Intraductal papillary mucinous neoplasm originating from a jejunal heterotopic pancreas: A case report.

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) is a rare pancreatic tumor and has the potential to become malignant. Surgery is the most effective treatment at present, but there is no consensus on the site of resection. Heterotopic pancreas occurs in the gastrointestinal tract, especially the stomach and duodenum but is asymptomatic and rare. We report a case of ectopic pancreas with IPMN located in the jejunum. CASE SUMMARY: A 56-year-old male patient suffered from severe pain, nausea and vomiting due to a traffic accident and sought emergency treatment at our hospital. Contrast-enhanced computed tomography of the whole abdomen suggested splenic congestion, which was considered to be splenic rupture. Emergency laparotomy was performed, and the ruptured spleen was removed during the operation. Unexpectedly, a cauliflower-like mass of about 2.5 cm × 2.5 cm in size was incidentally found about 80 cm from the ligament of Treitz during the operation. A partial small bowel resection was performed, and postoperative pathology confirmed the small bowel mass as heterotopic pancreas with low-grade IPMN. CONCLUSION: Ectopic pancreas occurs in the jejunum and is pathologically confirmed as IPMN after surgical resection.

Spatial transcriptomics reveals the heterogeneity and FGG+CRP+ inflammatory cancer-associated fibroblasts replace islets in pancreatic ductal adenocarcinoma.

Background: Understanding the spatial heterogeneity of the tumor microenvironment (TME) in pancreatic cancer (PC) remains challenging. Methods: In this study, we performed spatial transcriptomics (ST) to investigate the gene expression features across one normal pancreatic tissue, PC tissue, adjacent tumor tissue, and tumor stroma. We divided 18,075 spatial spots into 22 clusters with t-distributed stochastic neighbor embedding based on gene expression profiles. The biological functions and signaling pathways involved in each cluster were analyzed with gene set enrichment analysis. Results: The results revealed that KRT13+FABP5+ malignant cell subpopulation had keratinization characteristics in the tumor tissue. Fibroblasts from adjacent tumor tissue exhibited a tumor-inhibiting role such as "B-cell activation" and "positive regulation of leukocyte activation." The FGG+CRP+ inflammatory cancer-associated fibroblasts replaced the islets in tumor stroma. During PC progression, the damage to pancreatic structure and function was heavier in the pancreatic exocrine (AMYA2+PRSS1+) than in the endocrine (INS+GCG+). Conclusion: Our results revealed the spatial heterogeneity of dynamic changes and highlighted the significance of impaired exocrine function in PC.

Structural studies of the nucleus-like assembly of jumbo bacteriophage 201φ2-1.

The jumbo phages encode proteins that assemble to form a nucleus-like compartment in infected cells. Here we report the cryo-EM structure and biochemistry characterization of gp105, a protein that is encoded by the jumbo phage 201φ2-1 and is involved in the formation of the nucleus-like compartment in phage 201φ2-1 infected Pseudomonas chlororaphis. We found that, although most gp105 molecules are in the monomeric state in solution, a small portion of gp105 assemble to form large sheet-like assemblies and small cube-like particles. Reconstruction of the cube-like particles showed that the particle consists of six flat head-to-tail tetramers arranged into an octahedral cube. The four molecules at the contact interface of two head-to-tail tetramers are 2-fold symmetry-related and constitute a concave tetramer. Further reconstructions without applying symmetry showed that molecules in the particles around the distal ends of a 3-fold axis are highly dynamic and have the tendency to open up the assembly. Local classifications and refinements of the concave tetramers in the cube-like particle resulted in a map of the concave tetramer at a resolution of 4.09 Å. Structural analysis of the concave tetramer indicates that the N and C terminal fragments of gp105 are important for mediating the intermolecular interactions, which was further confirmed by mutagenesis studies. Biochemistry assays showed that, in solution, the cube-like particles of gp105 are liable to either disassemble to form the monomers or recruit more molecules to form the high molecular weight lattice-like assembly. We also found that monomeric gp105s can self-assemble to form large sheet-like assemblies in vitro, and the assembly of gp105 in vitro is a reversible dynamic process and temperature-dependent. Taken together, our results revealed the dynamic assembly of gp105, which helps to understand the development and function of the nucleus-like compartment assembled by phage-encoded proteins.

Alleviating early demyelination in ischaemia/reperfusion by inhibiting sphingosine-1-phosphate receptor 2 could protect visual function from impairment.

Retinal ischaemia/reperfusion (I/R) injury is a common cause of retinal ganglion cell (RGC) apoptosis and axonal degeneration, resulting in irreversible visual impairment. However, there are no available neuroprotective and neurorestorative therapies for retinal I/R injury, and more effective therapeutic approaches are needed. The role of the myelin sheath of the optic nerve after retinal I/R remains unknown. Here, we report that demyelination of the optic nerve is an early pathological feature of retinal I/R and identify sphingosine-1-phosphate receptor 2 (S1PR2) as a therapeutic target for alleviating demyelination in a model of retinal I/R caused by rapid changes in intraocular pressure. Targeting the myelin sheath via S1PR2 protected RGCs and visual function. In our experiment, we observed early damage to the myelin sheath and persistent demyelination accompanied by S1PR2 overexpression after injury. Blockade of S1PR2 by the pharmacological inhibitor JTE-013 reversed demyelination, increased the number of oligodendrocytes, and inhibited microglial activation, contributing to the survival of RGCs and alleviating axonal damage. Finally, we evaluated the postoperative recovery of visual function by recording visual evoked potentials and assessing the quantitative optomotor response. In conclusion, this study is the first to reveal that alleviating demyelination by inhibiting S1PR2 overexpression may be a therapeutic strategy for retinal I/R-related visual impairment.

Changes of bacterial community structure,monosaccharide composition and CO2 exchange along the successional stages of biological soil crusts.

Biological soil crusts (BSCs) are a dominant ecological landscape of drylands, which have a significant impact on global biogeochemical flux. However, it is unclear how bacterial community and physiological characteristics vary along the BSCs successional stages. In this study, bacterial community composition, physiological characteristics, and monosaccharide composition of extracellular polysaccharides (EPSs) were compared among different successional stages. Our findings demonstrated that besides the dominant bacterial species, the bacterial communities also showed considerable differences between these two stages. Cyanobacteria were keystone taxa in the early stage, while heterotrophic bacteria (Proteobacteria, Actinobacteria and Acidobacteria) were keystone taxa in the later stages. According to the results of CO2 exchange, cyanobacterial crusts accumulated net carbon faster than moss crusts, while moss crusts had a significantly higher respiration rate. The monosaccharide analysis indicated that the EPSs components also varied depending on BSCs' successional stages. Specifically, the contents of rhamnose and arabinose were higher in the cyanobacterial crusts than other types of crusts, while the contents of fucose, xylose, mannose and glucose were the highest in cyanobacterial-lichen crusts, and galactose content was highest in the moss crusts. Altogether, our results stress the heterogeneous variation of BSCs along with succession, and this work offered a fresh viewpoint for a deeper comprehension of the interactions between the monosaccharide components of EPS and the networks of bacterial communities in BSCs.

3D ZnO/Activated Carbon Alginate Beads for the Removal of Antibiotic-Resistant Bacteria and Antibiotic Resistance Genes.

The worldwide prevalence of antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) have become one of the most urgent issues for public health. Thus, it is critical to explore more sustainable methods with less toxicity for the long-term removal of both ARB and ARGs. In this study, we fabricated a novel material by encapsulating zinc oxide (ZnO) nanoflowers and activated carbon (AC) in an alginate biopolymer. When the dosage of ZnO was 1.0 g (≈2 g/L), the composite beads exhibited higher removal efficiency and a slight release of Zn2+ in water treatment. Fixed bed column experiments demonstrated that ZnO/AC alginate beads had excellent removal capacities. When the flow rate was 1 mL/min, and the initial concentration was 107 CFU/mL, the removal efficiency of ARB was 5.69-log, and the absolute abundance of ARGs was decreased by 2.44-2.74-log. Moreover, the mechanism demonstrated that ZnO significantly caused cell lysis, cytoplasmic leakage, and the increase of reactive oxygen species induced subsequent oxidative stress state. These findings suggested that ZnO/AC alginate beads can be a promising material for removing ARB and ARGs from wastewater with eco-friendly and sustainable properties.

Populus euphratica GLABRA3 Binds PLDδ Promoters to Enhance Salt Tolerance.

High NaCl (200 mM) increases the transcription of phospholipase Dδ (PLDδ) in roots and leaves of the salt-resistant woody species Populus euphratica. We isolated a 1138 bp promoter fragment upstream of the translation initiation codon of PePLDδ. A promoter-reporter construct, PePLDδ-pro::GUS, was introduced into Arabidopsis plants (Arabidopsis thaliana) to demonstrate the NaCl-induced PePLDδ promoter activity in root and leaf tissues. Mass spectrometry analysis of DNA pull-down-enriched proteins in P. euphratica revealed that PeGLABRA3, a basic helix-loop-helix transcription factor, was the target transcription factor for binding the promoter region of PePLDδ. The PeGLABRA3 binding to PePLDδ-pro was further verified by virus-induced gene silencing, luciferase reporter assay (LRA), yeast one-hybrid assay, and electrophoretic mobility shift assay (EMSA). In addition, the PeGLABRA3 gene was cloned and overexpressed in Arabidopsis to determine the function of PeGLABRA3 in salt tolerance. PeGLABRA3-overexpressed Arabidopsis lines (OE1 and OE2) had a greater capacity to scavenge reactive oxygen species (ROS) and to extrude Na+ under salinity stress. Furthermore, the EMSA and LRA results confirmed that PeGLABRA3 interacted with the promoter of AtPLDδ in transgenic plants. The upregulated AtPLDδ in PeGLABRA3-transgenic lines resulted in an increase in phosphatidic acid species under no-salt and saline conditions. We conclude that PeGLABRA3 activated AtPLDδ transcription under salt stress by binding to the AtPLDδ promoter region, conferring Na+ and ROS homeostasis control via signaling pathways mediated by PLDδ and phosphatidic acid.

Genome-wide SNP data and mitochondrial HVR-1 nucleotide sequence reveal the origin of the Akhal-Teke horse.

Objective: The study investigated the origin of the Akhal-Teke horse using genome-wide single-nucleotide polymorphism (SNP) data and mitochondrial hypervariable region 1 (HVR-1) nucleotide sequences. Methods: Genome-wide SNP data from 22 breeds (481 horses) and mitochondrial HVR-1 sequences from 24 breeds (544 sequences) worldwide to examine the origin of the Akhal-Teke horse. The data were analyzed using principal component analysis, linkage disequilibrium analysis, neighbor-joining dendrograms, and ancestry inference to determine the population relationships, ancestral source, genetic structure, and relationships with other varieties. Results: A close genetic relationship between the Akhal-Teke horse and horses from the Middle East was found. Analysis of mitochondrial HVR-1 sequences showed that there were no shared haplotypes between the Akhal-Teke and Tarpan horses, and the mitochondrial data indicated that the Akhal-Teke horse has not historically expanded its group. Ancestral inference suggested that Arabian and Caspian horses were the likely ancestors of the Akhal-Teke horse. Conclusion: The Akhal-Teke horse originated in the Middle East.

Engineering single-domain antibodies targeting Gasdermin E activation by the chemotherapeutic agent cis-diaminodichloroplatinum.

As mediators of pyroptosis, gasdermins (GSDMs) are closely associated with systemic cytotoxicity or so-called side effects and are also involved in the inflammatory response during chemotherapy. Using in situ proximity ligation assay followed by sequencing (isPLA-seq), which we recently developed, we screened a single-domain antibody (sdAb) library and identified several sdAbs against Gasdermin E (GSDME) that specifically recognize the N-terminal domain (1-270 aa) of GSDME (GSDME-NT). One of them mitigated the release of inflammatory damage-associated molecular patterns (DAMPs) and cytokines, including high mobility group protein b1 (Hmgb1) and interleukin-1ß (Il-1ß), in isolated mouse alveolar epithelial cells (AECs) upon chemotherapeutic agent cis-diaminodichloroplatinum (CDDP) treatment. Further investigation showed that this anti-GSDME sdAb also alleviated CDDP-induced pyroptotic cell death and lung tissue injury and decreased systemic Hmgb1 release in C57/BL6 mice, due to GSDME inactivation. Collectively, our data define an inhibitory role of the specific sdAb against GSDME, providing a potential strategy for systemically alleviating chemotherapeutic toxicities in vivo.

Traditional Chinese medicine in the era of immune checkpoint inhibitor: theory, development, and future directions.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer management and have been widely applied; however, they still have some limitations in terms of efficacy and toxicity. There are multiple treatment regimens in Traditional Chinese Medicine (TCM) that play active roles in combination with Western medicine in the field of oncology treatment. TCM with ICIs works by regulating the tumor microenvironment and modulating gut microbiota. Through multiple targets and multiple means, TCM enhances the efficacy of ICIs, reverses resistance, and effectively prevents and treats ICI-related adverse events based on basic and clinical studies. However, there have been few conclusions on this topic. This review summarizes the development of TCM in cancer treatment, the mechanisms underlying the combination of TCM and ICIs, existing studies, ongoing trials, and prospects for future development.

Classification and localization of maize leaf spot disease based on weakly supervised learning.

Precisely discerning disease types and vulnerable areas is crucial in implementing effective monitoring of crop production. This forms the basis for generating targeted plant protection recommendations and automatic, precise applications. In this study, we constructed a dataset comprising six types of field maize leaf images and developed a framework for classifying and localizing maize leaf diseases. Our approach involved integrating lightweight convolutional neural networks with interpretable AI algorithms, which resulted in high classification accuracy and fast detection speeds. To evaluate the performance of our framework, we tested the mean Intersection over Union (mIoU) of localized disease spot coverage and actual disease spot coverage when relying solely on image-level annotations. The results showed that our framework achieved a mIoU of up to 55.302%, indicating the feasibility of using weakly supervised semantic segmentation based on class activation mapping techniques for identifying disease spots in crop disease detection. This approach, which combines deep learning models with visualization techniques, improves the interpretability of the deep learning models and achieves successful localization of infected areas of maize leaves through weakly supervised learning. The framework allows for smart monitoring of crop diseases and plant protection operations using mobile phones, smart farm machines, and other devices. Furthermore, it offers a reference for deep learning research on crop diseases.

A Half-sandwich Ru(II) (N

Efficacy of clinical chemotherapeutic agents depends not only on direct cytostatic and cytotoxic effects but also involves in eliciting (re)activation of tumour immune effects. One way to provoke long-lasting antitumour immunity is coined as immunogenic cell death (ICD). Although metal-based antitumour complexes hold promise as potential chemotherapeutic agents, ruthenium (Ru)-based ICD inducers remain sparse. Herein, we report a half-sandwich complex Ru(Ⅱ) bearing aryl-bis(imino) acenaphthene chelating ligand with ICD inducing properties for melanoma in vitro and in vivo. Complex Ru(Ⅱ) displays strong anti-proliferative potency and potential cell migration inhibition against melanoma cell lines. Importantly, complex Ru(Ⅱ) drives the multiple biochemical hallmarks of ICD in melanoma cells. In vivo the inhibition of tumour growth in prophylactic tumour vaccination model further confirms that mice with complex Ru(Ⅱ)-treated dying cells lead to activate adaptive immune responses and anti-tumour immunity by the activation of ICD in melanoma cells. Mechanisms of action studies show that complex Ru(Ⅱ)-induced ICD could be associated with mitochondrial damage, ER stress and impairment of metabolic status in melanoma cells. We believe that the half-sandwich complex Ru(Ⅱ) as an ICD inducer in this work will help to design new half-sandwich Ru-based organometallic complexes with immunomodulatory response in melanoma treatments.

Cryo-EM structure of the Mon1-Ccz1-RMC1 complex reveals molecular basis of metazoan RAB7A activation.

Understanding of the evolution of metazoans from their unicellular ancestors is a fundamental question in biology. In contrast to fungi which utilize the Mon1-Ccz1 dimeric complex to activate the small GTPase RAB7A, metazoans rely on the Mon1-Ccz1-RMC1 trimeric complex. Here, we report a near-atomic resolution cryogenic-electron microscopy structure of the Drosophila Mon1-Ccz1-RMC1 complex. RMC1 acts as a scaffolding subunit and binds to both Mon1 and Ccz1 on the surface opposite to the RAB7A-binding site, with many of the RMC1-contacting residues from Mon1 and Ccz1 unique to metazoans, explaining the binding specificity. Significantly, the assembly of RMC1 with Mon1-Ccz1 is required for cellular RAB7A activation, autophagic functions and organismal development in zebrafish. Our studies offer a molecular explanation for the different degree of subunit conservation across species, and provide an excellent example of how metazoan-specific proteins take over existing functions in unicellular organisms.

Microbial metabolism regulation on the efficient degradation of aromatic compounds for biochemical treatment process of coal chemical wastewater in pilot scale.

At present, the common problems of biochemical treatment systems of coal chemical wastewater were the poor system stability and the difficulty in reaching COD discharge standards. Aromatic compounds were the main contributors to COD value. The effective removal of aromatic compounds was an urgent problem in the biochemical treatment systems of coal chemical wastewater. In this study, the dominant microbial strains that could degrade phenol, quinoline, and phenanthrene were isolated respectively and inoculated into the pilot scale biochemical tank of coal chemical wastewater. The regulation effect and mechanism of microbial metabolism on the efficient degradation of aromatic compounds were studied. The results indicated that the various aromatic compounds were significantly removed under the regulation of microbial metabolism, the removal efficiencies of COD, TOC, phenols, benzenes, N-CHs, and PAHs were increased by about 25%, 20%, 33%, 25%, 42%, and 45%, respectively, and their biotoxicity was also drastically reduced. Moreover, the abundance and diversity of microbial community, and the microbial activity were obviously improved, as well as the various functional strains were selectively enriched, suggesting that the regulation system could resist environmental stresses with high substrate concentration and toxicity, which could lead to more enhanced performance for aromatic compounds removal. In addition, the microbial EPS content was significantly increased, implying the formation of microbial hydrophobic cell surfaces, which could improve the bioavailability of aromatic compounds. Furthermore, the enzymatic activity analysis revealed that the relative abundance and activity of key enzymes were all obviously improved. In conclusion, multiple lines of evidence were provided to clarify the regulation mechanism of microbial metabolism on the efficient degradation of aromatic compounds for biochemical treatment process of coal chemical wastewater in pilot scale. The results laid a good foundation for realizing the harmless treatment of coal chemical wastewater.

Single-cell chromatin accessibility of developing murine pancreas identifies cell state-specific gene regulatory programs.

Numerous studies have characterized the existence of cell subtypes, along with their corresponding transcriptional profiles, within the developing mouse pancreas. The upstream mechanisms that initiate and maintain gene expression programs across cell states, however, remain largely unknown. Here, we generate single-nucleus ATAC-Sequencing data of developing murine pancreas and perform an integrated, multi-omic analysis of both chromatin accessibility and RNA expression to describe the chromatin landscape of the developing pancreas at both E14.5 and E17.5 at single-cell resolution. We identify candidate transcription factors regulating cell fate and construct gene regulatory networks of active transcription factor binding to regulatory regions of downstream target genes. This work serves as a valuable resource for the field of pancreatic biology in general and contributes to our understanding of lineage plasticity among endocrine cell types. In addition, these data identify which epigenetic states should be represented in the differentiation of stem cells to the pancreatic beta cell fate to best recapitulate in vitro the gene regulatory networks that are critical for progression along the beta cell lineage in vivo.

Speckle-tracking echocardiography provides sensitive measurements of subtle early alterations associated with cardiac dysfunction in T2DM rats.

BACKGROUND: Diabetic cardiomyopathy results in cardiac structural and functional abnormalities. Previous studies have demonstrated that inhibiting the RhoA/ROCK signalling pathway increases the injury resistance of cardiomyocytes. The early detection of cardiac structural and functional alterations may facilitate an improved understanding of the pathophysiologic progress and guide therapy. This study aimed to identify the optimal diagnostic measures for the subtle early alterations of cardiac dysfunction in type 2 diabetes mellitus (T2DM) rats. METHODS: Twenty-four rat models were divided into four groups and received treatments for 4 weeks: the CON group (control rats), the DM group (T2DM rats), the DMF group (T2DM rats receiving fasudil) and the CONF group (control rats receiving fasudil) group. Left ventricular (LV) structure was quantified by histological staining and transmission electron microscopy. LV function and myocardial deformation were assessed by high-frequency echocardiography. RESULTS: Treatment with fasudil, a ROCK inhibitor, significantly protected against diabetes-induced myocardial hypertrophy, fibrosis and mitochondrial dysfunction. Impaired LV performance was found in T2DM rats, as evidenced by significant reductions in the ejection fraction (EF), fractional shortening (FS) and the mitral valve (MV) E/A ratio (which decreased 26%, 34% and 20%, respectively). Fasudil failed to improve the conventional ultrasonic parameters in T2DM rats, but the myocardial deformation measured by speckle-tracking echocardiography (STE) were significantly improved (global circumferential strain, GCS: P = 0.003; GCS rate, GCSR: P = 0.021). When receiver operating characteristic (ROC) curves were used in combination with linear regression analysis, STE parameters were found to be characterized by both optimal prediction of cardiac damage [AUC (95% CI): fractional area change, FAC: 0.927 (0.744, 0.993); GCS: 0.819 (0.610, 0.945); GCSR: 0.899 (0.707, 0.984)] and stronger correlations with cardiac fibrosis (FAC: r = -0.825; GCS: r = 0.772; GCSR: r = 0.829) than conventional parameters. CONCLUSION: The results suggest that STE parameters are more sensitive and specific than conventional parameters in predicting the subtle cardiac functional changes that occur in the early stage, providing new insight into the management of diabetic cardiomyopathy.

Nasal spray of an IgM-like ACE2 fusion protein HH-120 accelerates SARS-CoV-2 clearance: A single-center propensity score-matched cohort study.

HH-120, a recently developed IgM-like ACE2 fusion protein with broad-spectrum neutralizing activity against all ACE2-utilizing coronaviruses, has been developed as a nasal spray for use as an early treatment agent to reduce disease progression and airborne transmission. The objective of this study was to evaluate the safety and efficacy of the HH-120 nasal spray in SARS-CoV-2-infected subjects. Eligible symptomatic or asymptomatic SARS-CoV-2-infected participants were enrolled in a single-arm trial to receive the HH-120 nasal spray for no longer than 6 days or until viral clearance at a single hospital between August 3 and October 7, 2022. An external control was built from real-world data of SARS-CoV-2-infected subjects contemporaneously hospitalized in the same hospital using a propensity score matching (PSM) method. After PSM, 65 participants in the HH-120 group and 103 subjects with comparable baseline characteristics in the external control group were identified. The viral clearance time was significantly shorter in participants receiving the HH-120 nasal spray than that in subjects of the control group (median 8 days vs. 10 days, p < 0.001); the difference was more prominent in those subgroup subjects with higher baseline viral load (median 7.5 days vs. 10.5 days, p < 0.001). The incidence of treatment-emergent adverse events and treatment-related adverse events of HH-120 group were 35.1% (27/77) and 3.9% (3/77), respectively. All the adverse events observed were mild, being of CTCAE grade 1 or 2, and transient. The HH-120 nasal spray showed a favorable safety profile and promising antiviral efficacy in SARS-CoV-2-infected subjects. The results from this study warrant further assessment of the efficacy and safety of the HH-120 nasal spray in large-scale randomized controlled clinical trials.

Befotertinib (D-0316) versus icotinib as first-line therapy for patients with EGFR-mutated locally advanced or metastatic non-small-cell lung cancer: a multicentre, open-label, randomised phase 3 study.

BACKGROUND: Befotertinib (D-0316) is a novel, selective oral third-generation epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor. This phase 3 trial compared the efficacy and safety of befotertinib with icotinib as a first-line treatment for patients with EGFR mutation-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: This study was a multicentre, open-label, randomised, controlled phase 3 study at 39 hospitals in China. Eligible patients were 18 years of age or older, had histologically confirmed locally advanced or metastatic stage IIIB, IIIC, or IV unresectable NSCLC, and had confirmed exon 19 deletions or exon 21 Leu858Arg mutation. Patients were randomly assigned (1:1) via an interactive web response system to receive either oral befotertinib (75-100 mg once daily) or oral icotinib (125 mg three times per day) in 21-day cycles until disease progression or withdrawal criteria were met. Randomisation was stratified by type of EGFR mutation, CNS metastasis status, and gender, and participants, investigators, and data analysts were not masked to treatment allocation. The primary endpoint was independent review committee (IRC)-assessed progression-free survival in the full analysis set, which comprised all randomly assigned patients. All patients who received at least one dose of the study drug were included in safety analyses. This study was registered with ClinicalTrials.gov, NCT04206072, and the overall survival follow-up is still in progress. FINDINGS: Between Dec 24, 2019, and Dec 18, 2020, 568 patients were screened, of whom 362 were randomly assigned to the befotertinib (n=182) or icotinib (n=180) group; all 362 patients were included in the full analysis set. Median follow-up was 20·7 months (IQR 10·2-23·5) in the befotertinib group and 19·4 months (10·3-23·5) in the icotinib group. Median IRC-assessed progression-free survival was 22·1 months (95% CI 17·9-not estimable) in the befotertinib group and 13·8 months (12·4-15·2) in the icotinib group (hazard ratio 0·49 [95% CI 0·36-0·68], p<0·0001). Grade 3 or higher treatment-related adverse events occurred in 55 (30%) of 182 patients in the befotertinib group and in 14 (8%) of 180 patients in the icotinib group. Treatment-related serious adverse events were reported in 37 (20%) patients in the befotertinib group and in five (3%) patients in the icotinib group. Two (1%) patients in the befotertinib group and one (1%) patient in the icotinib group died due to treatment-related adverse events. INTERPRETATION: Befotertinib demonstrated superior efficacy compared with icotinib in first-line treatment for patients with EGFR mutation-positive NSCLC. Although serious adverse events were more common in the befotertinib than the icotinib arm, the safety profile of befotertinib was manageable overall. FUNDING: Betta Pharmaceuticals (China). TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.