A small proportion of many cancers are due to inherited mutations in genes,which result in a high risk to the indi-vidual of developing specific cancers. There are several classes of genes that may be involved: tumour...A small proportion of many cancers are due to inherited mutations in genes,which result in a high risk to the indi-vidual of developing specific cancers. There are several classes of genes that may be involved: tumour suppressor genes,onco-genes,genes encoding proteins involved in DNA repair and cell cycle control,and genes involved in stimulating the angiogenic pathway. Alterations in susceptibility to cancer may also be due to variations in genes involved in carcinogen metabolism. This review discusses examples of some of these genes and the associated clinical conditions caused by the inheritance of mutations in such genes.展开更多
Glutamate is extensively involved in metabolic and oncogenic pathways. Univariate and multivariate analyses showed that serum glutamate levels directly correlated with Gleason score （≤ 6 vs.≥ 8） and primary prosta...Glutamate is extensively involved in metabolic and oncogenic pathways. Univariate and multivariate analyses showed that serum glutamate levels directly correlated with Gleason score （≤ 6 vs.≥ 8） and primary prostate cancer （PCa） aggressiveness. Compared with Caucasian Americans, serum glutamate levels were higher in African Americans with metastatic castrate- resistant PCa than in the patients with primary tumors.展开更多
Prostate cancer （PCa） remains the most common malignancy and a leading cause of cancer-related ＇deaths in men. Molecular discrimination at an early stage between indolent and aggressive primary tumors in pathologic...Prostate cancer （PCa） remains the most common malignancy and a leading cause of cancer-related ＇deaths in men. Molecular discrimination at an early stage between indolent and aggressive primary tumors in pathologically confirmed PCa is required to develop personalized therapeutic interventions.展开更多
Men of African ancestry in particular have a high incidence, mortality, and worst prognosis for prostate cancer （PCa） among other racial and ethnic populations. Environmental and genetic factors have been accounted ...Men of African ancestry in particular have a high incidence, mortality, and worst prognosis for prostate cancer （PCa） among other racial and ethnic populations. Environmental and genetic factors have been accounted at least partially as the underlying reasons for such disproportionate ethnic differences. Identification of inheritable genetic factors to predict PCa risk and aggressiveness in African men can assist epidemiologists, geneticists, and clinicians to target them for prevention, screening, and efficient treatment.展开更多
AIM To test whether Nox1 plays a role in typhlitis induced by Salmonella enterica serovar Typhimurium(S. Tm) in a mouse model.METHODS Eight-week-old male wild-type(WT) and Nox1 knockout(KO) C57BL6/J(B6) mice were admi...AIM To test whether Nox1 plays a role in typhlitis induced by Salmonella enterica serovar Typhimurium(S. Tm) in a mouse model.METHODS Eight-week-old male wild-type(WT) and Nox1 knockout(KO) C57BL6/J(B6) mice were administered metronidazole water for 4 d to make them susceptible to S. Tm infection by the oral route. The mice were given plain water and administered with 4 different doses of S. Tm by oral gavage. The mice were followed for another 4 d. From the time of the metronidazole application, the mice were observed twice daily and weighed daily. The ileum, cecum and colon were removed for sampling at the fourth day post-inoculation. Portions of all three tissues were fixed for histology and placed in RNAlater for m RNA/c DNA preparation and quantitative real-time PCR. The contents of the cecum were recovered for estimation of S. Tm CFU.RESULTS We found Nox1-knockout(Nox1-KO) mice were not more sensitive to S. Tm colonization and infection than WT B6 mice. This conclusion is based on the following observations:(1) S. Tm-infection induced similar weight loss in Nox1-KO mice compared to WT mice;(2) the same S. Tm CFU was recovered from the cecal content of Nox1-KO and WT mice regardless of the inoculation dose, except the lowest inoculation dose(2 × 106 CFU) for which the Nox1-KO had one-log lower CFU than WT mice;(3) there is no difference in cecal pathology between WT and Nox1-KO groups; and(4) there are no S. Tm infection-induced changes in gene expression levels(IL-1b, TNF-α, and Duox2) between WT and Nox1-KO groups. The Alpi gene expression was more suppressed by S. Tm treatment in WT than the Nox1-KO cecum. CONCLUSION Nox1 does not protect mice from S. Tm colonization. Nox1-KO provides a very minor protective effect against S. Tm infection. Using NOX1-specific inhibitors for colitis therapy should not increase risks in bacterial infection.展开更多
Regulation of the Hippo signaling pathway is essential for normal organ growth and tissue homeostasis.The proteins that act to regulate this pathway are important for ensuring proper function and cellular location.Deu...Regulation of the Hippo signaling pathway is essential for normal organ growth and tissue homeostasis.The proteins that act to regulate this pathway are important for ensuring proper function and cellular location.Deubiquitinases(DUBs)are a family of proteases that act upon many proteins.While ubiquitinases add ubiquitin and target proteins for degradation,DUBs act by removing ubiquitin(Ub)moieties.Changes in ubiquitin chain topology results in the stabilization of proteins,membrane trafficking,and the alteration of cellular localization.While the roles of these proteins have been well established in a cancer setting,their convergence in cancer is still under investigation.In this review,we discuss the roles that DUBs play in the regulation of the Hippo signaling pathway for homeostasis and disease.展开更多
Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the i...Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T cells.In doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose catabolism.ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events.Among these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector function.Importantly,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.展开更多
Objective. The aim of the study was to estimate the prevalence of hereditary cancers and the need for surveillance in Telemark county, Norway. Material and methods. All persons attending the Norwegian Colorectal Cance...Objective. The aim of the study was to estimate the prevalence of hereditary cancers and the need for surveillance in Telemark county, Norway. Material and methods. All persons attending the Norwegian Colorectal Cancer Prevention (NORCCAP) trial in Telemark were interviewed about cases of cancer in the family. Diagnoses were verified, pedigrees constructed and families classified according to preset criteria aiming at identifying hereditary cancer. Mutation analyses were performed in kindreds at risk for breast cancers when possible. Immunohistochemistry of tumors in assumed inherited colorectal cancer families was undertaken. Results. The screening examination was attended by 7224 persons among whom 2866 had cancer in the family. Of these, 2479 had no suspicion of any known inherited cancer syndrome. Family information questionnaires were mailed to 387 persons and returned by 191. Sixty-four of these 191 met the clinical criteria for familial cancer by family history after verification of diagnoses. Observed prevalences for being at risk for hereditary breast and breast-ovarian cancer (HBOC) or hereditary non-polyposis colorectal cancer (HNPCC) were 2.8‰and 0.77‰, respectively. Conclusions. The number of colonos-copies and mammograms obtained per year serving those who needed them was limited and reduced by clinical genetic work-up from 2866 with a family history of cancer to 64 proven cases. Continued surveillance of an unnecessarily high number leads to unjustified cancer worry, is costly and uses up health-care facilities. Genetic work-up is a one-time job that reduces input numbers to surveillance programs, provides a starting-point for mutation testing and is economically cost beneficial if inherited cancers are prevented or cured by the health-care programs offered.展开更多
Nucleases are a super family of enzymes that hydrolyze phosphodiester bonds present in genomes.They widely vary in substrates,causing differentiation in cleavage patterns and having a diversified role in maintaining g...Nucleases are a super family of enzymes that hydrolyze phosphodiester bonds present in genomes.They widely vary in substrates,causing differentiation in cleavage patterns and having a diversified role in maintaining genetic material.Through cellular evolution of prokaryotic to eukaryotic,nucleases become structure-specific in recognizing its own or foreign genomic DNA/RNA configurations as its substrates,including flaps,bubbles,and Holliday junctions.These special structural configurations are commonly found as intermediates in processes like DNA replication,repair,and recombination.The structure-specific nature and diversified functions make them essential to maintaining genome integrity and evolution in normal and cancer cells.In this article,we review their roles in various pathways,including Okazaki fragment maturation during DNA replication,end resection in homology-directed recombination repair of DNA double-strand breaks,DNA excision repair and apoptosis DNA fragmentation in response to exogenous DNA damage,and HIV life cycle.As the nucleases serve as key points for the DNA dynamics,cellular apoptosis,and cancer cell survival pathways,we discuss the efforts in the field in developing the therapeutic regimens,taking advantage of recently available knowledge of their diversified structures and functions.展开更多
Protein poly ADP-ribosylation（PARylation） is a widespread post-translational modification at DNA lesions,which is catalyzed by poly（ADP-ribose） polymerases（PARPs）.This modification regulates a number of biologic...Protein poly ADP-ribosylation（PARylation） is a widespread post-translational modification at DNA lesions,which is catalyzed by poly（ADP-ribose） polymerases（PARPs）.This modification regulates a number of biological processes including chromatin reorganization,DNA damage response（DDR）,transcriptional regulation,apoptosis,and mitosis.PARP1,functioning as a DNA damage sensor,can be activated by DNA lesions,forming PAR chains that serve as a docking platform for DNA repair factors with high biochemical complexity.Here,we highlight molecular insights into PARylation recognition,the expanding role of PARylation in DDR pathways,and the functional interaction between PARylation and ubiquitination,which will offer us a better understanding of the biological roles of this unique post-translational modification.展开更多
The mutation-mediated overexpression of epidermal growth factor receptor tyrosine kinase(EGFR TK)and its activation play an important role in the cellular proliferation and epithelial tumorigenesis.A series of inhibit...The mutation-mediated overexpression of epidermal growth factor receptor tyrosine kinase(EGFR TK)and its activation play an important role in the cellular proliferation and epithelial tumorigenesis.A series of inhibitors targeting the intracellular tyrosine kinase(TK)domain of EGFR have been developed and applied to clinical practice.Although these inhibitors safely and effectively restrain tumor cell proliferation and prolong survival in some patients,acquired resistance ultimately arises.DNA mutations contribute to druginduced cancer-cell resistance.展开更多
Human flap endonuclease 1 （FEN1） is a structure-specific, multi-functional endonuclease essential for DNA replication and repair. We and others have shown that during DNA replication, FEN1 processes Okazaki fragment...Human flap endonuclease 1 （FEN1） is a structure-specific, multi-functional endonuclease essential for DNA replication and repair. We and others have shown that during DNA replication, FEN1 processes Okazaki fragments via its interaction with the proliferating cell nuclear antigen （PCNA）. Alternatively, in response to DNA damage, FEN1 interacts with the PCNA-like Radg-Radl-Husl complex instead of PCNA to engage in DNA repair activities, such as homology-directed repair of stalled DNA replication forks. However, it is unclear how FEN1 is able to switch between these interactions and its roles in DNA replication and DNA repair. Here, we report that FEN1 undergoes SUMOylation by SUMO-1 in response to DNA replication fork-staUing agents, such as UV irradiation, hydroxyurea, and mitomycin C. This DNA damage-induced SUMO-1 modification promotes the interaction of FEN1 with the Radg-Rad1-Husl complex. Furthermore, we found that FEN1 mutations that prevent its SUMO-1 modification also impair its ability to interact with HUS1 and to rescue stalled replication forks. These impairments lead to the accumulation of DNA damage and heightened sensitivity to fork-staUing agents. Altogether, our findings suggest an important role of the SUMO-1 modification of FEN1 in regulating its roles in DNA replication and repair.展开更多
The lifetime of orthopaedic implants can be extended by coating the softer Ti6Al4V alloy with harder biocompatible thin films.In this work,thin films of Ti_((1-x))Au_((x))are grown on Ti_(6)Al_(4)V and glass substrate...The lifetime of orthopaedic implants can be extended by coating the softer Ti6Al4V alloy with harder biocompatible thin films.In this work,thin films of Ti_((1-x))Au_((x))are grown on Ti_(6)Al_(4)V and glass substrates by magnetron sputtering in the entire x=0-1 range,before their key biomechanical properties are performance tuned by thermal activation.For the first time,we explore the effect of in-situ substrate heating versus ex-situ post-deposition heat-treatment,on development of mechanical and biocompatibility performance in Ti-Au films.A~250% increase in hardness is achieved for Ti-Au films compared to bulk Ti6Al4V and a~40%improvement from 8.8 GPa as-grown to 11.9 and 12.3 GPa with in-situ and ex-situ heat-treatment respectively,is corelated to changes in structural,morphological and chemical properties,providing insights into the origins of super-hardness in the Ti rich regions of these materials.X-ray diffraction reveals that as-grown films are in nanocrystalline states of Ti-Au intermetallic phases and thermal activation leads to emergence of mechanically hard Ti-Au intermetallics,with films prepared by in-situ substrate heating having enhanced crystalline quality.Surface morphology images show clear changes in grain size,shape and surface roughness following thermal activation,while elemental analysis reveals that in-situ substrate heating is better for development of oxide free Ti3Auβ-phases.All tested Ti-Au films are non-cytotoxic against L929 mouse fibroblast cells,while extremely low leached ion concentrations confirm their biocompatibility.With peak hardness performance tuned to>12 GPa and excellent biocompatibility,Ti-Au films have potential as a future coating technology for load bearing medical implants.展开更多
Two of the unsolved but important questions in epigenetics are whether arginine demethylases （RDMs） exist and whether proteolytic cleavage of the histone tails and subsequent histone remodeling are a major epigeneti...Two of the unsolved but important questions in epigenetics are whether arginine demethylases （RDMs） exist and whether proteolytic cleavage of the histone tails and subsequent histone remodeling are a major epigenetic modification process. Jumonji domain （JmjC）-containing proteins have been characterized as lysine demethylases （KDMs） in a certain degree （Klose et al., 2006）. Emerging evidences indicate that they also catalyze demethylation reaction on the arginine residues and proteolytic removal of histone tails. These processes are likely associated with biological meanings.展开更多
p53 is a key transcription factor to regulate gene transcription.However,the molecular mechanism of chromatin-associated p53 on gene transcription remains elusive.Here,using unbiased protein affinity purification,we f...p53 is a key transcription factor to regulate gene transcription.However,the molecular mechanism of chromatin-associated p53 on gene transcription remains elusive.Here,using unbiased protein affinity purification,we found that the RNF20/40 complex associated with p53 on the chromatin.Further analyses indicated that p53 mediated the recruitment of the RNF20/40 complex to p53 target gene loci including p21 and PUMA loci and regulated the transcription of p21 and PUMA via the RNF20/40 complex-dependent histone H2B ubiquitination(ubH2B).Lacking the RNF20/40 complex suppressed not only ubH2B but also the generation of the mature mRNA of p21 and PUMA.Moreover,ubH2B was recognized by the ubiquitin-binding motif of pre-mRNA processing splicing factor 8(PRPF8),a subunit in the spliceosome,and PRPF8 was required for the maturation of the mRNA of p21 and PUMA.Our study unveils a novel p53-dependent pathway that regulates mRNA splicing for tumor suppression.展开更多
Mammalian topoisomerase 1（TOP1） is an essential enzyme for normal development.TOP1 relaxes supercoiled DNA to remove helical constraints that can otherwise hinder DNA replication and transcription and thus block cel...Mammalian topoisomerase 1（TOP1） is an essential enzyme for normal development.TOP1 relaxes supercoiled DNA to remove helical constraints that can otherwise hinder DNA replication and transcription and thus block cell growth.Unfortunately,this exact activity can covalently trap TOP1 on the DNA that could lead to cell death or mutagenesis,a precursor for tumorigenesis.It is therefore important for cells to find a proper balance between the utilization of the TOP1 catalytic activity to maintain DNA topology and the risk of accumulating the toxic DNA damages due to TOP1 trapping that prevents normal cell growth.In an apparent contradiction to the negative attribute of the TOP1 activity to genome stability,the detrimental effect of the TOP1-induced DNA lesions on cell survival has made this enzyme a prime target for cancer therapies to kill fast-growing cancer cells.In addition,cumulative evidence supports a direct role of TOP1 in promoting transcriptional progression independent of its topoisomerase activity.The involvement of TOP1 in transcriptional regulation has recently become a focus in developing potential new treatments for a subtype of autism spectrum disorders.Clearly,the impact of TOP1 on human health is multifold.In this review,we will summarize our current understandings on how TOP1 contributes to human diseases and how its activity is targeted for disease treatments.展开更多
Introduction:Plasma circulating tumor DNA(ctDNA)is an ideal approach to detecting the epidermal growth factor receptor(EGFR)T790M mutation,which is a major mechanism of resistance to first-generation EGFR-tyrosine kin...Introduction:Plasma circulating tumor DNA(ctDNA)is an ideal approach to detecting the epidermal growth factor receptor(EGFR)T790M mutation,which is a major mechanism of resistance to first-generation EGFR-tyrosine kinase inhibitor(TKI)therapy.The present study aimed to explore the association of ctDNA-identified T790M mutation with disease failure sites and clinical prognosis in non-small cell lung cancer(NSCLC)patients.Methods:Patients who progressed on first-generation TKIs were categorized into failure site groups of chest limited(CF),brain limited(BF)and other(OF).Amplification refractory mutation system(ARMS)and droplet digital PCR(ddPCR)were used to identify the T790M mutation in ctDNA.Prognosis was analyzed with Kaplan-Meier methods.Results:Overall concordance between the two methods was 78.3%.According to both ARMS and ddPCR,patients in the OF group had a significantly higher rate of T790M mutation than did patients in the BF and CF groups(P<0.001),and a significantly higher T790M mutation rate was also observed in OF-group patients than in those in the CF and BF groups(P<0.001).AZD9291 was found to be an excellent treatment option and yielded the longest survival for T790M+patients in all groups who had progressed on EGFR-TKIs;for other treatments,the prognosis of T790M−patient subgroups varied.Conclusions:The present study demonstrates that T790M mutation in ctDNA is associated with failure sites for NSCLC patients after EGFR-TKI therapy and indicates that both failure site and T790M mutational status greatly influ-ence treatment selection and prognosis.展开更多
文摘A small proportion of many cancers are due to inherited mutations in genes,which result in a high risk to the indi-vidual of developing specific cancers. There are several classes of genes that may be involved: tumour suppressor genes,onco-genes,genes encoding proteins involved in DNA repair and cell cycle control,and genes involved in stimulating the angiogenic pathway. Alterations in susceptibility to cancer may also be due to variations in genes involved in carcinogen metabolism. This review discusses examples of some of these genes and the associated clinical conditions caused by the inheritance of mutations in such genes.
文摘Glutamate is extensively involved in metabolic and oncogenic pathways. Univariate and multivariate analyses showed that serum glutamate levels directly correlated with Gleason score （≤ 6 vs.≥ 8） and primary prostate cancer （PCa） aggressiveness. Compared with Caucasian Americans, serum glutamate levels were higher in African Americans with metastatic castrate- resistant PCa than in the patients with primary tumors.
文摘Prostate cancer （PCa） remains the most common malignancy and a leading cause of cancer-related ＇deaths in men. Molecular discrimination at an early stage between indolent and aggressive primary tumors in pathologically confirmed PCa is required to develop personalized therapeutic interventions.
文摘Men of African ancestry in particular have a high incidence, mortality, and worst prognosis for prostate cancer （PCa） among other racial and ethnic populations. Environmental and genetic factors have been accounted at least partially as the underlying reasons for such disproportionate ethnic differences. Identification of inheritable genetic factors to predict PCa risk and aggressiveness in African men can assist epidemiologists, geneticists, and clinicians to target them for prevention, screening, and efficient treatment.
基金Supported by Federal funds from the National Cancer Institute(NCI)under Contract,No.HHSN261200800001E(to Chu FF)Research reported in this publication included work performed in the Animal Resources Center Core supported by the National Cancer Institute of the National Institutes of Health under award No.P30CA033572
文摘AIM To test whether Nox1 plays a role in typhlitis induced by Salmonella enterica serovar Typhimurium(S. Tm) in a mouse model.METHODS Eight-week-old male wild-type(WT) and Nox1 knockout(KO) C57BL6/J(B6) mice were administered metronidazole water for 4 d to make them susceptible to S. Tm infection by the oral route. The mice were given plain water and administered with 4 different doses of S. Tm by oral gavage. The mice were followed for another 4 d. From the time of the metronidazole application, the mice were observed twice daily and weighed daily. The ileum, cecum and colon were removed for sampling at the fourth day post-inoculation. Portions of all three tissues were fixed for histology and placed in RNAlater for m RNA/c DNA preparation and quantitative real-time PCR. The contents of the cecum were recovered for estimation of S. Tm CFU.RESULTS We found Nox1-knockout(Nox1-KO) mice were not more sensitive to S. Tm colonization and infection than WT B6 mice. This conclusion is based on the following observations:(1) S. Tm-infection induced similar weight loss in Nox1-KO mice compared to WT mice;(2) the same S. Tm CFU was recovered from the cecal content of Nox1-KO and WT mice regardless of the inoculation dose, except the lowest inoculation dose(2 × 106 CFU) for which the Nox1-KO had one-log lower CFU than WT mice;(3) there is no difference in cecal pathology between WT and Nox1-KO groups; and(4) there are no S. Tm infection-induced changes in gene expression levels(IL-1b, TNF-α, and Duox2) between WT and Nox1-KO groups. The Alpi gene expression was more suppressed by S. Tm treatment in WT than the Nox1-KO cecum. CONCLUSION Nox1 does not protect mice from S. Tm colonization. Nox1-KO provides a very minor protective effect against S. Tm infection. Using NOX1-specific inhibitors for colitis therapy should not increase risks in bacterial infection.
基金This work was supported by the Roswell Park Cancer Institute and National Cancer Institute(NCI)Grant#P30 CA016056,Roswell Park Alliance Foundation,the National Cancer Institute(NCI)R01 CA207504 and the American Cancer Society Research Scholar Grant RSG-14-214-01-TBE(to J.Z.).
文摘Regulation of the Hippo signaling pathway is essential for normal organ growth and tissue homeostasis.The proteins that act to regulate this pathway are important for ensuring proper function and cellular location.Deubiquitinases(DUBs)are a family of proteases that act upon many proteins.While ubiquitinases add ubiquitin and target proteins for degradation,DUBs act by removing ubiquitin(Ub)moieties.Changes in ubiquitin chain topology results in the stabilization of proteins,membrane trafficking,and the alteration of cellular localization.While the roles of these proteins have been well established in a cancer setting,their convergence in cancer is still under investigation.In this review,we discuss the roles that DUBs play in the regulation of the Hippo signaling pathway for homeostasis and disease.
基金supported by National Cancer Institute grants R00CA175189,R01AI155499(both to SHO),R01CA205246(to EAR),R01CA121044(to KPL),T32CA085183(to GAH and MML),and P30CA016056,involving the use of the Roswell Park Comprehensive Cancer Center Flow and Image Cytometry,Genomics,Laboratory Animal,and Immune Analysis Shared Resourcesby the Roswell Park Alliance Foundation.NMR experiments were carried out at the Center for Environmental and Systems Biochemistry Shared Resource Facility funded in part by the Markey Cancer Center(P30CA177558).
文摘Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T cells.In doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose catabolism.ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events.Among these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector function.Importantly,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.
文摘Objective. The aim of the study was to estimate the prevalence of hereditary cancers and the need for surveillance in Telemark county, Norway. Material and methods. All persons attending the Norwegian Colorectal Cancer Prevention (NORCCAP) trial in Telemark were interviewed about cases of cancer in the family. Diagnoses were verified, pedigrees constructed and families classified according to preset criteria aiming at identifying hereditary cancer. Mutation analyses were performed in kindreds at risk for breast cancers when possible. Immunohistochemistry of tumors in assumed inherited colorectal cancer families was undertaken. Results. The screening examination was attended by 7224 persons among whom 2866 had cancer in the family. Of these, 2479 had no suspicion of any known inherited cancer syndrome. Family information questionnaires were mailed to 387 persons and returned by 191. Sixty-four of these 191 met the clinical criteria for familial cancer by family history after verification of diagnoses. Observed prevalences for being at risk for hereditary breast and breast-ovarian cancer (HBOC) or hereditary non-polyposis colorectal cancer (HNPCC) were 2.8‰and 0.77‰, respectively. Conclusions. The number of colonos-copies and mammograms obtained per year serving those who needed them was limited and reduced by clinical genetic work-up from 2866 with a family history of cancer to 64 proven cases. Continued surveillance of an unnecessarily high number leads to unjustified cancer worry, is costly and uses up health-care facilities. Genetic work-up is a one-time job that reduces input numbers to surveillance programs, provides a starting-point for mutation testing and is economically cost beneficial if inherited cancers are prevented or cured by the health-care programs offered.
基金This work was supported by National Institutes of Health(NIH)/National Cancer Institute(NCI)grants(R01CA073764,R01CA085344,and R01CA233664 to B.S.and R50CA211397 to L.Z.)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(CIFMS,2023-I2M-3-006 to H.S.).
文摘Nucleases are a super family of enzymes that hydrolyze phosphodiester bonds present in genomes.They widely vary in substrates,causing differentiation in cleavage patterns and having a diversified role in maintaining genetic material.Through cellular evolution of prokaryotic to eukaryotic,nucleases become structure-specific in recognizing its own or foreign genomic DNA/RNA configurations as its substrates,including flaps,bubbles,and Holliday junctions.These special structural configurations are commonly found as intermediates in processes like DNA replication,repair,and recombination.The structure-specific nature and diversified functions make them essential to maintaining genome integrity and evolution in normal and cancer cells.In this article,we review their roles in various pathways,including Okazaki fragment maturation during DNA replication,end resection in homology-directed recombination repair of DNA double-strand breaks,DNA excision repair and apoptosis DNA fragmentation in response to exogenous DNA damage,and HIV life cycle.As the nucleases serve as key points for the DNA dynamics,cellular apoptosis,and cancer cell survival pathways,we discuss the efforts in the field in developing the therapeutic regimens,taking advantage of recently available knowledge of their diversified structures and functions.
基金funded by the National Institutes of Health of the United States(Grant Nos.CA132755,CA187209,and GM108647)
文摘Protein poly ADP-ribosylation（PARylation） is a widespread post-translational modification at DNA lesions,which is catalyzed by poly（ADP-ribose） polymerases（PARPs）.This modification regulates a number of biological processes including chromatin reorganization,DNA damage response（DDR）,transcriptional regulation,apoptosis,and mitosis.PARP1,functioning as a DNA damage sensor,can be activated by DNA lesions,forming PAR chains that serve as a docking platform for DNA repair factors with high biochemical complexity.Here,we highlight molecular insights into PARylation recognition,the expanding role of PARylation in DDR pathways,and the functional interaction between PARylation and ubiquitination,which will offer us a better understanding of the biological roles of this unique post-translational modification.
基金This work was supported by the National Institutes of Health[R01CA073764 to B.H.S.,R50CA211397 to L.Z.].
文摘The mutation-mediated overexpression of epidermal growth factor receptor tyrosine kinase(EGFR TK)and its activation play an important role in the cellular proliferation and epithelial tumorigenesis.A series of inhibitors targeting the intracellular tyrosine kinase(TK)domain of EGFR have been developed and applied to clinical practice.Although these inhibitors safely and effectively restrain tumor cell proliferation and prolong survival in some patients,acquired resistance ultimately arises.DNA mutations contribute to druginduced cancer-cell resistance.
基金This work was supported by grants from the National Basic Research Program of China （2015CB910600）, the National Natural Science Foundation of China （31700688）, the National Key Research and Development Program of China （2017YFA0503900）, and the Natural Science Foundation of Zhejiang Province （LY16C050003） to Y.I.H. and H.X. A part of the work presented in the current article was supported by the National Institutes of Health grants ROICA073764 to B.H.S and R50CA211397 to L.Z.
文摘Human flap endonuclease 1 （FEN1） is a structure-specific, multi-functional endonuclease essential for DNA replication and repair. We and others have shown that during DNA replication, FEN1 processes Okazaki fragments via its interaction with the proliferating cell nuclear antigen （PCNA）. Alternatively, in response to DNA damage, FEN1 interacts with the PCNA-like Radg-Radl-Husl complex instead of PCNA to engage in DNA repair activities, such as homology-directed repair of stalled DNA replication forks. However, it is unclear how FEN1 is able to switch between these interactions and its roles in DNA replication and DNA repair. Here, we report that FEN1 undergoes SUMOylation by SUMO-1 in response to DNA replication fork-staUing agents, such as UV irradiation, hydroxyurea, and mitomycin C. This DNA damage-induced SUMO-1 modification promotes the interaction of FEN1 with the Radg-Rad1-Husl complex. Furthermore, we found that FEN1 mutations that prevent its SUMO-1 modification also impair its ability to interact with HUS1 and to rescue stalled replication forks. These impairments lead to the accumulation of DNA damage and heightened sensitivity to fork-staUing agents. Altogether, our findings suggest an important role of the SUMO-1 modification of FEN1 in regulating its roles in DNA replication and repair.
基金funded and supported by the Leverhulme Trust Research Project Grant(RPG-2018-344)。
文摘The lifetime of orthopaedic implants can be extended by coating the softer Ti6Al4V alloy with harder biocompatible thin films.In this work,thin films of Ti_((1-x))Au_((x))are grown on Ti_(6)Al_(4)V and glass substrates by magnetron sputtering in the entire x=0-1 range,before their key biomechanical properties are performance tuned by thermal activation.For the first time,we explore the effect of in-situ substrate heating versus ex-situ post-deposition heat-treatment,on development of mechanical and biocompatibility performance in Ti-Au films.A~250% increase in hardness is achieved for Ti-Au films compared to bulk Ti6Al4V and a~40%improvement from 8.8 GPa as-grown to 11.9 and 12.3 GPa with in-situ and ex-situ heat-treatment respectively,is corelated to changes in structural,morphological and chemical properties,providing insights into the origins of super-hardness in the Ti rich regions of these materials.X-ray diffraction reveals that as-grown films are in nanocrystalline states of Ti-Au intermetallic phases and thermal activation leads to emergence of mechanically hard Ti-Au intermetallics,with films prepared by in-situ substrate heating having enhanced crystalline quality.Surface morphology images show clear changes in grain size,shape and surface roughness following thermal activation,while elemental analysis reveals that in-situ substrate heating is better for development of oxide free Ti3Auβ-phases.All tested Ti-Au films are non-cytotoxic against L929 mouse fibroblast cells,while extremely low leached ion concentrations confirm their biocompatibility.With peak hardness performance tuned to>12 GPa and excellent biocompatibility,Ti-Au films have potential as a future coating technology for load bearing medical implants.
文摘Two of the unsolved but important questions in epigenetics are whether arginine demethylases （RDMs） exist and whether proteolytic cleavage of the histone tails and subsequent histone remodeling are a major epigenetic modification process. Jumonji domain （JmjC）-containing proteins have been characterized as lysine demethylases （KDMs） in a certain degree （Klose et al., 2006）. Emerging evidences indicate that they also catalyze demethylation reaction on the arginine residues and proteolytic removal of histone tails. These processes are likely associated with biological meanings.
基金This work was supported by the National Natural Science Foundation of China(31670812 to C.W.)the grant for Returned Overseas Chinese Scholars of Hebei Province(CY201602 to C.W.)+1 种基金the Hundreds of Outstanding Talent Innovation Projects in Hebei Province(SLRC2017023 to C.W.)the Natural Science Foundation of Hebei Province(C2018201171 to C.W.).
文摘p53 is a key transcription factor to regulate gene transcription.However,the molecular mechanism of chromatin-associated p53 on gene transcription remains elusive.Here,using unbiased protein affinity purification,we found that the RNF20/40 complex associated with p53 on the chromatin.Further analyses indicated that p53 mediated the recruitment of the RNF20/40 complex to p53 target gene loci including p21 and PUMA loci and regulated the transcription of p21 and PUMA via the RNF20/40 complex-dependent histone H2B ubiquitination(ubH2B).Lacking the RNF20/40 complex suppressed not only ubH2B but also the generation of the mature mRNA of p21 and PUMA.Moreover,ubH2B was recognized by the ubiquitin-binding motif of pre-mRNA processing splicing factor 8(PRPF8),a subunit in the spliceosome,and PRPF8 was required for the maturation of the mRNA of p21 and PUMA.Our study unveils a novel p53-dependent pathway that regulates mRNA splicing for tumor suppression.
基金supported by a funding from the National Cancer Institute (Grant No.R01 CA151245),the United States
文摘Mammalian topoisomerase 1（TOP1） is an essential enzyme for normal development.TOP1 relaxes supercoiled DNA to remove helical constraints that can otherwise hinder DNA replication and transcription and thus block cell growth.Unfortunately,this exact activity can covalently trap TOP1 on the DNA that could lead to cell death or mutagenesis,a precursor for tumorigenesis.It is therefore important for cells to find a proper balance between the utilization of the TOP1 catalytic activity to maintain DNA topology and the risk of accumulating the toxic DNA damages due to TOP1 trapping that prevents normal cell growth.In an apparent contradiction to the negative attribute of the TOP1 activity to genome stability,the detrimental effect of the TOP1-induced DNA lesions on cell survival has made this enzyme a prime target for cancer therapies to kill fast-growing cancer cells.In addition,cumulative evidence supports a direct role of TOP1 in promoting transcriptional progression independent of its topoisomerase activity.The involvement of TOP1 in transcriptional regulation has recently become a focus in developing potential new treatments for a subtype of autism spectrum disorders.Clearly,the impact of TOP1 on human health is multifold.In this review,we will summarize our current understandings on how TOP1 contributes to human diseases and how its activity is targeted for disease treatments.
基金supported by grants from Projects of Medical and Health Technology in Zhejiang Province(WKJ-2J-1532)the Zhejiang Provincial Natural Science Foundation(LY15H160010)National Natural Science Foundation of China(Grant No.81602671).
文摘Introduction:Plasma circulating tumor DNA(ctDNA)is an ideal approach to detecting the epidermal growth factor receptor(EGFR)T790M mutation,which is a major mechanism of resistance to first-generation EGFR-tyrosine kinase inhibitor(TKI)therapy.The present study aimed to explore the association of ctDNA-identified T790M mutation with disease failure sites and clinical prognosis in non-small cell lung cancer(NSCLC)patients.Methods:Patients who progressed on first-generation TKIs were categorized into failure site groups of chest limited(CF),brain limited(BF)and other(OF).Amplification refractory mutation system(ARMS)and droplet digital PCR(ddPCR)were used to identify the T790M mutation in ctDNA.Prognosis was analyzed with Kaplan-Meier methods.Results:Overall concordance between the two methods was 78.3%.According to both ARMS and ddPCR,patients in the OF group had a significantly higher rate of T790M mutation than did patients in the BF and CF groups(P<0.001),and a significantly higher T790M mutation rate was also observed in OF-group patients than in those in the CF and BF groups(P<0.001).AZD9291 was found to be an excellent treatment option and yielded the longest survival for T790M+patients in all groups who had progressed on EGFR-TKIs;for other treatments,the prognosis of T790M−patient subgroups varied.Conclusions:The present study demonstrates that T790M mutation in ctDNA is associated with failure sites for NSCLC patients after EGFR-TKI therapy and indicates that both failure site and T790M mutational status greatly influ-ence treatment selection and prognosis.
