The Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutation is one of the most prevalent activating alterations in cancer. It indicates a poor overall prognosis due to its highly invasive nature. Although several KRAS inhibitors have been developed in recent years, a significant clinical challenge has emerged as a substantial proportion of patients eventually develop resistance to these therapies. Therefore, identifying determinants of drug resistance is critical for guiding treatment strategies. This review provides a comprehensive overview of the mutation landscape and molecular mechanisms of KRAS activity in various cancers. Meanwhile, it summaries the progress and prospects of small molecule KRAS inhibitors undergoing clinical trials. Furthemore, this review explores potential strategies to overcome drug resistance, with the ultimate goal of steering toward patient-centric precision oncology in the foreseeable future.
Humans ; Drug Resistance, Neoplasm/drug effects* ; Proto-Oncogene Proteins p21(ras)/metabolism* ; Mutation/genetics* ; Neoplasms/genetics* ; Antineoplastic Agents/therapeutic use*

UNLABELLED: OBJECTIVE：To explore the clinical characteristics and genetic etiology of a child with CAKUTHED syndrome. METHODS: A child who was admitted to the neonatal department of Gansu Provincial Maternal and Child Health Care Hospital due to "neonatal asphyxia" in May 2021 was selected as the study subject. Genomic DNA was extracted from peripheral venous blood samples from the child and his parents, and whole exome sequencing (WES) was carried out. Sanger sequencing was used to verify the candidate variant of the PBX1 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of candidate variants was rated. This study was approved by the Medical Ethics Committee of the Hospital [Ethics No.: 2021GSFY (65)]. RESULTS: The proband, a male neonate, manifested renal dysplasia, congenital heart disease, pulmonary dysplasia, mediastinal hernia, cryptorchidism, and clavicle dysplasia. WES revealed that he had harbored a heterozygous c.863G>A (p.Arg288Gln) missense variant in exon 6 of PBX1 gene, which resulted substitution of Arginine at position 288 by Glutamine, for which both parents were of the wild type. The variant was unreported previously and rated as pathogenic (PS2+PM1+PM2_Supporting+PP2+PP3) based on the ACMG guidelines. CONCLUSION The c.863G>A variant of the PBX1 gene probably underlay the pathogenesis in the proband. Above finding has enriched the mutational spectrum of the PBX1 gene.
Humans ; Male ; Pre-B-Cell Leukemia Transcription Factor 1/genetics* ; Phenotype ; Infant, Newborn ; Exome Sequencing ; Mutation, Missense ; Heart Defects, Congenital/genetics* ; Abnormalities, Multiple/genetics*

Metastasis is a pivotal and intricate process in the progression of malignant tumors,strongly correlating with poor prognosis.Approximately 90%of cancer-related mortality is attributed to metastasis,with the five-year survival rate for patients with metastatic solid tumors ranging from 5%to 30%.Consequently,a comprehensive understanding of the underlying biological mechanisms driving metastasis is essential for unraveling its core processes and developing novel therapeutic strategies.The metastatic cascade involves tumor cells navigating numerous biological barriers,including detachment from the primary tumor,invasion of blood vessels or lymphatics,survival in circulation,extravasation into distant organs and subsequent adaptation to the microenvironment.To surmount these challenges,tumor cells undergo phenotypic changes,genetic mutations and dysregulating signaling pathways.Additionally,microenvironmental factors(such as angiogenesis,matrix remodeling and immune evasion)play a critical role,orchestrating the initiation and growth of metastatic lesions in an interdependent manner.Organ-specific metastasis,a distinct subset of metastasis,involves dynamic bidirectional interactions between tumor cells and the microenvironment of target organs.These interactions determine the selectivity of metastatic spread and drive the adaptive evolution of both the tumor and the organ,which encompasses multiple layers of cellular interactions,including cell-cell and cell-matrix signaling.Tumor cell mutations,the release of specific signaling molecules,the capacity to withstand circulatory pressures,and signaling exchanges with target organs collectively govern the selective nature of organ-specific metastasis.Furthermore,factors intrinsic to the target organ-such as its regenerative potential,metabolic profile,immune surveillance mechanisms and matrix stiffness-further facilitate the adaptive remodeling of metastatic cells within these environments.Thus,the bidirectional selection and adaptation between tumor cells and target organs form a dynamic,complex system that reshapes our understanding of metastatic tumor development.While current research emphasizes shared biological features in metastasis,the successful formation of metastatic tumors depends not only on these common mechanisms but also on the unique characteristics governing organ-specific metastasis.The interplay between generalizable and organ-specific mechanisms profoundly influences the metastatic outcome.This review aimed to consolidate our current knowledge of these shared and distinct processes,analyze the evolving understanding of the bidirectional selection between tumor cells and target organs,and assess the current status of metastatic risk prediction models for patients without metastasis.Furthermore,the paper discussed the challenges and opportunities in managing advanced-stage metastatic tumors,offering new insights and potential clinical strategies to improve prognosis and treatment outcomes.

BACKGROUND:Monounsaturated fatty acids are mostly recognized as a fatty acid with beneficial effects on human health,and some studies have suggested that they may contribute to non-inflammatory pain at multiple sites in the body.OBJECTIVE:To investigate the effect of monounsaturated fatty acids on the incidence of low back pain and all-cause mortality,thereby providing potential biomarkers and intervention strategies for low back pain management and prevention.METHODS:A Mendelian randomization method was used to analyze the potential association of monounsaturated fatty acids on the incidence of low back pain and all-cause mortality in conjunction with large sample data from the National Health and Nutrition Examination Survey(NHANES)database.Results were validated and sensitivity analyzed using multiple statistical models(e.g.,inverse variance weighting,MR-Egger regression,simple median,weighted median,and weighted median)to enhance the reliability of causal inferences.In the NHANES study,multivariate Cox proportional risk regression models were used to assess the independent predictive values of different fatty acid ratios and to control for confounders.Potential nonlinear relationships between monounsaturated fatty acids and all-cause mortality were assessed using Kaplan-Meier curves,log-rank tests,and restricted cubic spline curves.RESULTS AND CONCLUSION:Elevated monounsaturated fatty acids have been found to be associated with a significantly higher risk of low back pain,suggesting an unfavorable effect of this fatty acid.Also,monounsaturated fatty acids may increase all-cause mortality in patients with low back pain.This provides new insights into the potential effects of monounsaturated fatty acids on low back pain and all-cause mortality,and provides a scientific basis for nutritional interventions for low back pain.The results support the use of dietary modification as one of the strategies for the prevention and management of low back pain in the European population,but further studies are needed to explore the specific biological mechanisms and potential for clinical application,thereby improving guidance for the prevention and treatment of diseases in China.

OBJECTIVE To investigate the inhibitory effect mechanism of Anzheng Kangliu Decoction against colorectal cancer by suppressing glycolysis through regulation of the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)signaling pathway.METHODS Human colorectal cancer SW620 cells were treated with Anzheng Kangliu De-coction,and cell proliferation and migration abilities were assessed.Forty-two BALB/c nude mice were randomly divided into a blank control group,model group,5-fluorouracil(5-FU)group(0.025 g·kg-1),Anzheng Kangliu Decoction low-dose group(7.67 g·kg-1),medium-dose group(15.34 g·kg-1),and high-dose group(30.68 g·kg-1).The inhibitory effect of Anzheng Kan-gliu Decoction on subcutaneous xenograft tumors was evaluated by observing body weight,tumor volume,tumor mass,HE staining,im-munohistochemical staining of Ki67 and other indicators.High-throughput transcriptome sequencing was performed to identify differen-tially expressed genes and pathways in tumor tissues between the model group and the Anzheng Kangliu Decoction medium-dose group,elucidating the potential mechanism of Anzheng Kangliu Decoction against colorectal cancer.Glucose and lactate assay kits were used to measure glucose consumption and lactate production in SW620 cells and tumor tissues after Anzheng Kangliu Decoction intervention.Western blot was employed to detect the expression levels of p-PI3K/PI3K,p-Akt/Akt,p-mTOR/mTOR,hexokinase 2(HK2),and lactate dehydrogenase A(LDHA)in SW620 cells and tumor tissues following Anzheng Kangliu Decoction treatment.RE-SULTS In vitro cell experiments demonstrated that,compared with the blank control group,Anzheng Kangliu Decoction intervention significantly inhibited the proliferation and migration of SW620 cells(P<0.01),reduced glucose consumption and lactate production(P<0.05,P<0.01),and downregulated the protein expression levels of p-PI3K/PI3K,p-Akt/Akt,p-mTOR/mTOR,HK2,and LDHA(P<0.05,P<0.01).In vivo animal experiments revealed that,compared with the model group,Anzheng Kangliu Decoction suppressed the growth of subcutaneous xenograft tumors in nude mice(P<0.01),increased tumor tissue necrosis,decreased glucose consumption and lactate production in tumor tissues(P<0.05,P<0.01),and reduced the protein expression levels of p-PI3K/PI3K,p-Akt/Akt,p-mTOR/mTOR,HK2,and LDHA(P<0.05,P<0.01).CONCLUSION Anzheng Kangliu Decoction exerts an in-hibitory effect on colorectal cancer,and its mechanism may be associated with the suppression of glycolysis through regulation of the PI3K/Akt/mTOR signaling pathway.

Metastasis is a pivotal and intricate process in the progression of malignant tumors,strongly correlating with poor prognosis.Approximately 90%of cancer-related mortality is attributed to metastasis,with the five-year survival rate for patients with metastatic solid tumors ranging from 5%to 30%.Consequently,a comprehensive understanding of the underlying biological mechanisms driving metastasis is essential for unraveling its core processes and developing novel therapeutic strategies.The metastatic cascade involves tumor cells navigating numerous biological barriers,including detachment from the primary tumor,invasion of blood vessels or lymphatics,survival in circulation,extravasation into distant organs and subsequent adaptation to the microenvironment.To surmount these challenges,tumor cells undergo phenotypic changes,genetic mutations and dysregulating signaling pathways.Additionally,microenvironmental factors(such as angiogenesis,matrix remodeling and immune evasion)play a critical role,orchestrating the initiation and growth of metastatic lesions in an interdependent manner.Organ-specific metastasis,a distinct subset of metastasis,involves dynamic bidirectional interactions between tumor cells and the microenvironment of target organs.These interactions determine the selectivity of metastatic spread and drive the adaptive evolution of both the tumor and the organ,which encompasses multiple layers of cellular interactions,including cell-cell and cell-matrix signaling.Tumor cell mutations,the release of specific signaling molecules,the capacity to withstand circulatory pressures,and signaling exchanges with target organs collectively govern the selective nature of organ-specific metastasis.Furthermore,factors intrinsic to the target organ-such as its regenerative potential,metabolic profile,immune surveillance mechanisms and matrix stiffness-further facilitate the adaptive remodeling of metastatic cells within these environments.Thus,the bidirectional selection and adaptation between tumor cells and target organs form a dynamic,complex system that reshapes our understanding of metastatic tumor development.While current research emphasizes shared biological features in metastasis,the successful formation of metastatic tumors depends not only on these common mechanisms but also on the unique characteristics governing organ-specific metastasis.The interplay between generalizable and organ-specific mechanisms profoundly influences the metastatic outcome.This review aimed to consolidate our current knowledge of these shared and distinct processes,analyze the evolving understanding of the bidirectional selection between tumor cells and target organs,and assess the current status of metastatic risk prediction models for patients without metastasis.Furthermore,the paper discussed the challenges and opportunities in managing advanced-stage metastatic tumors,offering new insights and potential clinical strategies to improve prognosis and treatment outcomes.

OBJECTIVE To investigate the inhibitory effect mechanism of Anzheng Kangliu Decoction against colorectal cancer by suppressing glycolysis through regulation of the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)signaling pathway.METHODS Human colorectal cancer SW620 cells were treated with Anzheng Kangliu De-coction,and cell proliferation and migration abilities were assessed.Forty-two BALB/c nude mice were randomly divided into a blank control group,model group,5-fluorouracil(5-FU)group(0.025 g·kg-1),Anzheng Kangliu Decoction low-dose group(7.67 g·kg-1),medium-dose group(15.34 g·kg-1),and high-dose group(30.68 g·kg-1).The inhibitory effect of Anzheng Kan-gliu Decoction on subcutaneous xenograft tumors was evaluated by observing body weight,tumor volume,tumor mass,HE staining,im-munohistochemical staining of Ki67 and other indicators.High-throughput transcriptome sequencing was performed to identify differen-tially expressed genes and pathways in tumor tissues between the model group and the Anzheng Kangliu Decoction medium-dose group,elucidating the potential mechanism of Anzheng Kangliu Decoction against colorectal cancer.Glucose and lactate assay kits were used to measure glucose consumption and lactate production in SW620 cells and tumor tissues after Anzheng Kangliu Decoction intervention.Western blot was employed to detect the expression levels of p-PI3K/PI3K,p-Akt/Akt,p-mTOR/mTOR,hexokinase 2(HK2),and lactate dehydrogenase A(LDHA)in SW620 cells and tumor tissues following Anzheng Kangliu Decoction treatment.RE-SULTS In vitro cell experiments demonstrated that,compared with the blank control group,Anzheng Kangliu Decoction intervention significantly inhibited the proliferation and migration of SW620 cells(P<0.01),reduced glucose consumption and lactate production(P<0.05,P<0.01),and downregulated the protein expression levels of p-PI3K/PI3K,p-Akt/Akt,p-mTOR/mTOR,HK2,and LDHA(P<0.05,P<0.01).In vivo animal experiments revealed that,compared with the model group,Anzheng Kangliu Decoction suppressed the growth of subcutaneous xenograft tumors in nude mice(P<0.01),increased tumor tissue necrosis,decreased glucose consumption and lactate production in tumor tissues(P<0.05,P<0.01),and reduced the protein expression levels of p-PI3K/PI3K,p-Akt/Akt,p-mTOR/mTOR,HK2,and LDHA(P<0.05,P<0.01).CONCLUSION Anzheng Kangliu Decoction exerts an in-hibitory effect on colorectal cancer,and its mechanism may be associated with the suppression of glycolysis through regulation of the PI3K/Akt/mTOR signaling pathway.

BACKGROUND:Monounsaturated fatty acids are mostly recognized as a fatty acid with beneficial effects on human health,and some studies have suggested that they may contribute to non-inflammatory pain at multiple sites in the body.OBJECTIVE:To investigate the effect of monounsaturated fatty acids on the incidence of low back pain and all-cause mortality,thereby providing potential biomarkers and intervention strategies for low back pain management and prevention.METHODS:A Mendelian randomization method was used to analyze the potential association of monounsaturated fatty acids on the incidence of low back pain and all-cause mortality in conjunction with large sample data from the National Health and Nutrition Examination Survey(NHANES)database.Results were validated and sensitivity analyzed using multiple statistical models(e.g.,inverse variance weighting,MR-Egger regression,simple median,weighted median,and weighted median)to enhance the reliability of causal inferences.In the NHANES study,multivariate Cox proportional risk regression models were used to assess the independent predictive values of different fatty acid ratios and to control for confounders.Potential nonlinear relationships between monounsaturated fatty acids and all-cause mortality were assessed using Kaplan-Meier curves,log-rank tests,and restricted cubic spline curves.RESULTS AND CONCLUSION:Elevated monounsaturated fatty acids have been found to be associated with a significantly higher risk of low back pain,suggesting an unfavorable effect of this fatty acid.Also,monounsaturated fatty acids may increase all-cause mortality in patients with low back pain.This provides new insights into the potential effects of monounsaturated fatty acids on low back pain and all-cause mortality,and provides a scientific basis for nutritional interventions for low back pain.The results support the use of dietary modification as one of the strategies for the prevention and management of low back pain in the European population,but further studies are needed to explore the specific biological mechanisms and potential for clinical application,thereby improving guidance for the prevention and treatment of diseases in China.

Objective:To discuss the effect of azathioprine(AZA)on ferroptosis in spermatocytes of the mice induced by reduced glutathione(GSH)peroxidase 4 inhibitor RSL3,and to clarify the potential mechanism.Methods:The spermatogonia GC-2 cells of the mice were randomly divided into control group(no treatment),RSL3 group(treated with 10 nmol·L-1 RSL3 for 24 h),RSL3+ferroptosis inhibitor(Ferrostatin-1,Fer-1)group(treated with 10 nmol·L-1 RSL3 for 24 h+2 μmol·L-1 Fer-1 for 12 h),RSL3+low dose of AZA group(treated with 10 nmol·L-1 RSL3 for 24 h+5 μmol·L-1 AZA for 12 h),RSL3+medium dose of AZA group(treated with 10 nmol·L-1 RSL3 for 24 h+10 μmol·L-1 AZA for 12 h),and RSL3+high dose of AZA group(treated with 10 nmol L-1 RSL3 for 24 h+20 μmol·L-1 AZA for 12 h).The MTT method was used to detect the activities of the GC-2 cells in various groups after treated with different concentrations of AZA and RSL3;the GSH and GSSG levels in the GC-2 cells were detected by GSH and oxidized glutathione(GSSG)detection kits;the malondialdehyde(MDA)levels in the GC-2 cells in various groups were detected by MDA detection kit;Western blotting method was used to detect the expression levels of long-chain acyl-CoA synthetase 4(ACSL4),heme oxygenase-1(HO-1),and glutathione peroxidase 4(GPX4)proteins in the cells in various groups;immunofluorescence staining was used to detect the expressions of ACSL4 protein in the cells in various groups.Results:Compared with control group,the differences in activities of the GC-2 cells in 5,10,and 20 μmol·L-1 AZA groups had no significant differences(P＞0.05),while the activities of the GC-2 cells in 30 and 40 μmol·L-1 AZA groups were significantly decreased(P＜0.01);therefore,the AZA concentration was selected to be within 20 μmol·L-1.Compared with control group,the differences of the activities of the GC-2 cells in 1,5,and 10 nmol·L-1 RSL3 groups had no significant differences(P＞0.05),while the activities of the GC-2 cells in 50,100,500,and 1 000 nmol·L-1 RSL3 groups were significantly decreased(P＜0.05 or P＜0.01);therefore,the RSL3 concentration was set to be within 10 nmol·L-1.The GSH and MDA detection kits results showed that compared with control group,the levels of GSSG and MDA in the GC-2 cells in RSL3 group were significantly increased(P＜0.05),while the GSH levels were significantly decreased(P＜0.05);compared with RSL3 group,the levels of GSSG and MDA in the GC-2 cells in RSL3+Fer-1 group and RSL3+AZA group were significantly decreased(P＜0.01),while the GSH levels were significantly increased(P＜0.01).The Western blotting results showed that compared with control group,the expression levels of ACSL4 and HO-1 proteins in the GC-2 cells in RSL3 group were significantly increased(P＜0.05),while the expression level of GPX4 protein was significantly decreased(P＜0.01);compared with RSL3 group,the expression levels of GPX4 protein in the GC-2 cells in RSL3+Fer-1 group and RSL3+AZA group were significantly increased(P＜0.05),while the expression levels of ACSL4 and HO-1 proteins were significantly decreased(P＜0.01).The immunofluorescence staining results showed that compared with control group,the expression amount of ACSL4 protein in the GC-2 cells in RSL3 group was significantly increased,and compared with RSL3 group,the expression amounts of ACSL4 protein in the cells in RSL3+Fer-1 group and RSL3+AZA group were significantly decreased.Conclusion:AZA can alleviate the ferroptosis-induced by RSL3 in spermatocytes of the mice.

Objective:To summarize the clinical features and gene variations in children with Townes-Brocks syndrome (TBS).Methods:The clinical data of a female infant diagnosed with TBS caused by human spalt-like transcription factor 1 ( SALL1) gene mutation in Gansu Maternal and Child Health Hospital in May 2022 were analyzed retrospectively. Relevant articles up to July 2022 were retrieved from several databases including CNKI, VIP, Wanfang, Chinese Medical Journal Network and PubMed with the terms of " SALL1 gene" and "Townes-Brocks syndrome". Patients diagnosed with TBS caused by SALL1 gene mutation were retrieved and the clinical phenotype-genotype correlations in patients with TBS caused by frameshift mutation in SALL1 gene were analyzed and summarized. Descriptive statistical analysis was applied. Results:(1) Clinical data: The index patient was a 40-day-old girl exhibiting major clinical manifestations of polycystic kidney dysplasia, congenital external ear deformity, preaxial polydactyly and recto-perineal fistula. Whole exome sequencing and Sanger sequencing revealed a heterozygous variation of c.420delC (p.S141fs*42) in the SALL1 gene, while the same gene was found to be wild type in her parents and sister. The variant was predicted to be pathogenic (PVS1+PS2+PM2). (2) Literature review retrieved 161 cases of TBS, of which 71 were attributable to a frameshift mutation in SALL1 gene. Clinical phenotypes of the 71 cases and the index case were summarized. TBS was mainly characterized by external ear, hand and anal deformities, sometimes accompanied by hearing loss, abnormal kidney development and foot deformity. A small number of affected cases presented with rare clinical phenotypes such as abnormal eyes, hypothyroidism and abnormal development. At present, the human gene mutation database records 110 variations in the SALL1 gene, with a majority located in exon 2. The most common mutation type was frameshift variation, accounting for 52%, followed by missense variation and nonsense variation. Conclusion:TBS should be considered in children with ear, hand and anal malformations, accompanied by renal dysfunction and hearing loss, and genetic testing is recommended for timely diagnosis.