The scientific community is continuously working to translate the novel biomedical techniques into effective medical treatments.CRISPR-Cas9 system(Clustered Regularly Interspaced Short Palindromic Repeats-9),commonly ...The scientific community is continuously working to translate the novel biomedical techniques into effective medical treatments.CRISPR-Cas9 system(Clustered Regularly Interspaced Short Palindromic Repeats-9),commonly known as the“molecular scissor”,represents a recently developed biotechnology able to improve the quality and the efficacy of traditional treatments,related to several human diseases,such as chronic diseases,neurodegenerative pathologies and,interestingly,oral diseases.Of course,dental medicine has notably increased the use of biotechnologies to ensure modern and conservative approaches:in this landscape,the use of CRISPR-Cas9 system may speed and personalize the traditional therapies,ensuring a good predictability of clinical results.The aim of this critical overview is to provide evidence on CRISPR efficacy,taking into specific account its applications in oral medicine.展开更多
Serous adenocarcinoma of the vaginal-urethral interspance with unknown origin has not previously been reported.Based on existing evidence,serous adenocarcinoma was considered to be a mesonephric adenocarcinoma.Mesonep...Serous adenocarcinoma of the vaginal-urethral interspance with unknown origin has not previously been reported.Based on existing evidence,serous adenocarcinoma was considered to be a mesonephric adenocarcinoma.Mesonephric adenocarcinoma is a rare tumor of the female genital tract derived from mesonephric duct remnants or hyperplasia.Among the small number of reported cases,most are related to the uterus and cervix.There is no literature pertaining to optimal therapy,and little is known about the response to chemotherapeutic agents and prognosis.Here,we reported a case of a mesonephric adenocarcinoma of the vaginal-urethral interspace in a 43-year-old woman with 4 years of follow-up.展开更多
BACKGROUND In recent years,many studies have shown that proteasome 26S subunit non-ATPase 6(PSMD6)plays an important role in the occurrence and development of malignant tumours.Unfortunately,there are no reports on th...BACKGROUND In recent years,many studies have shown that proteasome 26S subunit non-ATPase 6(PSMD6)plays an important role in the occurrence and development of malignant tumours.Unfortunately,there are no reports on the evaluation of the potential role of PSMD6 in hepatocellular carcinoma(HCC).AIM To comprehensively evaluate the overexpression pattern and clinical significance of PSMD6 in HCC tissues.METHODS This study integrated PSMD6 mRNA expression profiles from 4672 HCC and 3667 non-HCC tissues,along with immunohistochemical scores from 383 HCC and adjacent tissues,to assess PSMD6 overexpression in HCC.Clustered regularly interspaced short palindromic repeats knockout technology evaluated PSMD6’s essential role in HCC cell growth.Functional enrichment analysis explored the molecular mechanism of PSMD6 abnormalities in HCC.Drug sensitivity analysis and molecular docking analysed the effect of abnormal expression of PSMD6 on the drug sensitivity of HCC cells.RESULTS The results of 41 external and two internal datasets showed that PSMD6 mRNA(SMD=0.26,95%CI:0.09-0.42,P<0.05)and protein(SMD=2.85,95%CI:1.19-4.50,P<0.05)were significantly overexpressed in HCC tissues.The integrated analysis results showed that PSMD6 had a significant overexpression pattern in HCC tissues(SMD=0.40,95%CI:0.15-0.66,P<0.05).PSMD6 knockout inhibited HCC cell growth(chronos scores<-1).Functional enrichment implicated ribosome biogenesis and RNA splicing.Significant enrichment of signalling pathways such as RNA degradation,ribosomes,and chemical carcinogenesis—reactive oxygen species.Drug sensitivity analysis and a molecular docking model showed that high expression of PSMD6 was associated with the tolerance of HCC cells to drugs such as ML323,sepantronium bromide,and GDC0810.Overexpressed PSMD6 effectively distinguished HCC tissues(AUC=0.75,95%CI:0.71-0.79).CONCLUSION This study was the first to discover that PSMD6 was overexpressed in HCC tissues.PSMD6 is essential for the growth of HCC cells and may be involved in ribosome biogenesis and RNA splicing.展开更多
Gastric cancer(GC)remains one of the leading causes of cancer-related mortality worldwide,necessitating innovative approaches for its diagnosis and treatment.Clustered regularly interspaced short palindromic repeats(C...Gastric cancer(GC)remains one of the leading causes of cancer-related mortality worldwide,necessitating innovative approaches for its diagnosis and treatment.Clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPRassociated protein 9(Cas9),a revolutionary gene-editing technology,has emerged as a powerful tool for unraveling the molecular mechanisms underlying GC and for advancing precision medicine strategies.This review explores the current applications of CRISPR/Cas9 in GC research,including the identification of oncogenes and tumor suppressors,modeling tumor microenvironment interactions,and developing gene-based therapies.We highlight recent breakthroughs in genome editing that have enhanced our understanding of GC pathogenesis and resistance mechanisms to conventional therapies.Additionally,we discuss the potential of CRISPR/Cas9 for therapeutic gene editing in GC,addressing challenges such as off-target effects,delivery methods,and ethical considerations.By summarizing the progress and limitations of CRISPR/Cas9 in GC,this review aims to provide a comprehensive perspective on how this transformative technology could shape future strategies for the prevention,diagnosis,and treatment of GC.展开更多
BACKGROUND Although thymopoietin(TMPO)has been elucidated to be overexpressed in cancers,its underlying mechanisms are not yet fully understood.AIM To investigate the expression and clinical significance of TMPO in pa...BACKGROUND Although thymopoietin(TMPO)has been elucidated to be overexpressed in cancers,its underlying mechanisms are not yet fully understood.AIM To investigate the expression and clinical significance of TMPO in papillary thyroid carcinoma(PTC).METHODS Databases such as Gene Expression Omnibus,The Cancer Genome Atlas Proand summary receiver operating characteristic curves were plotted to evaluate diagnostic performance.A Gene Set Enrichment Analysis enrichment analysis was conducted to identify TMPO-related signaling pathways.A protein interaction network was constructed to identify hub genes.The impact of TMPO on PTC cell proliferation and the effects of its knockout were analyzed using clustered regularly interspaced short palindromic repeats(CRISPR)knockout screening and the Cancer Cell Line Encyclopedia database.RESULTS The TMPO protein was significantly overexpressed in PTC tissues,primarily localized in the cytoplasm and nuclear membrane.The mRNA level analysis showed mild overexpression of TMPO in PTC tissues,with a certain discriminatory value(area under the curve=0.66).TMPO may promote cancer through involvement in cell adhesion,focal adhesion,leukocyte migration,and multiple cancer-related signaling pathways.Additionally,CRISPR gene knockout experiments confirmed that TMPO knockout significantly inhibited the proliferation of PTC cell lines,indicating its important role in tumor growth.CONCLUSION TMPO is overexpressed in PTC and may serve as a therapeutic target and molecular biomarker for PTC.展开更多
A recent study by Qin et al emphasized the potential of zinc finger protein 71(ZNF71)as a promising biomarker for hepatocellular carcinoma(HCC).The authors offered valuable insights into the relationship between ZNF71...A recent study by Qin et al emphasized the potential of zinc finger protein 71(ZNF71)as a promising biomarker for hepatocellular carcinoma(HCC).The authors offered valuable insights into the relationship between ZNF71 and various clinical and pathological stages of HCC.However,several limitations are required to be addressed to improve the findings.These limitations include concerns regarding patient selection,the generalizability of the results,and the necessity for functional validation to establish ZNF71’s specific role in the progression of HCC.Furthermore,statistical issues related to multiple comparisons,confounding variables,and the inherent heterogeneity of high-throughput datasets warrant careful consideration.Future research should focus on multi-institutional cohorts,utilize in vivo models,and compare ZNF71 with established biomarkers to strengthen the clinical relevance of ZNF71.展开更多
BACKGROUND The prevalence of colorectal cancer(CRC)in younger people is increasing.Despite advances in precision medicine,the challenges of drug resistance and high costs persist.Nitidine chloride(NC)has pharmacologic...BACKGROUND The prevalence of colorectal cancer(CRC)in younger people is increasing.Despite advances in precision medicine,the challenges of drug resistance and high costs persist.Nitidine chloride(NC)has pharmacological potential,and kinesin family member 20A(KIF20A)is overexpressed in various tumors;however,their interaction in CRC remains unexplored.AIM To investigate the KIF20A expression characteristics in CRC cells and determine whether it is a potential target gene for NC in inhibiting CRC treatment.METHODS Single-cell RNA sequencing(scRNA-seq),spatial transcriptomics,and mRNA expression profiling were used to analyze KIF20A expression in CRC cells.Immunohistochemical staining was used to verify KIF20A expression in 416 clinical samples(208 CRC tissue samples and 208 noncancerous control tissue samples).Clustered regularly interspaced short palindromic repeats(CRISPR)technology was used to evaluate the impact of knocking out KIF20A on CRC cell growth.Molecular docking was applied to analyze NC–KIF20A binding.Finally,RNA sequencing and functional enrichment analysis were performed to explore the mechanism of action of NC in CRC cells.RESULTS Treating HCT116 cells with NC was found to significantly downregulate KIF20A(P<0.05),and the molecular docking analysis revealed high-affinity binding between NC and KIF20A(binding energy=-9.6 kcal/mol).The scRNA-seq,spatial transcriptomics,and mRNA expression profiling results confirmed the significantly high expression of KIF20A in CRC tissues(standardized mean difference=1.33,95%confidence interval:0.885-1.77,summary receiver operating characteristic curve area=0.94).The immunohistochemical analysis of the clinical samples showed high KIF20A expression in the CRC tissues(P<0.05),with significant correlation between the level of expression and gender,tumor size,and tumor grade(P<0.05).Knocking out KIF20A significantly inhibited the growth of various CRC cell lines(CRISPR score<-0.3).The functional enrichment analysis indicated that NC may inhibit CRC by disrupting several biological processes,such as mitotic nuclear division,chromosome segregation,and microtubule binding.CONCLUSION Our results indicate that NC binds to KIF20A with high affinity and downregulates its expression in CRC cells,leading to reduced proliferation.Hence,NC has promise as a therapeutic agent in the treatment of CRC,and targeting KIF20A also has potential as a therapeutic strategy.Further KIF20A knockout studies are needed to confirm the binding specificity and mechanistic roles of NC in CRC.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)remains a lethal malignancy due to its molecular complexity and chemoresistance.Rac family small GTPase 3(RAC3),a tumorigenic GTPase understudied in HCC,drives recurrence via E2...BACKGROUND Hepatocellular carcinoma(HCC)remains a lethal malignancy due to its molecular complexity and chemoresistance.Rac family small GTPase 3(RAC3),a tumorigenic GTPase understudied in HCC,drives recurrence via E2F transcription factor 1(E2F1)-mediated transcriptional activation.This study integrates multiomics and clustered regularly interspaced short palindromic repeats(CRISPR)screening to delineate RAC3’s roles.RAC3 overexpression correlates with advanced HCC and patient age,while its knockout suppresses proliferation.Mechanistically,RAC3 dysregulates cell-cycle checkpoints through E2F1 binding.Pharmacological RAC3 inhibition disrupts tumor growth and synergizes with chemotherapy to overcome resistance.AIM To explore RAC3’s expression,clinical links,and HCC mechanisms via multiomics and functional genomics.METHODS Multiomic integration of The Cancer Genome Atlas(TCGA),Gene Expression Omnibus,and Genotype-Tissue Expression datasets was performed to analyze RAC3 mRNA expression.Immunohistochemistry quantified RAC3 protein in 108 HCC/adjacent tissue pairs.Kaplan–Meier/Cox regression assessed prognostic significance using TCGA data.CRISPR screening validated RAC3’s necessity for HCC proliferation.Functional enrichment identified associated pathways;hTFtarget/JASPAR predicted transcription factors,validated via chromatin immunoprecipitation sequencing(ChIP-seq).RESULTS RAC3 exhibited significant mRNA and protein overexpression in HCC tissues,which was correlated with advanced tumor stages and reduced overall survival rates(hazard ratio=1.82,95%CI:1.31–2.53).Genetic ablation of RAC3 suppressed HCC cell proliferation across 16 cell lines.Pathway analysis revealed RAC3’s predominant involvement in cell-cycle regulation,DNA replication,and nucleocytoplasmic transport.Mechanistic investigations identified E2F1 as a pivotal upstream transcriptional regulator,and ChIP-seq analysis validated its direct binding to the RAC3 promoter region.These findings suggest that RAC3 drives HCC progression through E2F1-mediated cell-cycle dysregulation.CONCLUSION This study identified RAC3 as a key HCC oncogenic driver;its overexpression links to poor prognosis/resistance.Targeting the RAC3/E2F1 axis offers a new therapy,which highlights RAC3 as a biomarker/target.展开更多
Recently, an epoch-making genome engineering technology using clustered regularly at interspaced short palindromic repeats(CRISPR) and CRISPR associated(Cas) nucleases, was developed. Previous technologies for genome ...Recently, an epoch-making genome engineering technology using clustered regularly at interspaced short palindromic repeats(CRISPR) and CRISPR associated(Cas) nucleases, was developed. Previous technologies for genome manipulation require the time-consuming design and construction of genome-engineered nucleases for each target and have, therefore, not been widely used in mouse research where standard techniques based on homologous recombination are commonly used. The CRISPR/Cas system only requires the design of sequences complementary to a target locus, making this technology fast and straightforward. In addition, CRISPR/Cas can be used to generate mice carrying mutations in multiple genes in a single step, an achievement not possible using other methods. Here, we review the uses of this technology in genetic analysis and manipulation, including achievements made possible to date and the prospects for future therapeutic applications.展开更多
Gene editing has recently emerged as a promising technology to engineer genetic modifications precisely in the genome to achieve long-term relief from corneal disorders.Recent advances in the molecular biology leading...Gene editing has recently emerged as a promising technology to engineer genetic modifications precisely in the genome to achieve long-term relief from corneal disorders.Recent advances in the molecular biology leading to the development of clustered regularly interspaced short palindromic repeats(CRISPRs) and CRISPR-associated systems,zinc finger nucleases and transcription activator like effector nucleases have ushered in a new era for high throughput in vitro and in vivo genome engineering.Genome editing can be successfully used to decipher complex molecular mechanisms underlying disease pathophysiology,develop innovative next generation gene therapy,stem cell-based regenerative therapy,and personalized medicine for corneal and other ocular diseases.In this review we describe latest developments in the field of genome editing,current challenges,and future prospects for the development of personalized genebased medicine for corneal diseases.The gene editing approach is expected to revolutionize current diagnostic and treatment practices for curing blindness.展开更多
The rapid developments of science and technology in China over recent decades, particularly in biomedical research, have brought forward serious challenges regarding ethical governance. Recently, Jian-kui HE, a Chines...The rapid developments of science and technology in China over recent decades, particularly in biomedical research, have brought forward serious challenges regarding ethical governance. Recently, Jian-kui HE, a Chinese scientist, claimed to have "created" the first gene-edited babies, designed to be naturally immune to the human immunodeficiency virus(HIV). The news immediately triggered widespread criticism, denouncement, and debate over the scientific and ethical legitimacy of HE’s genetic experiments. China’s guidelines and regulations have banned germline genome editing on human embryos for clinical use because of scientific and ethical concerns, in accordance with the international consensus. HE’s human experimentation has not only violated these Chinese regulations, but also breached other ethical and regulatory norms. These include questionable scientific value, unreasonable risk-benefit ratio, illegitimate ethics review, invalid informed consent, and regulatory misconduct. This series of ethical failings of HE and his team reveal the institutional failure of the current ethics governance system which largely depends on scientist’s self-regulation. The incident highlights the need for urgent improvement of ethics governance at all levels, the enforcement of technical and ethical guidelines, and the establishment of laws relating to such bioethical issues.展开更多
Since it was first recognized in bacteria and archaea as a mechanism for innate viral immunity in the early 2010 s,clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein(Cas)has ra...Since it was first recognized in bacteria and archaea as a mechanism for innate viral immunity in the early 2010 s,clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein(Cas)has rapidly been developed into a robust,multifunctional genome editing tool with many uses.Following the discovery of the initial CRISPR/Cas-based system,the technology has been advanced to facilitate a multitude of different functions.These include development as a base editor,prime editor,epigenetic editor,and CRISPR interference(CRISPRi)and CRISPR activator(CRISPRa)gene regulators.It can also be used for chromatin and RNA targeting and imaging.Its applications have proved revolutionary across numerous biological fields,especially in biomedical and agricultural improvement.As a diagnostic tool,CRISPR has been developed to aid the detection and screening of both human and plant diseases,and has even been applied during the current coronavirus disease 2019(COVID-19)pandemic.CRISPR/Cas is also being trialed as a new form of gene therapy for treating various human diseases,including cancers,and has aided drug development.In terms of agricultural breeding,precise targeting of biological pathways via CRISPR/Cas has been key to regulating molecular biosynthesis and allowing modification of proteins,starch,oil,and other functional components for crop improvement.Adding to this,CRISPR/Cas has been shown capable of significantly enhancing both plant tolerance to environmental stresses and overall crop yield via the targeting of various agronomically important gene regulators.Looking to the future,increasing the efficiency and precision of CRISPR/Cas delivery systems and limiting off-target activity are two major challenges for wider application of the technology.This review provides an in-depth overview of current CRISPR development,including the advantages and disadvantages of the technology,recent applications,and future considerations.展开更多
Alzheimer’s disease （AD） is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved...Alzheimer’s disease （AD） is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons. The pathophysiology of AD is complex; mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress are antecedent and potentially play a causal role in the disease pathogenesis. Dysfunctional mitochondria accumulate from the combination of impaired mitophagy, which can also induce injurious inflammatory responses, and inadequate neuronal mitochondrial biogenesis. Altering the metabolic capacity of the brain by modulating/potentiating its mitochondrial bioenergetics may be a strategy for disease prevention and treatment. We present insights into the mechanisms of mitochondrial dysfunction in AD brain as well as an overview of emerging treatments with the potential to prevent, delay or reverse the neurodegenerative process by targeting mitochondria.展开更多
Chimeric antigen receptor T(CAR-T)cell therapy is the novel treatment strategy for hematological malignancies such as acute lymphoblastic leukemia(ALL),lymphoma and multiple myeloma.However,treatment-related toxicitie...Chimeric antigen receptor T(CAR-T)cell therapy is the novel treatment strategy for hematological malignancies such as acute lymphoblastic leukemia(ALL),lymphoma and multiple myeloma.However,treatment-related toxicities such as cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)have become significant hurdles to CAR-T treatment.Multiple strategies were established to alter the CAR structure on the genomic level to improve efficacy and reduce toxicities.Recently,the innovative gene-editing technology-clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated nuclease9(Cas9)system,which particularly exhibits preponderance in knock-in and knockout at specific sites,is widely utilized to manufacture CAR-T products.The application of CRISPR/Cas9 to CAR-T cell therapy has shown promising clinical results with minimal toxicity.In this review,we summarized the past achievements of CRISPR/Cas9 in CAR-T therapy and focused on the potential CAR-T targets.展开更多
BACKGROUND Currently,intrahepatic cholangiocarcinoma(ICC)poses a continuing,significant health challenge,but the relationship has yet to be established between ICC and the proteasome 26S subunit non-ATPase 6(PSMD6).AI...BACKGROUND Currently,intrahepatic cholangiocarcinoma(ICC)poses a continuing,significant health challenge,but the relationship has yet to be established between ICC and the proteasome 26S subunit non-ATPase 6(PSMD6).AIM To investigate the protein expression and clinicopathological significance of PSMD6 in ICC.METHODS The potential impact of the PSMD6 gene on the growth of ICC cell lines was analyzed using clustered regularly interspaced short palindromic repeat knockout screening technology.Forty-two paired specimens of ICC and adjacent noncancerous tissues were collected.PSMD6 protein expression was determined by immunohistochemistry.Receiver operating characteristic curve analysis was performed to validate PSMD6 expression level,and its association with ICC patients’various clinicopathological characteristics was investigated.RESULTS The PSMD6 gene was found to be essential for the growth of ICC cell lines.PSMD6 protein was significantly overexpressed in ICC tissues(P<0.001),but showed no significant association with patient age,gender,pathological grade,or tumor-node-metastasis stage(P>0.05).CONCLUSION PSMD6 can promote the growth of ICC cells,thus playing a pro-oncogenic role.展开更多
文摘The scientific community is continuously working to translate the novel biomedical techniques into effective medical treatments.CRISPR-Cas9 system(Clustered Regularly Interspaced Short Palindromic Repeats-9),commonly known as the“molecular scissor”,represents a recently developed biotechnology able to improve the quality and the efficacy of traditional treatments,related to several human diseases,such as chronic diseases,neurodegenerative pathologies and,interestingly,oral diseases.Of course,dental medicine has notably increased the use of biotechnologies to ensure modern and conservative approaches:in this landscape,the use of CRISPR-Cas9 system may speed and personalize the traditional therapies,ensuring a good predictability of clinical results.The aim of this critical overview is to provide evidence on CRISPR efficacy,taking into specific account its applications in oral medicine.
文摘Serous adenocarcinoma of the vaginal-urethral interspance with unknown origin has not previously been reported.Based on existing evidence,serous adenocarcinoma was considered to be a mesonephric adenocarcinoma.Mesonephric adenocarcinoma is a rare tumor of the female genital tract derived from mesonephric duct remnants or hyperplasia.Among the small number of reported cases,most are related to the uterus and cervix.There is no literature pertaining to optimal therapy,and little is known about the response to chemotherapeutic agents and prognosis.Here,we reported a case of a mesonephric adenocarcinoma of the vaginal-urethral interspace in a 43-year-old woman with 4 years of follow-up.
基金Supported by National Natural Science Foundation of China,No.82160762Guangxi Zhuang Autonomous Region Administration of Traditional Chinese Medicine Scientific Research Project,No.GXZYA20230267+2 种基金China Undergraduate Innovation and Entrepreneurship Training Program,No.S202410598060XChina Undergraduate Innovation and Entrepreneurship Training Program,No.X202410598360Future Academic Star of Guangxi Medical University,No.WLXSZX24074.
文摘BACKGROUND In recent years,many studies have shown that proteasome 26S subunit non-ATPase 6(PSMD6)plays an important role in the occurrence and development of malignant tumours.Unfortunately,there are no reports on the evaluation of the potential role of PSMD6 in hepatocellular carcinoma(HCC).AIM To comprehensively evaluate the overexpression pattern and clinical significance of PSMD6 in HCC tissues.METHODS This study integrated PSMD6 mRNA expression profiles from 4672 HCC and 3667 non-HCC tissues,along with immunohistochemical scores from 383 HCC and adjacent tissues,to assess PSMD6 overexpression in HCC.Clustered regularly interspaced short palindromic repeats knockout technology evaluated PSMD6’s essential role in HCC cell growth.Functional enrichment analysis explored the molecular mechanism of PSMD6 abnormalities in HCC.Drug sensitivity analysis and molecular docking analysed the effect of abnormal expression of PSMD6 on the drug sensitivity of HCC cells.RESULTS The results of 41 external and two internal datasets showed that PSMD6 mRNA(SMD=0.26,95%CI:0.09-0.42,P<0.05)and protein(SMD=2.85,95%CI:1.19-4.50,P<0.05)were significantly overexpressed in HCC tissues.The integrated analysis results showed that PSMD6 had a significant overexpression pattern in HCC tissues(SMD=0.40,95%CI:0.15-0.66,P<0.05).PSMD6 knockout inhibited HCC cell growth(chronos scores<-1).Functional enrichment implicated ribosome biogenesis and RNA splicing.Significant enrichment of signalling pathways such as RNA degradation,ribosomes,and chemical carcinogenesis—reactive oxygen species.Drug sensitivity analysis and a molecular docking model showed that high expression of PSMD6 was associated with the tolerance of HCC cells to drugs such as ML323,sepantronium bromide,and GDC0810.Overexpressed PSMD6 effectively distinguished HCC tissues(AUC=0.75,95%CI:0.71-0.79).CONCLUSION This study was the first to discover that PSMD6 was overexpressed in HCC tissues.PSMD6 is essential for the growth of HCC cells and may be involved in ribosome biogenesis and RNA splicing.
文摘Gastric cancer(GC)remains one of the leading causes of cancer-related mortality worldwide,necessitating innovative approaches for its diagnosis and treatment.Clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPRassociated protein 9(Cas9),a revolutionary gene-editing technology,has emerged as a powerful tool for unraveling the molecular mechanisms underlying GC and for advancing precision medicine strategies.This review explores the current applications of CRISPR/Cas9 in GC research,including the identification of oncogenes and tumor suppressors,modeling tumor microenvironment interactions,and developing gene-based therapies.We highlight recent breakthroughs in genome editing that have enhanced our understanding of GC pathogenesis and resistance mechanisms to conventional therapies.Additionally,we discuss the potential of CRISPR/Cas9 for therapeutic gene editing in GC,addressing challenges such as off-target effects,delivery methods,and ethical considerations.By summarizing the progress and limitations of CRISPR/Cas9 in GC,this review aims to provide a comprehensive perspective on how this transformative technology could shape future strategies for the prevention,diagnosis,and treatment of GC.
基金Supported by Guangxi Zhuang Autonomous Region Health Commission Scientific Research Project,No.Z-A20220521Guangxi Higher Education Undergraduate Teaching Reform Project,No.2022JGA147The National College Students’Innovation and Entrepreneurship Training Program,No.202310598042.
文摘BACKGROUND Although thymopoietin(TMPO)has been elucidated to be overexpressed in cancers,its underlying mechanisms are not yet fully understood.AIM To investigate the expression and clinical significance of TMPO in papillary thyroid carcinoma(PTC).METHODS Databases such as Gene Expression Omnibus,The Cancer Genome Atlas Proand summary receiver operating characteristic curves were plotted to evaluate diagnostic performance.A Gene Set Enrichment Analysis enrichment analysis was conducted to identify TMPO-related signaling pathways.A protein interaction network was constructed to identify hub genes.The impact of TMPO on PTC cell proliferation and the effects of its knockout were analyzed using clustered regularly interspaced short palindromic repeats(CRISPR)knockout screening and the Cancer Cell Line Encyclopedia database.RESULTS The TMPO protein was significantly overexpressed in PTC tissues,primarily localized in the cytoplasm and nuclear membrane.The mRNA level analysis showed mild overexpression of TMPO in PTC tissues,with a certain discriminatory value(area under the curve=0.66).TMPO may promote cancer through involvement in cell adhesion,focal adhesion,leukocyte migration,and multiple cancer-related signaling pathways.Additionally,CRISPR gene knockout experiments confirmed that TMPO knockout significantly inhibited the proliferation of PTC cell lines,indicating its important role in tumor growth.CONCLUSION TMPO is overexpressed in PTC and may serve as a therapeutic target and molecular biomarker for PTC.
文摘A recent study by Qin et al emphasized the potential of zinc finger protein 71(ZNF71)as a promising biomarker for hepatocellular carcinoma(HCC).The authors offered valuable insights into the relationship between ZNF71 and various clinical and pathological stages of HCC.However,several limitations are required to be addressed to improve the findings.These limitations include concerns regarding patient selection,the generalizability of the results,and the necessity for functional validation to establish ZNF71’s specific role in the progression of HCC.Furthermore,statistical issues related to multiple comparisons,confounding variables,and the inherent heterogeneity of high-throughput datasets warrant careful consideration.Future research should focus on multi-institutional cohorts,utilize in vivo models,and compare ZNF71 with established biomarkers to strengthen the clinical relevance of ZNF71.
基金Supported by the Promoting Project of Basic Capacity for Young and Middle-aged University Teachers in Guangxi,No.2025KY0164Youth Science Foundation of Guangxi Medical University,No.GXMUYSF202423Guangxi Zhuang Autonomous Region Health Commission Scientific Research Project,No.Z-A20220415 and No.Z20210442.
文摘BACKGROUND The prevalence of colorectal cancer(CRC)in younger people is increasing.Despite advances in precision medicine,the challenges of drug resistance and high costs persist.Nitidine chloride(NC)has pharmacological potential,and kinesin family member 20A(KIF20A)is overexpressed in various tumors;however,their interaction in CRC remains unexplored.AIM To investigate the KIF20A expression characteristics in CRC cells and determine whether it is a potential target gene for NC in inhibiting CRC treatment.METHODS Single-cell RNA sequencing(scRNA-seq),spatial transcriptomics,and mRNA expression profiling were used to analyze KIF20A expression in CRC cells.Immunohistochemical staining was used to verify KIF20A expression in 416 clinical samples(208 CRC tissue samples and 208 noncancerous control tissue samples).Clustered regularly interspaced short palindromic repeats(CRISPR)technology was used to evaluate the impact of knocking out KIF20A on CRC cell growth.Molecular docking was applied to analyze NC–KIF20A binding.Finally,RNA sequencing and functional enrichment analysis were performed to explore the mechanism of action of NC in CRC cells.RESULTS Treating HCT116 cells with NC was found to significantly downregulate KIF20A(P<0.05),and the molecular docking analysis revealed high-affinity binding between NC and KIF20A(binding energy=-9.6 kcal/mol).The scRNA-seq,spatial transcriptomics,and mRNA expression profiling results confirmed the significantly high expression of KIF20A in CRC tissues(standardized mean difference=1.33,95%confidence interval:0.885-1.77,summary receiver operating characteristic curve area=0.94).The immunohistochemical analysis of the clinical samples showed high KIF20A expression in the CRC tissues(P<0.05),with significant correlation between the level of expression and gender,tumor size,and tumor grade(P<0.05).Knocking out KIF20A significantly inhibited the growth of various CRC cell lines(CRISPR score<-0.3).The functional enrichment analysis indicated that NC may inhibit CRC by disrupting several biological processes,such as mitotic nuclear division,chromosome segregation,and microtubule binding.CONCLUSION Our results indicate that NC binds to KIF20A with high affinity and downregulates its expression in CRC cells,leading to reduced proliferation.Hence,NC has promise as a therapeutic agent in the treatment of CRC,and targeting KIF20A also has potential as a therapeutic strategy.Further KIF20A knockout studies are needed to confirm the binding specificity and mechanistic roles of NC in CRC.
基金Supported by National Natural Science Foundation of China,No.82260581.
文摘BACKGROUND Hepatocellular carcinoma(HCC)remains a lethal malignancy due to its molecular complexity and chemoresistance.Rac family small GTPase 3(RAC3),a tumorigenic GTPase understudied in HCC,drives recurrence via E2F transcription factor 1(E2F1)-mediated transcriptional activation.This study integrates multiomics and clustered regularly interspaced short palindromic repeats(CRISPR)screening to delineate RAC3’s roles.RAC3 overexpression correlates with advanced HCC and patient age,while its knockout suppresses proliferation.Mechanistically,RAC3 dysregulates cell-cycle checkpoints through E2F1 binding.Pharmacological RAC3 inhibition disrupts tumor growth and synergizes with chemotherapy to overcome resistance.AIM To explore RAC3’s expression,clinical links,and HCC mechanisms via multiomics and functional genomics.METHODS Multiomic integration of The Cancer Genome Atlas(TCGA),Gene Expression Omnibus,and Genotype-Tissue Expression datasets was performed to analyze RAC3 mRNA expression.Immunohistochemistry quantified RAC3 protein in 108 HCC/adjacent tissue pairs.Kaplan–Meier/Cox regression assessed prognostic significance using TCGA data.CRISPR screening validated RAC3’s necessity for HCC proliferation.Functional enrichment identified associated pathways;hTFtarget/JASPAR predicted transcription factors,validated via chromatin immunoprecipitation sequencing(ChIP-seq).RESULTS RAC3 exhibited significant mRNA and protein overexpression in HCC tissues,which was correlated with advanced tumor stages and reduced overall survival rates(hazard ratio=1.82,95%CI:1.31–2.53).Genetic ablation of RAC3 suppressed HCC cell proliferation across 16 cell lines.Pathway analysis revealed RAC3’s predominant involvement in cell-cycle regulation,DNA replication,and nucleocytoplasmic transport.Mechanistic investigations identified E2F1 as a pivotal upstream transcriptional regulator,and ChIP-seq analysis validated its direct binding to the RAC3 promoter region.These findings suggest that RAC3 drives HCC progression through E2F1-mediated cell-cycle dysregulation.CONCLUSION This study identified RAC3 as a key HCC oncogenic driver;its overexpression links to poor prognosis/resistance.Targeting the RAC3/E2F1 axis offers a new therapy,which highlights RAC3 as a biomarker/target.
基金Supported by The Grants from the Ministry of EducationCulture+7 种基金SportsScience and Technology of Japanthe Ministry of HealthLabour and Welfare of Japanthe National Institute of Biomedical Innovationthe Asahi Glass Foundationthe Ichiro Kanehara Foundationthe Program for Cultivating Global Leaders in Heavy Ion Therapeutics and Engineering
文摘Recently, an epoch-making genome engineering technology using clustered regularly at interspaced short palindromic repeats(CRISPR) and CRISPR associated(Cas) nucleases, was developed. Previous technologies for genome manipulation require the time-consuming design and construction of genome-engineered nucleases for each target and have, therefore, not been widely used in mouse research where standard techniques based on homologous recombination are commonly used. The CRISPR/Cas system only requires the design of sequences complementary to a target locus, making this technology fast and straightforward. In addition, CRISPR/Cas can be used to generate mice carrying mutations in multiple genes in a single step, an achievement not possible using other methods. Here, we review the uses of this technology in genetic analysis and manipulation, including achievements made possible to date and the prospects for future therapeutic applications.
文摘Gene editing has recently emerged as a promising technology to engineer genetic modifications precisely in the genome to achieve long-term relief from corneal disorders.Recent advances in the molecular biology leading to the development of clustered regularly interspaced short palindromic repeats(CRISPRs) and CRISPR-associated systems,zinc finger nucleases and transcription activator like effector nucleases have ushered in a new era for high throughput in vitro and in vivo genome engineering.Genome editing can be successfully used to decipher complex molecular mechanisms underlying disease pathophysiology,develop innovative next generation gene therapy,stem cell-based regenerative therapy,and personalized medicine for corneal and other ocular diseases.In this review we describe latest developments in the field of genome editing,current challenges,and future prospects for the development of personalized genebased medicine for corneal diseases.The gene editing approach is expected to revolutionize current diagnostic and treatment practices for curing blindness.
基金Project supported by the National Natural Science Foundation of China(No.L1824000)
文摘The rapid developments of science and technology in China over recent decades, particularly in biomedical research, have brought forward serious challenges regarding ethical governance. Recently, Jian-kui HE, a Chinese scientist, claimed to have "created" the first gene-edited babies, designed to be naturally immune to the human immunodeficiency virus(HIV). The news immediately triggered widespread criticism, denouncement, and debate over the scientific and ethical legitimacy of HE’s genetic experiments. China’s guidelines and regulations have banned germline genome editing on human embryos for clinical use because of scientific and ethical concerns, in accordance with the international consensus. HE’s human experimentation has not only violated these Chinese regulations, but also breached other ethical and regulatory norms. These include questionable scientific value, unreasonable risk-benefit ratio, illegitimate ethics review, invalid informed consent, and regulatory misconduct. This series of ethical failings of HE and his team reveal the institutional failure of the current ethics governance system which largely depends on scientist’s self-regulation. The incident highlights the need for urgent improvement of ethics governance at all levels, the enforcement of technical and ethical guidelines, and the establishment of laws relating to such bioethical issues.
基金supported in part by Cotton Incorporated and the National Science Foundation(award 1658709)supported by the National Natural Science Foundation of China(No.31700316)+1 种基金the Fundamental Research Funds for the Central Nonprofit Scientific Institution(No.1610172018009)the Natural Science Foundation of Hubei Province(No.2018CFB543),China。
文摘Since it was first recognized in bacteria and archaea as a mechanism for innate viral immunity in the early 2010 s,clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein(Cas)has rapidly been developed into a robust,multifunctional genome editing tool with many uses.Following the discovery of the initial CRISPR/Cas-based system,the technology has been advanced to facilitate a multitude of different functions.These include development as a base editor,prime editor,epigenetic editor,and CRISPR interference(CRISPRi)and CRISPR activator(CRISPRa)gene regulators.It can also be used for chromatin and RNA targeting and imaging.Its applications have proved revolutionary across numerous biological fields,especially in biomedical and agricultural improvement.As a diagnostic tool,CRISPR has been developed to aid the detection and screening of both human and plant diseases,and has even been applied during the current coronavirus disease 2019(COVID-19)pandemic.CRISPR/Cas is also being trialed as a new form of gene therapy for treating various human diseases,including cancers,and has aided drug development.In terms of agricultural breeding,precise targeting of biological pathways via CRISPR/Cas has been key to regulating molecular biosynthesis and allowing modification of proteins,starch,oil,and other functional components for crop improvement.Adding to this,CRISPR/Cas has been shown capable of significantly enhancing both plant tolerance to environmental stresses and overall crop yield via the targeting of various agronomically important gene regulators.Looking to the future,increasing the efficiency and precision of CRISPR/Cas delivery systems and limiting off-target activity are two major challenges for wider application of the technology.This review provides an in-depth overview of current CRISPR development,including the advantages and disadvantages of the technology,recent applications,and future considerations.
文摘Alzheimer’s disease （AD） is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons. The pathophysiology of AD is complex; mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress are antecedent and potentially play a causal role in the disease pathogenesis. Dysfunctional mitochondria accumulate from the combination of impaired mitophagy, which can also induce injurious inflammatory responses, and inadequate neuronal mitochondrial biogenesis. Altering the metabolic capacity of the brain by modulating/potentiating its mitochondrial bioenergetics may be a strategy for disease prevention and treatment. We present insights into the mechanisms of mitochondrial dysfunction in AD brain as well as an overview of emerging treatments with the potential to prevent, delay or reverse the neurodegenerative process by targeting mitochondria.
基金the National Natural Science Foundation of China(No.81230014,No.81470341,No.81520108002 and No.81500157)the Key Project of Science and Technology Department of Zhejiang Province(No.2018C03016-2)the Key Research and Development Program of Zhejiang Province(No.2019C03016).
文摘Chimeric antigen receptor T(CAR-T)cell therapy is the novel treatment strategy for hematological malignancies such as acute lymphoblastic leukemia(ALL),lymphoma and multiple myeloma.However,treatment-related toxicities such as cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)have become significant hurdles to CAR-T treatment.Multiple strategies were established to alter the CAR structure on the genomic level to improve efficacy and reduce toxicities.Recently,the innovative gene-editing technology-clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated nuclease9(Cas9)system,which particularly exhibits preponderance in knock-in and knockout at specific sites,is widely utilized to manufacture CAR-T products.The application of CRISPR/Cas9 to CAR-T cell therapy has shown promising clinical results with minimal toxicity.In this review,we summarized the past achievements of CRISPR/Cas9 in CAR-T therapy and focused on the potential CAR-T targets.
文摘BACKGROUND Currently,intrahepatic cholangiocarcinoma(ICC)poses a continuing,significant health challenge,but the relationship has yet to be established between ICC and the proteasome 26S subunit non-ATPase 6(PSMD6).AIM To investigate the protein expression and clinicopathological significance of PSMD6 in ICC.METHODS The potential impact of the PSMD6 gene on the growth of ICC cell lines was analyzed using clustered regularly interspaced short palindromic repeat knockout screening technology.Forty-two paired specimens of ICC and adjacent noncancerous tissues were collected.PSMD6 protein expression was determined by immunohistochemistry.Receiver operating characteristic curve analysis was performed to validate PSMD6 expression level,and its association with ICC patients’various clinicopathological characteristics was investigated.RESULTS The PSMD6 gene was found to be essential for the growth of ICC cell lines.PSMD6 protein was significantly overexpressed in ICC tissues(P<0.001),but showed no significant association with patient age,gender,pathological grade,or tumor-node-metastasis stage(P>0.05).CONCLUSION PSMD6 can promote the growth of ICC cells,thus playing a pro-oncogenic role.
