1.Electroacupuncture Ameliorates NLRP3-mediated Pyroptosis in Spinal Cord Injury Rats by Reshaping The Gut Microbiota
Yin-Jie CUI ; Hong-Ru LI ; Jing-Yi LIU ; Hai-Lin DU ; Shu-Wen LIU ; Yuan YANG ; Chen-Guang ZHENG ; Jian-Qin XIANG ; Xiao-Juan SONG
Progress in Biochemistry and Biophysics 2026;53(5):1132-1153
ObjectiveSpinal cord injury (SCI) directly impairs the regulatory function of the autonomic nervous system, induces intestinal dysfunction, and significantly reduces patients’ quality of life. Preclinical studies have shown that electroacupuncture (EA) therapy can regulate the brain-gut axis and is used to treat central nervous system diseases such as major depressive disorder, Alzheimer’s disease and Parkinson’s disease. Recent research has established that fecal microbiota transplantation (FMT) from EA-treated SCI rats restored intestinal motility and colonic morphology. However, it remains unclear whether the regulation of gut microbiota by EA therapy directly contributes to neural repair after SCI. This study aims to explore whether gut microbiota mediates the neuroprotective effect of EA in the treatment of SCI and its possible mechanism. MethodsThe study employed RNA transcriptome analysis of spinal cord tissue to characterize gene expression profiles and to identify key signaling pathways following EA treatment for SCI. Hematoxylin-Eosin (HE) staining and Nissl staining were used to observe the morphological changes in spinal cord tissue. Western blot (WB) and enzyme-linked immunosorbent assay (ELISA) were applied to detect the effects of EA on the expression of proteins related to nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3) -dependent pyroptosis. Using 16S rDNA sequencing, the study observed alterations in gut microbiota diversity and community composition in SCI rats. Prior to establishing SCI models, rats were pretreated with an antibiotic cocktail to induce gut dysbiosis, and the effects on intestinal function and spinal cord neural repair were evaluated. FMT was performed to investigate the regulatory effects of post-EA FMT on motor function, general status, liver and spleen indices, and NLRP3-mediated pyroptosis in SCI rats. ResultsEA improved motor function and reduced regulated neuronal cell death in SCI rats. Transcriptomic analysis demonstrated the activation of immune- and inflammation-related pathways post-SCI, including NOD-like receptors, nuclear factor-kappa B(NF-κB), and Toll-like receptor (TLR) pathways. EA primarily influenced intestinal inflammation and autoimmune functions. 16S rDNA sequencing illustrated that EA did not alter the diversity of gut microbiota. However, EA altered the gut microbiota composition in SCI rats, increasing Lactobacillus and Akkermansia genera while rebalancing the Firmicutes/Bacteroidetes ratio. Furthermore, depletion of gut microbiota by antibiotics disrupted the intestinal barrier, reduced the expression of intestinal barrier proteins Zonula Occludens-1 (ZO-1) and Occludin, elevated serum lipopolysaccharide-binding protein (LBP) levels, exacerbated spinal cord tissue damage, and hindered motor function recovery in SCI rats. FMT from donors treated with EA reduced LBP levels in the intestine, blood, and spinal cord of rats, inhibited the TLR4 myeloid differentiation primary response protein 88 (MyD88)-NF‑κB pathway and NLRP3-dependent pyroptosis, and improved motor function. On the other hand, FMT treatment resulted in decreased body weight and food intake, whereas FMT using EA-treated donors effectively alleviated these alterations. ConclusionEA effectively alleviated neuroinflammatory responses in rats with SCI, primarily through regulating the gut microbiota and suppressing the NLRP3-dependent pyroptosis signaling pathway.
2.Electroacupuncture Ameliorates NLRP3-mediated Pyroptosis in Spinal Cord Injury Rats by Reshaping The Gut Microbiota
Yin-Jie CUI ; Hong-Ru LI ; Jing-Yi LIU ; Hai-Lin DU ; Shu-Wen LIU ; Yuan YANG ; Chen-Guang ZHENG ; Jian-Qin XIANG ; Xiao-Juan SONG
Progress in Biochemistry and Biophysics 2026;53(5):1132-1153
ObjectiveSpinal cord injury (SCI) directly impairs the regulatory function of the autonomic nervous system, induces intestinal dysfunction, and significantly reduces patients’ quality of life. Preclinical studies have shown that electroacupuncture (EA) therapy can regulate the brain-gut axis and is used to treat central nervous system diseases such as major depressive disorder, Alzheimer’s disease and Parkinson’s disease. Recent research has established that fecal microbiota transplantation (FMT) from EA-treated SCI rats restored intestinal motility and colonic morphology. However, it remains unclear whether the regulation of gut microbiota by EA therapy directly contributes to neural repair after SCI. This study aims to explore whether gut microbiota mediates the neuroprotective effect of EA in the treatment of SCI and its possible mechanism. MethodsThe study employed RNA transcriptome analysis of spinal cord tissue to characterize gene expression profiles and to identify key signaling pathways following EA treatment for SCI. Hematoxylin-Eosin (HE) staining and Nissl staining were used to observe the morphological changes in spinal cord tissue. Western blot (WB) and enzyme-linked immunosorbent assay (ELISA) were applied to detect the effects of EA on the expression of proteins related to nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3) -dependent pyroptosis. Using 16S rDNA sequencing, the study observed alterations in gut microbiota diversity and community composition in SCI rats. Prior to establishing SCI models, rats were pretreated with an antibiotic cocktail to induce gut dysbiosis, and the effects on intestinal function and spinal cord neural repair were evaluated. FMT was performed to investigate the regulatory effects of post-EA FMT on motor function, general status, liver and spleen indices, and NLRP3-mediated pyroptosis in SCI rats. ResultsEA improved motor function and reduced regulated neuronal cell death in SCI rats. Transcriptomic analysis demonstrated the activation of immune- and inflammation-related pathways post-SCI, including NOD-like receptors, nuclear factor-kappa B(NF-κB), and Toll-like receptor (TLR) pathways. EA primarily influenced intestinal inflammation and autoimmune functions. 16S rDNA sequencing illustrated that EA did not alter the diversity of gut microbiota. However, EA altered the gut microbiota composition in SCI rats, increasing Lactobacillus and Akkermansia genera while rebalancing the Firmicutes/Bacteroidetes ratio. Furthermore, depletion of gut microbiota by antibiotics disrupted the intestinal barrier, reduced the expression of intestinal barrier proteins Zonula Occludens-1 (ZO-1) and Occludin, elevated serum lipopolysaccharide-binding protein (LBP) levels, exacerbated spinal cord tissue damage, and hindered motor function recovery in SCI rats. FMT from donors treated with EA reduced LBP levels in the intestine, blood, and spinal cord of rats, inhibited the TLR4 myeloid differentiation primary response protein 88 (MyD88)-NF‑κB pathway and NLRP3-dependent pyroptosis, and improved motor function. On the other hand, FMT treatment resulted in decreased body weight and food intake, whereas FMT using EA-treated donors effectively alleviated these alterations. ConclusionEA effectively alleviated neuroinflammatory responses in rats with SCI, primarily through regulating the gut microbiota and suppressing the NLRP3-dependent pyroptosis signaling pathway.
3.International clinical practice guideline on the use of traditional Chinese medicine for functional dyspepsia (2025).
Sheng-Sheng ZHANG ; Lu-Qing ZHAO ; Xiao-Hua HOU ; Zhao-Xiang BIAN ; Jian-Hua ZHENG ; Hai-He TIAN ; Guan-Hu YANG ; Won-Sook HONG ; Yu-Ying HE ; Li LIU ; Hong SHEN ; Yan-Ping LI ; Sheng XIE ; Jin SHU ; Bin-Fang ZENG ; Jun-Xiang LI ; Zhen LIU ; Zheng-Hua XIAO ; Jing-Dong XIAO ; Pei-Yong ZHENG ; Shao-Gang HUANG ; Sheng-Liang CHEN ; Gui-Jun FEI
Journal of Integrative Medicine 2025;23(5):502-518
Functional dyspepsia (FD), characterized by persistent or recurrent dyspeptic symptoms without identifiable organic, systemic or metabolic causes, is an increasingly recognized global health issue. The objective of this guideline is to equip clinicians and nursing professionals with evidence-based strategies for the management and treatment of adult patients with FD using traditional Chinese medicine (TCM). The Guideline Development Group consulted existing TCM consensus documents on FD and convened a panel of 35 clinicians to generate initial clinical queries. To address these queries, a systematic literature search was conducted across PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP Database, China Biology Medicine (SinoMed) Database, Wanfang Database, Traditional Medicine Research Data Expanded (TMRDE), and the Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS). The evidence from the literature was critically appraised using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. The strength of the recommendations was ascertained through a consensus-building process involving TCM and allopathic medicine experts, methodologists, pharmacologists, nursing specialists, and health economists, leveraging their collective expertise and empirical knowledge. The guideline comprises a total of 43 evidence-informed recommendations that span a range of clinical aspects, including the pathogenesis according to TCM, diagnostic approaches, therapeutic interventions, efficacy assessments, and prognostic considerations. Please cite this article as: Zhang SS, Zhao LQ, Hou XH, Bian ZX, Zheng JH, Tian HH, Yang GH, Hong WS, He YY, Liu L, Shen H, Li YP, Xie S, Shu J, Zeng BF, Li JX, Liu Z, Xiao ZH, Xiao JD, Zheng PY, Huang SG, Chen SL, Fei GJ. International clinical practice guideline on the use of traditional Chinese medicine for functional dyspepsia (2025). J Integr Med. 2025; 23(5):502-518.
Dyspepsia/drug therapy*
;
Humans
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Medicine, Chinese Traditional/methods*
;
Practice Guidelines as Topic
;
Drugs, Chinese Herbal/therapeutic use*
4.Shewanella biofilm formation regulated by acyl-homoserine lactones and its application in UO22+ electrosorption.
Tingting LIU ; Hong SHU ; Qian LI ; Zhao CUI ; Guangyue LI ; Ting LI ; Yongdong WANG ; Jing SUN
Chinese Journal of Biotechnology 2025;41(8):3081-3097
Shewanella oneidensis MR-1, a Gram-negative bacterium with a significant role in the adsorption and reduction of uranium in wastewater and a quorum-sensing effect, can be used to remove uranium from wastewater. Exogenous signaling molecules (acyl-homoserine lactones, AHLs) can be added to induce the quorum sensing behavior for rapid biofilm formation, thereby improving the removal efficiency of this bacterium for uranium. Extracellular polymeric substances (EPS), as the significant components of biofilm, play a key role in biofilm formation. To investigate the quorum sensing behavior induced by AHLs, we systematically investigated the effects of AHLs on the EPS secretion and biofilm properties of S. oneidensis MR-1 by regulating parameters such as AHL species, concentration, addition time point, and contact time. The results showed that the addition of 10 μmol/L N-butyryl-l-homoserine lactone (C4-HSL) after 6 h of culture and continued incubation to reach the time point of 72 h significantly promoted the secretion of EPSs, in which the content of extracellular proteins and extracellular polysaccharides was increased by 15.2% and 28.2%, respectively, compared with that of the control group. The biofilm electrodes induced by signaling molecules showed superior properties, which were evidenced by an increase of exceeding 20 μm in biofilm thickness, an increase of 33.9% in the proportion of living cells, enhanced electroactivity, and an increase of 10.7% in the uranium removal rate. The biofilm electrode was confirmed to immobilize uranium in wastewater mainly by electrosorption, physicochemical adsorption, and electro-reduction through characterization means such as X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). This study provides a new technical idea for the efficient recovery of uranium in wastewater and enriches the theoretical system of quorum sensing regulation of electroactive biofilms.
Biofilms/drug effects*
;
Acyl-Butyrolactones/pharmacology*
;
Quorum Sensing/drug effects*
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Uranium/metabolism*
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Shewanella/metabolism*
;
Adsorption
;
Uranium Compounds/metabolism*
;
Wastewater/chemistry*
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Biodegradation, Environmental
;
Extracellular Polymeric Substance Matrix/metabolism*
5.Analysis of factors influencing frequent episodes in children with moderate-to-severe atopic dermatitis: a national multicenter cross-sectional study
Jing TIAN ; Yifeng GUO ; Xiaoyan LUO ; Yuan LIANG ; Ping LI ; Jinping CHEN ; Yao LU ; Jianping TANG ; Yunsheng LIANG ; Ying GAO ; Qiufang QIAN ; Hong SHU ; Hongxiang CHEN ; Pingshen FAN ; Xiuping HAN ; Hua QIAN ; Qinfeng LI ; Ming LI ; Shengchun WANG ; Ying LIU ; Hua WANG ; Lin MA
Chinese Journal of Dermatology 2025;58(10):943-951
Objective:To investigate factors influencing frequent episodes (≥ 4 episodes within 1 year) in children with moderate-to-severe atopic dermatitis (AD) in China.Methods:A national multicenter cross-sectional study was conducted. Patients under the age of 18 years diagnosed with moderate-to-severe AD were enrolled at dermatology clinics in 18 medical institutions across 12 provinces and municipalities in China between June 12 and August 8, 2023. At the time of the visit, their guardians completed a structured questionnaire covering demographic characteristics, clinical features of AD, personal and family history, factors associated with frequent episodes of moderate-to-severe AD, compliance with treatment, and disease awareness. Statistical analyses included t tests, one-way analysis of variance, rank-sum tests, and chi-square tests, with multiple-response analysis applied for multiple-choice questions. Results:A total of 965 valid questionnaires were collected, and 965 children with moderate-to-severe AD were included. Among them, there were 531 males and 434 females, 678 (70.3%) were aged 2 - < 12 years, 837 (86.7%) were from urban areas, the age at onset was 2.47 ± 3.03 years, and the median frequency of AD episodes in the past year was 4 times. These children were divided into 2 groups based on the median episode frequency: < 4-episode group (439 cases, 45.5%) and ≥ 4-episode group (526 cases, 54.5%). Compared with the < 4-episode group, children in the ≥ 4-episode group showed younger ages at onset (2.22 ± 2.98 years vs. 2.76 ± 3.06 years, P = 0.006) and higher proportions of patients with comorbid allergic diseases in both the children themselves (82.9% [436/526] vs. 69.7% [306/439], χ2 = 23.42, P < 0.001) and their relatives (66.0% [347/526] vs. 57.4% [252/439], χ2 = 7.46, P = 0.006). Children in the ≥ 4- episode group also had higher monthly usage of moisturizers (150 [30, 300] g vs. 60 [6, 200] g) and daily frequency of moisturizer use, greater disease awareness, but more severe fear of medication use (all P < 0.05). The region and the human development index level were both significantly associated with the episode frequency (both P < 0.001), with the highest proportion of children from South China in the ≥ 4- episode group (36.3%, 191/526). Children in the ≥ 4-episode group also had a longer duration of topical glucocorticoid use than those in the < 4-episode group ( Z = -2.21, P = 0.027). External triggers associated with AD episodes mainly included heat exposure (50.36%, 486/965), hot water bathing (40.73%, 393/965), seafood (23.52%, 227/965), and dust mites (33.37%, 322/965) . Conclusion:In children with moderate-to-severe AD in China, factors influencing frequent episodes may include residence in southern or economically developed regions, earlier age at onset, having a personal or family history of allergic diseases, and fear of medication use.
6.EEG phase prediction method based on long short-term memory network
Zi-yan PANG ; Xin-yu ZHAO ; Wen-shu MAI ; Yue-zhuo ZHAO ; Zhi-peng LIU ; Tao YIN ; Jing-na JIN
Chinese Medical Equipment Journal 2025;46(3):1-8
Objective To propose a brain electrical phase prediction method based on long short-term memory network(LSTM)to improve the accuracy and robustness of phase synchronization prediction in transcranial magnetic stimulation(TMS).Methods First,an LSTM consisting of an input layer,an LSTM layer,an ReLU activation layer,a fully connected layer and a regression layer was constructed to capture the EEG signal features through the synergistic action of input gates,forgetting gates and output gates.Second,eye-open resting-state EEG data from 30 healthy subjects were trained using the LSTM to obtain a predictive model for EEG signal and EEG phase prediction.Finally,the LSTM method and the traditional autoregressive(AR)method were compared in terms of the phase prediction errors at the overall and individual levels and the prediction performance for peaks and troughs.A regression model was used to explore the relationships between instantaneous EEG amplitude,signal-to-noise ratio and phase prediction error with the LSTM method.Results The LSTM method achieved a total phase prediction error of 0.04°±5.69°,which was lower than that of the traditional AR method(-3.36°±51.13°).For each subject,the LSTM method demonstrated superior phase prediction accuracy compared to the traditional AR method(P<0.001).The accuracy for predicting peaks(troughs)by the LSTM method(about 89%)was higher than that by the traditional AR method(about 10%).Unlike the traditional AR method,the LSTM method didnot result in linear relationships between instantaneous EEG amplitude,signal-to-noise ratio and phase prediction error,with Pvalues being 0.58 and 0.18,respectively.Conclusion The LSTM-based brain electrical phase prediction method shows high accuracy and robustness when used for EEG phase-synchronized TMS.[Chinese Medical Equipment Journal,2025,46(3):1-8]
7.Evaluation of effectiveness of reagent burstbead applied to field blood transfusion compatibility testing
Yi ZHANG ; Xiao-di LIU ; Yi-man ZHAO ; Jing-yan ZHOU ; Shu-mei YANG ; Hao YAN ; Yin-tu MA
Chinese Medical Equipment Journal 2025;46(2):39-42
Objective To explore the reliability of the reagent burstbead for field blood transfusion compatibility testing by applying it to bloodtype detection,antibody screening and cross matching tests and conduting parallel contrast with the existing arrays.Methods A field treatment shelter was used as the testing site to simulate the scene of emergency blood transfusion for the wounded under the conditions of field blood station,and 1 358 pieces of blood samples sent to some hospital for examination before transfusion were considered as the objects.Parallel contrast tests were carried out between the reagent burstbead method and the tube method for bloodtype detection and between the reagent burstbead method and the manual polybrene method for antibody screening and cross matching.The reagent burstbead method was compared with other methods in terms of the coin-cidence rate of the bloodtype detection results,the detection rate of positive samples for antibody screening and crossmatch incompatibility.Results The reagent burstbead method and the tube method had high consistency when used for bloodtype detection,with the coincidence rate being 100%.During antibody screening and cross matching tests,the reagent burstbead method found 5 cases of antibody-positive samples leading to major crossmatch incompatibility(positive rate being 0.37%),the manual polybrene method detected 2 cases of irregular antibody-positive samples(positive rate being 0.15%),and the two methods both identified 3 cases of minor crossmatch incompatibility.Conclusion The reagent burstbead has high accuracy and reliability when applied to bloodtype detection,antibody screening and cross matching tests,and thus can be used for blood transfusion compatibility testing in field conditions.[Chinese Medical Equipment Journal,2025,46(2):39-42]
8.Research progress on the role of NF-κB signaling pathway in drug resistance mechanisms of pancreatic cancer
Ya-Ting SHU ; Jing-Wen SHI ; Fan LEI ; Zhao CUI ; Mei-Fang LIU ; Mei-Yu PENG
Medical Journal of Chinese People's Liberation Army 2025;50(6):665-671
Pancreatic cancer is characterized by significant drug resistance,and despite continuous advancements in treatment regimens,the 5-year survival rate of patients remains low.The nuclear factor-κB(NF-κB)signaling pathway,frequently mutated in tumors,has been identified as a critical factor in triggering drug resistance.Multiple studies have demonstrated that strategies targeting NF-κB signaling transduction exhibit promising outcomes in pancreatic cancer treatment.Therefore,exploring the relationship between the NF-κB signaling pathway and drug resistance in pancreatic cancer has become a research hotspot in pancreatic cancer treatment.This review summarizes recent advances in the relationship between NF-κB signaling pathway and tumor drug resistance,as well as its role in pancreatic cancer treatment.Specifically,the mechanisms by which the NF-κB signaling pathway mediates drug resistance in pancreatic cancer are elaborated from two perspectives:chemotherapy and immunotherapy,aiming to provide insights for pancreatic cancer treatment and future research.
9.Additional role of low-density lipoprotein cholesterol on the risk of osteoporosis in men with or without coronary heart disease: a real-world longitudinal study.
Jing ZENG ; Zi-Mo PAN ; Ting LI ; Ze-Yu CHEN ; Xiao-Yan CAI ; Mei-Liang GONG ; Xin-Li DENG ; Sheng-Shu WANG ; Nan LI ; Miao LIU ; Chun-Lin LI
Journal of Geriatric Cardiology 2025;22(2):219-228
BACKGROUND:
Early control of low-density lipoprotein cholesterol (LDL-C) is crucial for reducing the progress of cardiovascular disease. However, its additional role to the risk of primary osteoporosis in men with coronary heart disease was inconclusive. Our study aims to determine the association of LDL-C and its trajectories for osteoporosis risk in the middle-aged and aged men of China.
METHODS:
The retrospective cohort study of 1546 men aged 69.74 ± 11.30 years conducted in Beijing, China from 2015 to 2022. And the incidence of primary osteoporosis was annually recorded. LDL-C trajectories were further identified by latent class growth model using repeated measurements of LDL-C. The association of baseline LDL-C for osteoporosis was estimated using hazard ratio (HR) with 95% CI in Cox proportional hazard model, while mean level and trajectories of LDL-C for osteoporosis were evaluated using odds ratio (OR) with 95% CI in logistic regression model.
RESULTS:
During the median 6.2-year follow-up period, 70 men developed primary osteoporosis. The higher level of baseline LDL-C (HR = 1.539, 95% CI: 1.012-2.342) and mean LDL-C (OR = 2.190, 95% CI: 1.443-3.324) were associated with higher risk of osteoporosis in men with coronary heart disease after adjusted for covariates. Compared with those in the LDL-C trajectory of low-stable decrease, participants with medium-fluctuant trajectory, whose longitudinal LDL-C started with a medium LDL-C level and appeared an increase and then decrease, were negatively associated with osteoporosis risk (OR = 2.451, 95% CI: 1.152-5.216). And participants with initially high LDL-C level and then a rapid decrease demonstrated a tendency towards reduced risk (OR = 0.718, 95% CI: 0.212-2.437).
CONCLUSIONS
Elevated LDL-C level and its long-term fluctuation may increase the risk of primary osteoporosis in men. Early controlling a stable level of LDL-C is also essential for bone health.
10.Molecular targeted therapy for progressive low-grade gliomas in children.
Yan-Ling SUN ; Miao LI ; Jing-Jing LIU ; Wen-Chao GAO ; Yue-Fang WU ; Lu-Lu WAN ; Si-Qi REN ; Shu-Xu DU ; Wan-Shui WU ; Li-Ming SUN
Chinese Journal of Contemporary Pediatrics 2025;27(6):682-689
OBJECTIVES:
To evaluate the efficacy of molecular targeted agents in children with progressive pediatric low-grade gliomas (pLGG).
METHODS:
A retrospective analysis was conducted on pLGG patients treated with oral targeted therapies at the Department of Pediatrics, Beijing Shijitan Hospital, Capital Medical University, from July 2021. Treatment responses and safety profiles were assessed.
RESULTS:
Among the 20 enrolled patients, the trametinib group (n=12, including 11 cases with BRAF fusions and 1 case with BRAF V600E mutation) demonstrated 4 partial responses (33%) and 2 minor responses (17%), with a median time to response of 3.0 months. In the vemurafenib group (n=6, all with BRAF V600E mutation), 5 patients achieved partial responses (83%), showing a median time to response of 1.0 month. Comparative analysis revealed no statistically significant difference in progression-free survival rates between the two treatment groups (P>0.05). The median duration of clinical benefit (defined as partial response + minor response + stable disease) was 11.0 months for vemurafenib and 18.0 months for trametinib. Two additional cases, one with ATM mutation treated with olaparib for 24 months and one with NF1 mutation receiving everolimus for 21 months, discontinued treatment due to sustained disease stability. No severe adverse events were observed in any treatment group.
CONCLUSIONS
Molecular targeted therapy demonstrates clinical efficacy with favorable tolerability in pLGG. Vemurafenib achieves high response rates and induces early tumor shrinkage in patients with BRAF V600E mutations, supporting its utility as a first-line therapy.
Humans
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Glioma/genetics*
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Male
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Female
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Child
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Child, Preschool
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Retrospective Studies
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Brain Neoplasms/genetics*
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Molecular Targeted Therapy/adverse effects*
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Adolescent
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Infant
;
Proto-Oncogene Proteins B-raf/genetics*
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Pyrimidinones/therapeutic use*
;
Mutation

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