The incidence and mortality rates of hepatocellular carcinoma(HCC)remain high in China,and the application of surgical resection is often limited due to the fact that most patients are in the advanced stage at the time of confirmed diagnosis.This article reviews commonly used advanced locoregional therapies for HCC and the advances in mainstream techniques such as local ablation(radiofrequency ablation,microwave ablation,irreversible electroporation,and cryoablation),intravascular intervention(transcatheter arterial chemoembolization,hepatic arterial infusion chemotherapy,and Y90 hepatic arterial infusion chemotherapy),and radiotherapy(CyberKnife,proton therapy,and heavy-ion therapy),and a multidimensional decision-making framework is constructed for HCC locoregional therapy by comparing treatment principles,indications,limitations,and clinical data of these techniques.This article aims to provide evidence-based support for persistent dilemmas in clinical decision-making,promote the role of locoregional therapies in clinical practice,and propose the directions for future research and clinical application.This article also establishes a comprehensive clinical roadmap for HCC locoregional therapy,which helps to address current challenges regarding technique selection and delineate future directions for innovation,in order to reshape the treatment of HCC through technological integration and paradigm innovation.

The incidence and mortality rates of hepatocellular carcinoma(HCC)remain high in China,and the application of surgical resection is often limited due to the fact that most patients are in the advanced stage at the time of confirmed diagnosis.This article reviews commonly used advanced locoregional therapies for HCC and the advances in mainstream techniques such as local ablation(radiofrequency ablation,microwave ablation,irreversible electroporation,and cryoablation),intravascular intervention(transcatheter arterial chemoembolization,hepatic arterial infusion chemotherapy,and Y90 hepatic arterial infusion chemotherapy),and radiotherapy(CyberKnife,proton therapy,and heavy-ion therapy),and a multidimensional decision-making framework is constructed for HCC locoregional therapy by comparing treatment principles,indications,limitations,and clinical data of these techniques.This article aims to provide evidence-based support for persistent dilemmas in clinical decision-making,promote the role of locoregional therapies in clinical practice,and propose the directions for future research and clinical application.This article also establishes a comprehensive clinical roadmap for HCC locoregional therapy,which helps to address current challenges regarding technique selection and delineate future directions for innovation,in order to reshape the treatment of HCC through technological integration and paradigm innovation.

Isoflavones which mainly distributed in leguminous plants have plenty of health benefits.Isoflavone synthase(IFS)is a membrane-associated cytochrome P450 enzyme(CYP450)which carries out the unique aryl-ring migration and hydroxylation.So far,few crystal structures of plant P450s have been obtained.We determined the crystal structure of IFS from Medicago truncatula at 1.9 ? by MAD method using a selenomethionine substituted crystal and conducted molecular docking and mutagenesis study.The structure of IFS complexed with imidazole exhibits the helix Ⅰa-loop-helix Ⅰβ motif which cor-responds to helix Ⅰ of other P450s.Compared with structures of common P450s,IFS/imidazole structure contains an extra domain,i.e.,the γ-domain.The structure reveals a homodimer in which the γ-domain of one molecule interacts with the β-domain of another.The plane of heme group makes an angle of ap-proximately 40° with the helix Ⅰa-loop-helix Ⅰβ motif.Molecular docking combined with mutagenesis study suggested that Trp-128 and Asp-300 might play important roles in substrate binding and recogni-tion.Phe-301,Ser-303 and Gly-305 from the helix Ⅰa-loop-helix Ⅰβ motif may play important roles in the aryl-ring migration.These novel structural features reveal insights into the unique reaction mechanism of IFS and provide a basis for engineering IFS in leguminous crops for health purpose.

Isoflavones which mainly distributed in leguminous plants have plenty of health benefits.Isoflavone synthase(IFS)is a membrane-associated cytochrome P450 enzyme(CYP450)which carries out the unique aryl-ring migration and hydroxylation.So far,few crystal structures of plant P450s have been obtained.We determined the crystal structure of IFS from Medicago truncatula at 1.9 ? by MAD method using a selenomethionine substituted crystal and conducted molecular docking and mutagenesis study.The structure of IFS complexed with imidazole exhibits the helix Ⅰa-loop-helix Ⅰβ motif which cor-responds to helix Ⅰ of other P450s.Compared with structures of common P450s,IFS/imidazole structure contains an extra domain,i.e.,the γ-domain.The structure reveals a homodimer in which the γ-domain of one molecule interacts with the β-domain of another.The plane of heme group makes an angle of ap-proximately 40° with the helix Ⅰa-loop-helix Ⅰβ motif.Molecular docking combined with mutagenesis study suggested that Trp-128 and Asp-300 might play important roles in substrate binding and recogni-tion.Phe-301,Ser-303 and Gly-305 from the helix Ⅰa-loop-helix Ⅰβ motif may play important roles in the aryl-ring migration.These novel structural features reveal insights into the unique reaction mechanism of IFS and provide a basis for engineering IFS in leguminous crops for health purpose.

Objective:To analyze the changes in the incidence trend of liver cancer in Taizhou of Jiangsu Province, from 2012 to 2020 and provide reference for tumor prevention and control and management.Methods:Liver cancer incidence data from 2012 to 2020 were extracted from the Taizhou Center for Disease Control and Prevention's tumor registry system. Demographic data were used to calculate the crude incidence rate, age-standardized incidence rate (ASIR), Chinese age-standardized incidence rate (CASIR; based on China's 2010 standard population), and world age-standardized incidence rate (WASIR; based on Segi's world standard population). The Joinpoint regression model was applied to identify inflection points in liver cancer incidence trends during 2012-2020, and annual percentage change (APC) with average annual percentage change (AAPC) were calculated.Results:In 2020, the crude incidence ratio (CIR) of liver cancer in Taizhou was 34.6 per 100 000, with CASIR and WASIR at 19.6 per 100 000 and 14.9 per 100 000, respectively. From 2012 to 2020, the male-to-female ratio of new liver cancer cases was 2.94∶1 (10 455 males vs. 3 559 females), with male incidence consistently higher than female. Overall liver cancer incidence in Taizhou initially increased and then decreased after 2017 (2012-2017: APC=6.4%, P=0.014; 2017-2020: APC=-9.5%, P=0.035), peaking at a CASIR of 26.2 per 100 000 in 2017. The trend in male incidence mirrored the overall pattern, rising before 2017 and declining thereafter (2012-2017: APC=6.2%, P=0.005; 2017-2020: APC=-9.0%, P=0.016). Female incidence remained relatively stable (2012-2016: APC=11.0%, P=0.054; 2016-2020: APC=-6.5%, P=0.130). Conclusions:Liver cancer incidence in Taizhou increased before 2017 and declined thereafter, with 2017 as the turning point. Amid population aging, liver cancer remains a persistent public health challenge requiring sustained attention.

AIM: To delineate the specific mutation responsible for retinitis pigmentosa(RP)in a Yi pedigree, and to analyze the correlation of RHO gene mutation with clinical phenotype.METHODS:A comprehensive clinical evaluation was conducted on the proband diagnosed with RP and other familial members, complemented by a thorough ophthalmic examination. Peripheral blood samples were obtained from the proband and familial members, from which genomic DNA was extracte. Subsequent whole exome sequencing(WES)was employed to identify the variant genes in the proband. The identified variant gene was validated through Sanger sequencing, then an in-depth analysis of the mutation genes was carried out using genetic databases to ascertain the pathogenic mutation sites. Furthermore, an exhaustive analysis was performed to delineate the genotype and phenotype characteristics.RESULTS:The RP pedigree encompasses 5 generations with 42 members, including 19 males and 23 females. A total of 13 cases of RP were identified, consisting of 4 males and 9 females, which conforms to the autosomal dominant inheritance pattern. The clinical features of this family include an early onset age, rapid progression, and a more severe condition. The patients were found to have night blindness around 6 years old, representing the earliest reported case of night blindness in RP families. The retina was manifested by progressive osteocytoid pigmentation of the fundus, a reduced visual field, and significantly decreased or even vanished a and b amplitudes of ERG. The combined results of WES and Sanger sequencing indicated that the proband had a heterozygous missense mutation of the RHO gene c.1040C>T:p.P347L, where the 1 040 base C of cDNA was replaced by T, causing codon 347 to encode leucine instead of proline. Interestingly, this mutation has not been reported in the Chinese population.CONCLUSION:This study confirmed that the mutant gene of RP in a Yi nationality pedigree was RHO(c.1040C>T). This variant leads to the change of codon 347 from encoding proline to encoding leucine, resulting in a severe clinical phenotype among family members. This study provides a certain molecular, clinical, and genetic basis for genetic counseling and gene diagnosis of RHO.

AIM: To delineate the specific mutation responsible for retinitis pigmentosa(RP)in a Yi pedigree, and to analyze the correlation of RHO gene mutation with clinical phenotype.METHODS:A comprehensive clinical evaluation was conducted on the proband diagnosed with RP and other familial members, complemented by a thorough ophthalmic examination. Peripheral blood samples were obtained from the proband and familial members, from which genomic DNA was extracte. Subsequent whole exome sequencing(WES)was employed to identify the variant genes in the proband. The identified variant gene was validated through Sanger sequencing, then an in-depth analysis of the mutation genes was carried out using genetic databases to ascertain the pathogenic mutation sites. Furthermore, an exhaustive analysis was performed to delineate the genotype and phenotype characteristics.RESULTS:The RP pedigree encompasses 5 generations with 42 members, including 19 males and 23 females. A total of 13 cases of RP were identified, consisting of 4 males and 9 females, which conforms to the autosomal dominant inheritance pattern. The clinical features of this family include an early onset age, rapid progression, and a more severe condition. The patients were found to have night blindness around 6 years old, representing the earliest reported case of night blindness in RP families. The retina was manifested by progressive osteocytoid pigmentation of the fundus, a reduced visual field, and significantly decreased or even vanished a and b amplitudes of ERG. The combined results of WES and Sanger sequencing indicated that the proband had a heterozygous missense mutation of the RHO gene c.1040C>T:p.P347L, where the 1 040 base C of cDNA was replaced by T, causing codon 347 to encode leucine instead of proline. Interestingly, this mutation has not been reported in the Chinese population.CONCLUSION:This study confirmed that the mutant gene of RP in a Yi nationality pedigree was RHO(c.1040C>T). This variant leads to the change of codon 347 from encoding proline to encoding leucine, resulting in a severe clinical phenotype among family members. This study provides a certain molecular, clinical, and genetic basis for genetic counseling and gene diagnosis of RHO.

Glutamine provides carbon and nitrogen to support the proliferation of cancer cells. However, the precise reason why cancer cells are particularly dependent on glutamine remains unclear. In this study, we report that glutamine modulates the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) to promote cancer cell proliferation and survival. Specifically, lysine 604 (K604) in the sixth of the 7 substrate-recruiting WD repeats of FBW7 undergoes glutaminylation (Gln-K604) by glutaminyl tRNA synthetase. Gln-K604 inhibits SCFFBW7-mediated degradation of c-Myc and Mcl-1, enhances glutamine utilization, and stimulates nucleotide and DNA biosynthesis through the activation of c-Myc. Additionally, Gln-K604 promotes resistance to apoptosis by activating Mcl-1. In contrast, SIRT1 deglutaminylates Gln-K604, thereby reversing its effects. Cancer cells lacking Gln-K604 exhibit overexpression of c-Myc and Mcl-1 and display resistance to chemotherapy-induced apoptosis. Silencing both c-MYC and MCL-1 in these cells sensitizes them to chemotherapy. These findings indicate that the glutamine-mediated signal via Gln-K604 is a key driver of cancer progression and suggest potential strategies for targeted cancer therapies based on varying Gln-K604 status.
Glutamine/metabolism* ; Myeloid Cell Leukemia Sequence 1 Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-myc/genetics* ; Cell Proliferation ; Signal Transduction ; Neoplasms/pathology* ; F-Box-WD Repeat-Containing Protein 7/genetics* ; Cell Survival ; Cell Line, Tumor ; Apoptosis

OBJECTIVE: The study aim was to investigate the effects of exposure to multiple environmental organic pollutants on cardiopulmonary health with a focus on the potential mediating role of oxidative stress. METHODS: A repeated-measures randomized crossover study involving healthy college students in Beijing was conducted. Biological samples, including morning urine and venous blood, were collected to measure concentrations of 29 typical organic pollutants, including hydroxy polycyclic aromatic hydrocarbons (OH-PAHs), bisphenol A and its substitutes, phthalates and their metabolites, parabens, and five biomarkers of oxidative stress. Health assessments included blood pressure measurements and lung function indicators. RESULTS: Urinary concentrations of 2-hydroxyphenanthrene (2-OH-PHE) ( β = 4.35% [95% confidence interval ( CI): 0.85%, 7.97%]), 3-hydroxyphenanthrene ( β = 3.44% [95% CI: 0.19%, 6.79%]), and 4-hydroxyphenanthrene (4-OH-PHE) ( β = 5.78% [95% CI: 1.27%, 10.5%]) were significantly and positively associated with systolic blood pressure. Exposures to 1-hydroxypyrene (1-OH-PYR) ( β = 3.05% [95% CI: -4.66%, -1.41%]), 2-OH-PHE ( β = 2.68% [95% CI: -4%, -1.34%]), and 4-OH-PHE ( β = 3% [95% CI: -4.68%, -1.29%]) were negatively associated with the ratio of forced expiratory volume in the first second to forced vital capacity. These findings highlight the adverse effects of exposure to multiple pollutants on cardiopulmonary health. Biomarkers of oxidative stress, including 8-hydroxy-2'-deoxyguanosine and extracellular superoxide dismutase, mediated the effects of multiple OH-PAHs on blood pressure and lung function. CONCLUSION Exposure to multiple organic pollutants can adversely affect cardiopulmonary health. Oxidative stress is a key mediator of the effects of OH-PAHs on blood pressure and lung function.
Humans ; Oxidative Stress/drug effects* ; Male ; Cross-Over Studies ; Female ; Young Adult ; Environmental Pollutants/toxicity* ; Environmental Exposure/adverse effects* ; Biomarkers/blood* ; Adult ; Blood Pressure/drug effects* ; Polycyclic Aromatic Hydrocarbons/urine* ; Beijing

Objective:To analyze the changes in the incidence trend of liver cancer in Taizhou of Jiangsu Province, from 2012 to 2020 and provide reference for tumor prevention and control and management.Methods:Liver cancer incidence data from 2012 to 2020 were extracted from the Taizhou Center for Disease Control and Prevention's tumor registry system. Demographic data were used to calculate the crude incidence rate, age-standardized incidence rate (ASIR), Chinese age-standardized incidence rate (CASIR; based on China's 2010 standard population), and world age-standardized incidence rate (WASIR; based on Segi's world standard population). The Joinpoint regression model was applied to identify inflection points in liver cancer incidence trends during 2012-2020, and annual percentage change (APC) with average annual percentage change (AAPC) were calculated.Results:In 2020, the crude incidence ratio (CIR) of liver cancer in Taizhou was 34.6 per 100 000, with CASIR and WASIR at 19.6 per 100 000 and 14.9 per 100 000, respectively. From 2012 to 2020, the male-to-female ratio of new liver cancer cases was 2.94∶1 (10 455 males vs. 3 559 females), with male incidence consistently higher than female. Overall liver cancer incidence in Taizhou initially increased and then decreased after 2017 (2012-2017: APC=6.4%, P=0.014; 2017-2020: APC=-9.5%, P=0.035), peaking at a CASIR of 26.2 per 100 000 in 2017. The trend in male incidence mirrored the overall pattern, rising before 2017 and declining thereafter (2012-2017: APC=6.2%, P=0.005; 2017-2020: APC=-9.0%, P=0.016). Female incidence remained relatively stable (2012-2016: APC=11.0%, P=0.054; 2016-2020: APC=-6.5%, P=0.130). Conclusions:Liver cancer incidence in Taizhou increased before 2017 and declined thereafter, with 2017 as the turning point. Amid population aging, liver cancer remains a persistent public health challenge requiring sustained attention.