients). After propensity-score matching (PSM) to reduce the effects of biases and confounding variables, the progression-free survival time (PFS), occurrence of adverse events, disease control rate (DCR), and objective response rate (ORR) of the 2 groups were compared. The effects of clinical factors, including age, gender, gene mutations, tumor proportion score, metastases, and combined radiotherapy, were also analyzed. Results: After PSM, the baseline clinical characteristics were well balanced and the 2 group had a good comparability. Patients in the ICI + anlotinib group had significantly longer median PFS in both the 2nd-line treatment (7.73 vs. 4.70 months; P=0.003) and 3rd-line treatment (5.90 vs. 3.37 months; P=0.020), but the difference lacked statistical significance in the 1st-line treatment (8.40 vs. 5.20 months; P=0.229). The overall ^ ORCID: 0000-0001-6458-2458.median PFS of patients in the ICI + anlotinib group was also much longer than that of patients in the ICI monotherapy group (6.37 vs. 3.90 months; P<0.001). The ICI + anlotinib group also tended to have a higher DCR, a higher ORR, and a higher probability of severe adverse drug reactions during the treatment than the ICI monotherapy group, but the differences were not statistically significant. Combining ICI + anlotinib could improve the outcomes of patients with bone metastasis.Conclusions: Anlotinib + ICI therapy could have greater efficacy in the treatment of advanced NSCLC patients than ICI monotherapy. The probability of adverse events might increase in the combined treatment, but could be controlled.

BackgroundBilateral multiple ground glass opacities (GGOs) are observed in quite a part of patients with early-stage lung adenocarcinoma. For this so-called synchronous multiple primary lung cancer (sMPLC), targeting immune checkpoint is a favorable option in addition to surgical resection. The purpose of this study is to reveal the safety and efficacy of performing immune checkpoint inhibitors (ICIs) on patients with sMPLC and to explore the biomarkers of the efficacy.MethodsA total of 21 patients with sMPLC were enrolled and all included cases were pathologically confirmed adenocarcinoma after conducting surgical treatment for unilateral GGOs. ICIs of Sintilimab were then used to target programmed death 1 (200mg i.v., Q3W) for up to 10 cycles. Seven patients of them received the other surgery for contralateral GGOs, and multiomics assessments, including neoantigens, somatic mutations, and methylated loci, were further performed to investigate potential biomarkers.ResultsGrade 1 or 2 treatment-related adverse events (AEs) occurred in most of the patients (12/21, 57.1%), and one subject withdrawn for grade 3 AEs. For the seven patients underwent twice surgeries, twelve and thirteen GGOs were achieved before and after the use of ICIs separately, and a favorable efficacy was observed among six lesions after immunotherapy (&gt; 50% pathologic tumor regression). Tumor infiltration T-cell and B-cell were further shown to be associated with the biological activity of ICIs. According to mechanism-based multiomics analyses, MUC19- and PCDHB5- mutations were indicated to correlate with a favorable prognosis of sMPLC underwent immunotherapy, and our results suggested that immunogenetic mutation and associated promoter methylation could provide a quantitative explanation for the pathologic response of GGOs.ConclusionOur study provides evidence that the use of ICIs contributed favorable efficacy and safety to patients with sMPLC. Immune infiltration and immunogenic biomarkers are revealed to be implications of performing ICIs on sMPLC. These preliminary findings exhibit the prospects in performing neoadjuvant or adjuvant immunotherapies on patients with sMPLC.Clinical Trial Registrationhttps://www.chictr.org.cn/showproj.aspx?proj=36878, identifier ChiCTR1900022159.

Salinity is one of the major abiotic constraints affecting the growth and yield of plants including soybean. In this context, the previous studies have documented the role of the mitogen‐activated protein kinase (MAPK) cascade in the regulation of salt signaling in model plants. However, there is not a systematic analysis of salt‐related MAPKs in soybean. Hence, in this study, we identified a total of 32 GmMAPKs via., genome‐wide reanalysis of the MAPK family using the soybean genome v4.0. Based on the transcriptome datasets in the public database, we observed that GmMAPKs are induced by different abiotic stresses, especially salt stress. Furthermore, based on the candidate gene association mapping and haplotype analysis of the GmMAPKs, we identified a salt‐related MAPK member, GmMMK1. GmMMK1 possesses significant sequence variations, which affect salt tolerance in soybean at the germination stage. Besides, the overexpression of the GmMMK1 in soybean hairy roots has a significant negative effect on the root growth, leading to increased sensitivity of the GmMMK1‐OE plants to salt stress. Moreover, the heterologous expression of the GmMMK1 in Arabidopsis has been also observed to have a negative effect on the germination and root growth under salt stress. The transcriptome analysis and yeast two‐hybrid screening showed that hormone signaling and the homeostasis of reactive oxygen species are involved in the GmMMK1 regulation network. In conclusion, the results of this work demonstrated that GmMMK1 is an important negative regulator of the salt stress response, and provides better insights for understanding the role of the MAPKs in soybean salt signaling.