Regorafenib monotherapy or combined with an immune-checkpoint inhibitor as later-line treatment for metastatic colorectal cancer: a multicenter, real-world retrospective study in China.

OBJECTIVE: To evaluate the efficacy and safety of regorafenib monotherapy or in combination with immune-checkpoint inhibitor while treating Chinese patients with metastatic colorectal cancer (mCRC): a real-world study. METHODS: The data of patients with metastatic colorectal cancer who received regorafenib-containing regimen as the third or later line treatment at ten Chinese hospitals from Aug 2017 to Jun 2020 were retrospectively analyzed, including dosing details, survival data as well as adverse events. Survival analysis was further performed for patients administrated with regorafenib monotherapy and combined with an immune-checkpoint inhibitor based on Kaplan-Meier and Cox regression methods. The primary endpoint was overall survival. RESULTS: A total of 537 patients were included with a median age of 61, among whom 376 received regorafenib monotherapy and 245 received regorafenib combined with immune-checkpoint inhibitors. The clinicopathological characteristics of the two groups at baseline were mainly balanced. No significant difference in progression-free survival (PFS) was observed in patients receiving regorafenib monotherapy or combination therapy (3.8 vs. 5.5 months, p = 0.170). In contrast, patients receiving combination therapy had a more prolonged overall survival (OS) than those receiving regorafenib monotherapy (13.5 vs. 10.0 months, p = 0.001). The treatment regimen and regorafenib dosage were significant prognostic factors in the multivariate analysis. Significant benefits in PFS and OS were achieved in KRAS mutant and anti-angiogenesis treatment-naïve subgroups receiving combination therapy compared to monotherapy. No apparent increase was recorded in treatment-related adverse events in patients receiving combination therapy. CONCLUSION: Regorafenib plus an immune-checkpoint inhibitor has already been a widely adopted strategy in the later-line treatment for mCRC in the real world. The combination therapy yielded a significantly prolonged overall survival than regorafenib alone, with a manageable safety profile in Chinese patients, and warrants further investigation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04835324. Registered 6th April 2021.

Exploration of the Linkages between Lignin and Carbohydrates in Kraft Pulp from Wheat Straw Using a 13C/2H Isotopic Tracer.

To further our understanding of the change in association between lignin and carbohydrates after kraft pulping, isotope-labeled kraft pulp (KP) was prepared using 13C and D double-isotope-labeled wheat straw, and it was subjected to enzymatic hydrolysis and ionic liquid treatment to explore the linkages between lignin and carbohydrate complexes in wheat straw. Isotope abundance determination showed that 13C and D abundances in the experimental groups were substantially higher than those in the control group, indicating that the injected exogenous coniferin-[α-13C], coniferin-[γ-13C], and d-glucose-[6-D2] were effectively absorbed and metabolized during wheat internode growth. Solid-state CP/MAS 13C-NMR spectroscopy showed that lignin was mainly linked to polysaccharides via acetal, benzyl ether, and benzyl ester bonds. Kraft pulp (KP) from the labeled wheat straw was degraded by cellulase. The obtained residue was fractionated using the ionic liquid DMSO/TBAH to separate the cellulose-lignin complex (KP-CLC) and xylan-lignin complex (KP-XLC). X-ray diffractometer determination showed that the KP-CLC regenerated cellulose type II from type I after the ionic liquid conversion. The 13C-NMR spectrum of Ac-En-KP-CLC showed that the cellulose-lignin complex structure was chemically bonded between the lignin and cellulose through acetal and benzyl ether bonds. The 13C-NMR spectrum of En-KP-XLC showed a lignin-hemicellulose complex structure, wherein lignin and xylan were chemically bonded by benzyl ether and acetal bonds. These results indicate that the cross-linking between lignin and carbohydrates exists in lignocellulosic fibers even after kraft pulping.

Real-world outcomes of regorafenib combined with immune checkpoint inhibitors in patients with advanced or metastatic microsatellite stable colorectal cancer: A multicenter study.

BACKGROUND: Treatment strategies are limited for patients with chemotherapy refractory microsatellite stable (MSS) colorectal cancer. We aim to evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) combined with regorafenib in this population in routine clinical practice. METHODS: We retrospectively analyzed patients with advanced or metastatic colorectal cancer who received at least one dose of ICIs combined with regorafenib in 14 Chinese medical centers. The primary outcome was objective response rate (ORR). This study was registered at ClinicalTrials.gov on February 2020 (NCT04771715). RESULTS: Eighty-four patients received ICIs combined with regorafenib from January 2019 to January 2021. Most patients (91%) received two or more systemic treatment lines before the study treatment. Seventy-six patients (90%) had confirmed MSS status. At a median follow-up of 5.5 months, four patients achieved partial response (5%) and 37 patients achieved stable disease (45%) as the best response. The median progression-free survival (PFS) was 3.1 months, and the median overall survival was 17.3 months. Eleven patients (13%) remained progression-free for more than 6 months. Baseline liver metastasis (HR 1.98, 95%CI 1.07-3.69, P = 0.03) and neutrophil-lymphocyte ratio (NLR) of ≥ 1.5 (HR 2.83, 95%CI 1.00-7.98, P = 0.05) were associated with shorter PFS in multivariate analysis. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 16 patients (19%). CONCLUSION: The combination of ICIs with regorafenib can be a valuable treatment option for a proportion of patients with chemotherapy refractory MSS colorectal cancer. Patients with no liver metastasis and a low NLR at baseline may derive most benefit from this strategy.

Catalyst-dependent chemoselective insertion of diazoalkanes into the N-H/C-H/O-H/C-O bonds of 2-hydroxybenzothiazoles.

The control of chemoselective insertions of diazoalkanes into 2-hydroxybenzothiazoles is challenging. Herein, the chemoselective N-H, O-H, C-O or C-H bond insertions of diazoalkanes into 2-hydroxybenzothiazoles are achieved using B(C6F5)3, Rh2(OAc)4 or TfOH as the catalyst. This affords routes to 54 benzothiazole derivatives. These protocols are scalable and demonstrate the complementary nature of Lewis acid, transition metal and Brønsted acid catalyses.

Antibacterial Vancomycin@ZIF-8 Loaded PVA Nanofiber Membrane for Infected Bone Repair.

Bone substitutes with strong antibacterial properties and bone regeneration effects have an inherent potential in the treatment of severe bone tissue infections, such as osteomyelitis. In this study, vancomycin (Van) was loaded into zeolitic imidazolate framework-8 (ZIF-8) to prepare composite particles, which is abbreviated as V@Z. As a pH-responsive particle, ZIF-8 can be cleaved in the weak acid environment caused by bacterial infection to realize the effective release of drugs. Then, V@Z was loaded into polyvinyl alcohol (PVA) fiber by electrospinning to prepare PVA/V@Z composite bone filler. The drug-loading rate of V@Z was about 6.735%. The membranes exhibited super hydrophilicity, water absorption and pH-controlled Van release behavior. The properties of anti E. coli and S. aureus were studied under the pH conditions of normal physiological tissues and infected tissues (pH 7.4 and pH 6.5, respectively). It was found that the material had good surface antibacterial adhesion and antibacterial property. The PVA/V@Z membrane had the more prominent bacteria-killing effect compared with the same amount of single antibacterial agent containing membrane such as ZIF-8 or Van loaded PVA, and the antibacterial rate was up to 99%. The electrospun membrane had good biocompatibility and can promote MC3T3-E1 cell spreading on it.

Acrosomal vesicle protein in predicting progression of pancreatitis in Chinese patients with acute pancreatitis.

The present preliminary investigation was designed to identify biomarkers in the progression of pancreatitis in Chinese patients with acute pancreatitis. Chinese patients aged <60 years with a confirmed diagnosis of acute pancreatitis were enrolled. A saliva sample was collected using salimetrics oral swab in precooled polypropylene tubes to prevent degradation of sensitive peptides. All samples were then centrifuged at 700 × g for 15 min at 4°C to remove debris. The supernatant of each sample was fractionated into 100µL aliquots and frozen at -70°C until analyses using affymetrix HG U133 Plus 2.0 array technique. Bedside index for severity acute pancreatitis (BISAP) score and CT severity index were recorded for each enrolled patient to assess the progression and severity of acute pancreatitis. Data from a total of 210 patients (105 patients in each group) were analyzed. Among identified biomarkers, acrosomal vesicle protein 1 was significantly higher in patients with disease progression as compared to patient without disease progression. Logistic regression model showed that acrosomal vesicle protein 1 (ACRV1) were positively correlated with the progression of diseases. The present reports showed that a mRNA salivary biomarker (ACRV1) are associated with progression of pancreatitis in patients with early stage of pancreatitis. This study suggest that mRNA salivary biomarker (ACRV1) is a predictor of pancreatitis progression.

Suppression of PAPP-A mitigates atherosclerosis by mediating macrophage polarization via STAT3 signaling.

Pregnancy-associated plasma protein-A (PAPP-A), a type of metalloproteinase in the insulin-like growth factor (IGF) system, has been implicated in atherosclerosis progression, but its function and mechanism in atherosclerosis is not fully understood. The study was performed to further explore the effects of PAPP-A on inflammation, macrophage polarization and atherosclerosis. In mouse macrophages stimulated by oxidized low-density lipoprotein (ox-LDL), PAPP-A expression was significantly increased. Its knockdown markedly mitigated inflammatory response and polarized macrophages to an M2-like phenotype in RAW264.7 cells upon ox-LDL treatment. Additionally, ox-LDL-induced activation of nuclear factor-κB (NF-κB) signaling pathway was dramatically restricted by PAPP-A knockdown in macrophages. However, JAK2/STAT3 activation was significantly up-regulated in RAW264.7 cells with PAPP-A inhibition after ox-LDL treatment. Importantly, we found that PAPP-A knockdown-induced polarization of M2-like phenotype in macrophages was mainly dependent on STAT3 activation. Clinical studies showed that serum PAPP-A levels were higher in patients with coronary artery disease (CAD) than that of healthy individuals. Apolipoprotein E-knockout (ApoE-/-) mice with high fat diet (HFD)-induced atherosclerosis exhibited higher expression of PAPP-A in aortas, which was mainly colocalized with F4/80. Subsequently, we found that PAPP-A deficiency greatly alleviated plaque formation, lesion burden and collagen accumulation in HFD-fed ApoE-/- mice. Consistent with in vitro macrophage phenotype, PAPP-A-/- reduced F4/80 expression, NF-κB activation and inflammatory response, while improved janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling and polarized macrophages to an M2-like phenotype in aortas of ApoE-/- mice after HFD feeding. In conclusion, these findings identified PAPP-A as a positive regulator of atherosclerosis by regulating macrophage polarization via STAT3 signal, and thus could be considered as a potential therapeutic target for atherosclerosis treatment.

3D MXene microspheres with honeycomb architecture for tumor photothermal/photodynamic/chemo combination therapy.

The MXene combining high surface area, prominent biocompatibility, and wide near infrared (NIR) absorption has been recognized as one of the most promising materials for tumor therapy. The application of MXene in tumor therapy is negatively affected by the current design methods lack the control of size distribution and the great tendency to agglomerate as well as poor photodynamic therapy. To solve the above problems, we report a facile strategy to process Ti3C2 nanosheets into three-dimensional (3D) structure with honeycomb structure and anti-aggregation properties for synergistic therapy of chemotherapy, photothermal and photodynamic therapy. The 3D MXene is synthesized by spray drying, in which the MXene surface is oxidized to TiO2. The microspheres present prominent NIR light trigger photothermal effect and excellent NIR light photostability, which respond in an on-off manner. Moreover, the microspheres exhibit outstanding drug-loading capability of doxorubicin (DOX) as high as 87.3%, and substantial singlet oxygen generation (1O2) was shown under 808 nm laser and UV light irradiation. Our studies indicate that 3D MXene-DOX could effectively achieve Hela cells killing in vitro, which provides a multifunctional drug delivery platform as a prospective candidate for future combined cancer therapy.

High-throughput metabolomics discovers metabolite biomarkers and insights the protective mechanism of schisandrin B on myocardial injury rats.

Schisandrin B has been proved to possess anti-inflammatory and anti-endoplasmic effects, could improve cardiac function, inhibit apoptosis, and reduce inflammation after ischemic injury. However, the detailed metabolic mechanism and potential pathways of Schisandrin B effects on myocardial injury are unclear. Metabolomics could yield in-depth mechanistic insights and explore the potential therapeutic effect of natural products. In this study, the preparation of doxorubicin-induced myocardial injury rat model for evaluation of Schisandrin B on viral myocarditis sequelae related pathological changes and its mechanism. The metabolite profiling of myocardial injury rats was performed through ultra-high performance liquid chromatography combined with mass spectrometry combined with pattern recognition approaches and pathway analysis. A total of 15 metabolites (nine in positive ion mode and six in negative ion mode) were considered as potential biomarkers of myocardial injury, and these metabolites may correlate with the regulation of Schisandrin B treatment. A total of six metabolic pathways are closely related to Schisandrin B treatment, including glycerophospholipid metabolism, sphingolipid metabolism, purine metabolism, etc. This study revealed the potential biomarkers and metabolic network pathways of myocardial injury, and illuminated the protective mechanism of Schisandrin B on myocardial injury.

Feature Extraction of Surface Electromyography Based on Improved Small-World Leaky Echo State Network.

Surface electromyography (sEMG) is an electrophysiological reflection of skeletal muscle contractile activity that can directly reflect neuromuscular activity. It has been a matter of research to investigate feature extraction methods of sEMG signals. In this letter, we propose a feature extraction method of sEMG signals based on the improved small-world leaky echo state network (ISWLESN). The reservoir of leaky echo state network (LESN) is connected by a random network. First, we improved the reservoir of the echo state network (ESN) by these networks and used edge-added probability to improve these networks. That idea enhances the adaptability of the reservoir, the generalization ability, and the stability of ESN. Then we obtained the output weight of the network through training and used it as features. We recorded the sEMG signals during different activities: falling, walking, sitting, squatting, going upstairs, and going downstairs. Afterward, we extracted corresponding features by ISWLESN and used principal component analysis for dimension reduction. At the end, scatter plot, the class separability index, and the Davies-Bouldin index were used to assess the performance of features. The results showed that the ISWLESN clustering performance was better than those of LESN and ESN. By support vector machine, it was also revealed that the performance of ISWLESN for classifying the activities was better than those of ESN and LESN.

Metabolomics approach based on utra-performance liquid chromatography coupled to mass spectrometry with chemometrics methods for high-throughput analysis of metabolite biomarkers to explore the abnormal metabolic pathways associated with myocardial dysfunction.

Ultra-performance liquid chromatography/mass spectrometry-based metabolomics can been used for discovery of metabolite biomarkers to explore the metabolic pathway of diseases. Identification of metabolic pathways is key to understanding the pathogenesis and mechanism of disease. Myocardial dysfunction induced by sepsis (SMD) is a severe complication of septic shock and represents major causes of death in intensive care units; however its pathological mechanism is still not clear. In this study, ultrahigh-pressure liquid chromatography with mass spectrometry-based metabolomics with chemometrics anaylsis and multivariate pattern recognition analysis were used to detect urinary metabolic profile changes in a lipopolysaccharide-induced SMD mouse model. Multivariate statistical analysis including principal component analysis and orthogonapartial least squares discriminant analysis for the discrimination of SMD was conducted to identify potential biomarkers. A total of 19 differential metabolites were discovered by high-resolution mass spectrometry-based urinary metabolomics strategy. The altered biochemical pathways based on these metabolites showed that tyrosine metabolism, phenylalanine metabolism, ubiquinone biosynthesis and vitamin B6 metabolism were closely connected to the pathological processes of SMD. Consequently, integrated chemometric analyses of these metabolic pathways are necessary to extract information for the discovery of novel insights into the pathogenesis of disease.

Stereoconvergent, Redox-Neutral Access to Tetrahydroquinoxalines through Relay Epoxide Opening/Amination of Alcohols.

We present an economical catalytic procedure to convert readily available 1,2-diaminobenzenes and terminal epoxides into valuable 1,2,3,4-tetrahydroquinoxalines in a highly enantioselective fashion. This procedure operates through relay zinc and iridium catalysis, and achieves redox-neutral and stereoconvergent production of valuable chiral heterocycles from racemic starting materials with water as the only side product. The use of commercially available reagents and catalysts and a convenient procedure also make this catalytic method attractive for practical application.

Successful treatment with pazopanib plus PD-1 inhibitor and RAK cells for advanced primary hepatic angiosarcoma: a case report.

BACKGROUND: Primary hepatic angiosarcoma (PHA) is a rare and aggressive solid tumor, with high rates of local recurrence and distant metastasis, and poor prognosis. There are no established treatment guidelines for PHA. CASE PRESENTATION: A 78-year-old asymptomatic man with PHA that was successfully treated with pazopanib plus PD-1 inhibitor and RetroNectin-activated killer cells (RAK cells). After one month of treatment, there was a clear reduction in the size and number of the liver metastases; and after nearly 15 months, most of the lesions were stable, no new lesions had developed, and the side effect of treatment was minor. CONCLUSION: Pazopanib, PD-1 inhibitor and RAK cells could serve as a potential option for the treatment of advanced PHA.

Progression of targeted therapy in advanced cholangiocarcinoma.

It is necessary to establish an effective therapy to improve the survival of patients with advanced cholangiocarcinoma (CCA). Recently, with the development of pathology research in CCA, a lot of special bio-markers such as EGFR, VEGF, HER2, and MEK et al. could be over expression or mutations in CCA patients. According to their changes, combinations of targeted therapy plus chemotherapy are now recognized as effective therapies for advanced CCA. The aim of this paper is to analyze recent promising studies about targeted therapy alone or combination with each other or with chemotherapies.

Comparative efficacy of different interventions on executive function in adolescents with internet use disorder.

BACKGROUND: The formation and relapse of Internet use disorder (IUD) are related to the decline in executive function. Previous studies have indicated that exercise intervention and high-definition transcranial direct current stimulation (HD-tDCS) can improve the cognitive abilities of adolescents with IUD. However, the combined intervention's impact on executive function in these adolescents remains unclear. Therefore, this study aims to explore the effects and differences of multimodal exercise, HD-tDCS intervention, and combined intervention on the executive function of adolescents with IUD. METHODS: Forty-eight adolescents with IUD were randomly assigned to the multimodal exercise group, HD-tDCS intervention group, combined intervention group, and control group. The intervention groups received 4 weeks of moderate-intensity multimodal exercise, HD-tDCS intervention (2 mA, 20min/session, 3 times/week), or combined multimodal exercise with HD-tDCS intervention. The control group received conventional educational learning. Executive function measurements were taken before intervention, after intervention, and 2 weeks post-intervention. RESULTS: Compared to pre-intervention, different interventions effectively improved the behavioral performance of adolescents with IUD in executive function tasks. In comparison to single interventions, the combined intervention significantly outperformed multimodal exercise and HD-tDCS intervention in influencing the executive function (especially inhibitory control and working memory) in adolescents with IUD. CONCLUSION: Combined multimodal exercise with HD-tDCS intervention proves to be an effective means of enhancing executive function in adolescents with IUD, particularly contributing to the improvement of explicit behavioral performance related to executive function.

Unified Fuzzy Control of High-Order Nonlinear Systems With Multitype State Constraints.

This article presents a unified adaptive fuzzy control approach for high-order nonlinear systems (HONSs) with multitype state constraints. Existing methods always require the upper and lower constraint boundaries are strictly positive and negative functions (or constants), respectively, which is often inconsistent with the actual constraints. In this article, "multitype state constraint" means that the upper and lower constraint boundaries include multiple types, such as both being strictly positive (or negative), sometime be positive or negative, and so on (cases ①-⑥). By designing a unified mapping function (UMF), the multitype state constraints are processed under removal the feasibility conditions (FCs). Furthermore, a technical design makes the proposed method also applicable to unconstrained HONSs without changing the control structure. By means of a fuzzy-logic system (FLS) and fixed-time stability theory (FTST), the proposed algorithm can ensure that the tracking error converges to a zero-centered neighborhood within a fixed time, and the singularity which often appears in the existing fixed-time control (FTC) methods of HONSs is effectively avoided. Simulation results demonstrate the scheme developed.

Prescribed-Time Output Feedback Control for Cyber-Physical Systems Under Output Constraints and Malicious Attacks.

This article presents a prescribed-time output feedback control (PTOFC) algorithm for cyber-physical systems (CPSs) under output constraint occurring in any finite time interval (OC-AFT) and malicious attacks. The OC-AFT meaning that the output constraint only occurs during a finite number of time periods while being absent in others, which is more general and complex than traditional infinite-time/deferred output constraints. A stretch model-based nonlinear mapping function is constructed to handle the OC-AFT, and a salient advantage is that the proposed algorithm is also suit for CPSs with infinite-time/deferred output (or funnel) constraints, as well as those that are constraint-free, without necessitating changes to the control structure. The uncertain terms (including system model uncertainties, malicious attacks, and external disturbances) are compensated by fuzzy logic systems. Furthermore, a novel practical prescribed-time stability criterion is proposed, under which a novel PTOFC scheme is given. The results demonstrate that the proposed scheme can ensure that both tracking error and observation error converge to a neighborhood centered on zero within a prescribed time, while accommodating the OC-AFT and malicious attacks. Additionally, the settling time remains unaffected by control parameters and initial states, and the limitations of excessive initial control inputs and singularity problems in existing prescribed-time control algorithms are eliminated. The developed algorithm is exemplified through simulation instances.

Partial response to crizotinib + regorafenib + PD-1 inhibitor in a metastatic BRAF V600EMT colon cancer patient with acquired C-MET amplification and TPM4-ALK fusion: a case report.

Background: Colorectal cancer (CRC) with the Raf murine sarcoma viral oncogene homolog B (BRAF) V600E had a relatively poor prognosis. Anaplastic lymphoma kinase (ALK) fusion and the mesenchymal-to-epithelial transition factor (MET) amplification have been recognized as potentially important therapeutic targets in non-small cell lung cancer (NSCLC). However, both of them are of extremely lower frequencies (<2%) in metastatic CRC, and few studies have mentioned the real application of their inhibitors in CRC treatment. Case Description: A 49-year-old Chinese male was diagnosed with ascending colon adenocarcinoma (cT3N+?M1) with liver metastases. The patient performed next-generation sequencing (NGS) using tissue and circulating tumor DNA (ctDNA), and the results showed a BRAF V600E mutation. He received an initial combination treatment with cetuximab, dabrafenib, and trametinib with a partial response (PR) assessment. We changed the therapy regimen on this patient several times because of the patient's intolerance to the drugs or the inefficacy of the treatment. During this period, we detected the c-MET amplification and tropomyosin 4 (TPM4)-ALK fusion by NGS after triplet targeted therapy (tislelizumab, dabrafenib, and trametinib), thus he was finally treated with programmed cell death protein 1 (PD-1) inhibitor (tislelizumab), MET/ALK inhibitor (crizotinib) plus multikinase inhibitor (regorafenib). Imageological examinations showed that PR was achieved and ctDNA sequencing results indicated a significantly reduced BRAF mutation frequency, MET amplification and TPM4-ALK fusion were undetectable. NGS analysis of peripheral blood showed a recurrence of the MET acquired resistant amplification mutation over 2 months of ongoing treatment. but the patient was assessed as PR and still under treatment of crizotinib, tislelizumab and regorafenib within good physical condition. At the last follow-up on October 2021, the patient died of symptomatic treatment fail for obstructive jaundice. The patient finally achieved 11 months overall survival. Conclusions: This study reported a co-existence of a BRAF V600E mutation, c-MET amplification and TPM4-ALK fusion in a CRC patient. Administration of crizotinib combined with regorafenib and tislelizumab obtained an obvious response. Furthermore, continuous ctDNA detection appears to be a promising technique to monitor tumor burden, which may provide better clinical decision support during the disease course.

Clinical features and mutation analysis of class 1/2/3 BRAF mutation colorectal cancer.

BACKGROUND: BRAF (B-Raf proto-oncogene, serine/threonine kinase)-mutated colorectal cancer (CRC) still has poor prognostic. The efficacy of BRAF inhibitor is unpredictable just that intrinsic genetic complexity, immune microenvironment and partially unknown reason. Understanding the co-mutation mechanism can help improve treatment and follow-up strategies. METHODS: We retrospectively analyzed 35 (BRAF-mutated/BRAF wild-type) Chinese CRC and 125 Western CRC who underwent next-generation sequencing (NGS). Co-occurrence mutation analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was enabled in this study. RESULTS: Thirty-five (10.32%) patients were BRAF-mutated, with 17 patients were BRAF V600E in Beijing Hospital. Patients with BRAF mutation had significant association with high tumor mutational burden (TMB-H) (P=0.0004) and high microsatellite instability (MSI-H) (P=0.0003) than those with BRAF wild-type. In 125 BRAF-mutated Western CRC patients, the frequency of age at diagnosis, gender, sample type, Tumor-Node-Metastasis (TNM), MSI, TMB, and BRAF mutation type was consistent with Chinese data. However, the primary tumor location showed significant statistical differences (P<0.0001). Class 1 were more likely to occur in elder and female. Western cohort was consistent with above in Chinese cohort. Other clinicopathological features were not significantly associated with mutation type. However, Western cohort showed class 1 exhibited primary sample type predominance in both class 1 vs. others (P<0.05) and class 1 vs. class 3 (P<0.05). Meanwhile, the data showed TMB-H (57.69% vs. 11.76%, P<0.001) and MSI-H (28.21% vs. 0%, P<0.05) of the class 1 BRAF mutation proportion were significantly higher, compared with class 3 BRAF mutation. In concurrent oncogenic mutations, compared with non-class 1 BRAF mutation, class 1 are more likely to co-occur with passenger mutation. Data from Western populations showed similar results. We also found that the class 1 mutation was mutually exclusive with co-KRAS (Kirsten rat sarcoma viral oncogene homologue) mutation in CRC, and co-APC (APC regulator of WNT signaling pathway) mutation appeared more frequently in non-class 1 BRAF mutation. KEGG pathway showed that fewer proto-cancer signaling pathways were enriched in the class 1, which further confirmed that this type had stronger tumorigenicity. GO enrichment also proved that class 1 had stronger tumorigenicity. Finally, prognostic analysis showed median overall survival (mOS) of 19.43 months in class 1 vs. 47.57 months in non-class 1 (P=0.0002). Further study showed that the mOS of class 1, class 2, class 3 and class NA (unknown) was 19.43, 28.50, 47.57 months and not reached (P=0.0001), respectively. CONCLUSIONS: This study showed class 1/non-class 1 BRAF mutation in CRC had significantly differences in co-mutation features, genomic markers and prognostic. Understanding BRAF mutation types and co-mutation mechanism will contribute to accurately grasping treatment and follow-up strategies and promoting the development of precision therapy for CRC in the future.