Oral squamous cell carcinoma (OSCC) develops on the mucosal epithelium of the oral cavity. It accounts for approximately 90% oforal malignancies and impairs appearance, pronunciation, swallowing, and flavor perception...Oral squamous cell carcinoma (OSCC) develops on the mucosal epithelium of the oral cavity. It accounts for approximately 90% oforal malignancies and impairs appearance, pronunciation, swallowing, and flavor perception. In 2020, 377,713 OSCC cases werereported globally. According to the Global Cancer Observatory (GCO), the incidence of OSCC will rise by approximately 40% by2040, accompanied by a growth in mortality. Persistent exposure to various risk factors, including tobacco, alcohol, betel quid (BQ),and human papillomavirus (HPV), will lead to the development of oral potentially malignant disorders (OPMDs), which are oralmucosal lesions with an increased risk of developing into OSCC. Complex and multifactorial, the oncogenesis process involvesgenetic alteration, epigenetic modification, and a dysregulated tumor microenvironment. Although various therapeuticinterventions, such as chemotherapy, radiation, immunotherapy, and nanomedicine, have been proposed to prevent or treat OSCCand OPMDs, understanding the mechanism of malignancies will facilitate the identification of therapeutic and prognostic factors,thereby improving the efficacy of treatment for OSCC patients. This review summarizes the mechanisms involved in OSCC.Moreover, the current therapeutic interventions and prognostic methods for OSCC and OPMDs are discussed to facilitatecomprehension and provide several prospective outlooks for the fields.展开更多
Prostate cancer preferentially metastasizes to the bone. However, the underlying molecular mechanisms are still unclear. To explore the effects of a bone-mimicking microenvironment on PC3 prostate cancer cell growth a...Prostate cancer preferentially metastasizes to the bone. However, the underlying molecular mechanisms are still unclear. To explore the effects of a bone-mimicking microenvironment on PC3 prostate cancer cell growth and metastasis, we used osteoblast differentiation medium（ODM; minimal essential medium alpha supplemented with L-ascorbic acid） to mimic the bone microenvironment. PC3 cells grown in ODM underwent epithelial-mesenchymal transition and showed enhanced colony formation, migration, and invasion abilities compared to the cells grown in normal medium. PC3 cells grown in ODM showed enhanced metastasis when injected in mice. A screening of signaling pathways related to invasion and metastasis revealed that the NF-κB pathway was activated, which could be reversed by Bay 11-7082, a NF-κB pathway inhibitor. These results indicate that the cells in different culture conditions manifested significantly different biological behaviors and the NF-κB pathway is a potential therapeutic target for prostate cancer bone metastasis.展开更多
Dear Editor,Canine distemper virus(CDV)is the causal agent of a highly contagious viral infectious disease that affects domestic and wild carnivores globally.It is an enveloped,non-segmented negative sense RNA virus t...Dear Editor,Canine distemper virus(CDV)is the causal agent of a highly contagious viral infectious disease that affects domestic and wild carnivores globally.It is an enveloped,non-segmented negative sense RNA virus that belongs to the Morbillivirus genus in Paramyxoviridae family,which contains viruses of epidemiological relevance to humans and animals.Based on the variability of the hemagglutinin gene(H),CDV strains have been at least 21 major genetic lineages:America-1 to America-5,Canada-1 and-2,Asia-1 to Asia-6,Europe wild-life,Arctic,Africa-1/South Africa,Africa-2,South America-1 to South America-3 and Rockborn-like(Giacinti et al.,2022).Mutations in the binding sites of the H protein,which interact with viral entry receptors such as signaling lymphocytic activation molecule(SLAM)and nectin-4,are associated with the emergence of the disease in new host species(Beineke et al.,2015).展开更多
The changes associated with malignancy are not only in cancer cells but also in environment in which cancer cells live.Metabolic reprogramming supports tumor cells’high demand of biogenesis for their rapid proliferat...The changes associated with malignancy are not only in cancer cells but also in environment in which cancer cells live.Metabolic reprogramming supports tumor cells’high demand of biogenesis for their rapid proliferation,and helps tumor cells to survive under certain genetic or environmental stresses.Emerging evidence suggests that metabolic alteration is ultimately and tightly associated with genetic changes,in particular the dysregulation of key oncogenic and tumor suppressive signaling pathways.Cancer cells activate HIF signaling even in the presence of oxygen and in the absence of growth factor stimulation.This cancer metabolic phenotype,described firstly by German physiologist Otto Warburg,ensures enhanced glycolytic metabolism for the biosynthesis of macromolecules.The conception of metabolite signaling,i.e.,metabolites are regulators of cell signaling,provides novel insights into how reactive oxygen species(ROS)and other metabolites deregulation may regulate redox homeostasis,epigenetics,and proliferation of cancer cells.Moreover,the unveiling of noncanonical functions of metabolic enzymes,such as the moonlighting functions of phosphoglycerate kinase 1(PGK1),reassures the importance of metabolism in cancer development.The metabolic,microRNAs,and ncRNAs alterations in cancer cells can be sorted and delivered either to intercellular matrix or to cancer adjacent cells to shape cancer microenvironment via media such as exosome.Among them,cancer microenvironmental cells are immune cells which exert profound effects on cancer cells.Understanding of all these processes is a prerequisite for the development of a more effective strategy to contain cancers.展开更多
Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestin...Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestinal damage were commonly characterized by the sharp upregulation of tryptophan(Trp)àkynurenine(KYN)àkynurenic acid(KA) axis metabolism. Mechanistically,chemotherapy-induced intestinal damage triggered the formation of an interleukin-6(IL-6)àindoleamine2,3-dioxygenase 1(IDO1)àaryl hydrocarbon receptor(AHR) positive feedback loop, which accelerated kynurenine pathway metabolism in gut. Besides, AHR and G protein-coupled receptor 35(GPR35) negative feedback regulates intestinal damage and inflammation to maintain intestinal integrity and homeostasis through gradually sensing kynurenic acid level in gut and macrophage, respectively. Moreover, based on virtual screening and biological verification, vardenafil and linagliptin as GPR35 and AHR agonists respectively were discovered from 2388 approved drugs. Importantly, the results that vardenafil and linagliptin significantly alleviated chemotherapy-induced intestinal toxicity in vivo suggests that chemotherapeutics combined with the two could be a promising therapeutic strategy for cancer patients in clinic.This work highlights GPR35 and AHR as the guardian of kynurenine pathway metabolism and core component of defense responses against intestinal damage.展开更多
Resistance to cancer therapy is a major barrier to cancer management.Conventional views have proposed that acquisition of resistance may result from genetic mutations.However,accumulating evidence implicates a key rol...Resistance to cancer therapy is a major barrier to cancer management.Conventional views have proposed that acquisition of resistance may result from genetic mutations.However,accumulating evidence implicates a key role of non-mutational resistance mechanisms underlying drug tolerance,the latter of which is the focus that will be discussed here.Such non-mutational processes are largely driven by tumor cell plasticity,which renders tumor cells insusceptible to the drug-targeted pathway,thereby facilitating the tumor cell survival and growth.The concept of tumor cell plasticity highlights the significance of re-activation of developmental programs that are closely correlated with epithelial–mesenchymal transition,acquisition properties of cancer stem cells,and transdifferentiation potential during drug exposure.From observations in various cancers,this concept provides an opportunity for investigating the nature of anticancer drug resistance.Over the years,our understanding of the emerging role of phenotype switching in modifying therapeutic response has considerably increased.This expanded knowledge of tumor cell plasticity contributes to developing novel therapeutic strategies or combination therapy regimens using available anticancer drugs,which are likely to improve patient outcomes in clinical practice.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is characterized by the highest mortality among carcinomas.The pathogenesis of PDAC requires elevated autophagy,inhibition of which using hydroxychloroquine has shown promise.Howe...Pancreatic ductal adenocarcinoma(PDAC)is characterized by the highest mortality among carcinomas.The pathogenesis of PDAC requires elevated autophagy,inhibition of which using hydroxychloroquine has shown promise.However,current realization is impeded by its suboptimal use and unpredictable toxicity.Attempts to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessible approach.Here,using a patient-derived organoid model,we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents,through which econazole(ECON),an antifungal compound,emerged as the top candidate.Further testing in cell-line and xenograft models of PDAC validated this activity,which occurred as a direct consequence of dysfunctional autophagy.More specifically,ECON boosted autophagy initiation but blocked lysosome biogenesis.RNA sequencing analysis revealed that this autophagic induction was largely attributed to the altered expression of activation transcription factor 3(ATF3).Increased nuclear import of ATF3 and its transcriptional repression of inhibitor of differentiation-1(ID-1)led to inactivation of the AKT/mammalian target of rapamycin(m TOR)pathway,thus giving rise to autophagosome accumulation in PDAC cells.The magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated apoptosis.Furthermore,ECON,as an autophagy inhibitor,exhibited synergistic effects with trametinib on PDAC.This study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereby ECON inhibits PDAC growth.展开更多
The single-nucleotide polymorphism(SNP)of p53,in particular the codon 72 variants,has recently been implicated as a critical regulator in tumor progression.However,the underlying mechanism remains elusive.Here we foun...The single-nucleotide polymorphism(SNP)of p53,in particular the codon 72 variants,has recently been implicated as a critical regulator in tumor progression.However,the underlying mechanism remains elusive.Here we found that cancer cells carrying codon 72-Pro variant of p53 showed impaired metastatic potential upon serine supplementation.Proteome-wide mapping of p53-interacting proteins uncovered a specific interaction of the codon 72 proline variant(but not p5372R)with phosphoserine aminotransferase 1(PSAT1).Interestingly,p53^(72P)-PSAT1 interaction resulted in dissociation of peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α)that otherwise bound to p53^(72P),leading to subsequent nuclear translocation of PGC-1αand activation of oxidative phosphorylation(OXPHOS)and tricarboxylic acid(TCA)cycle.Depletion of PSAT1 restored p53^(72P)-PGC-1αinteraction and impeded the OXPHOS and TCA function,resulting in mitochondrial dysfunction and metastasis suppression.Notably,pharmacological targeting the PSAT1-p53^(72P)interaction by aminooxyacetic acid(AOA)crippled the growth of liver cancer cells carrying the p53^(72P)variant in both in vitro and patient-derived xenograft models.Moreover,AOA plus regorafenib,an FDA-proved drug for hepatocellular carcinoma and colorectal cancer,achieved a better anti-tumor effect on tumors carrying the p53^(72P)variant.Therefore,our findings identified a gain of function of the p53^(72P)variant on mitochondrial function and provided a promising precision strategy to treat tumors vulnerable to p53^(72P)-PSAT1 perturbation.展开更多
Four species of porcine circoviruses(PCV1–4)have been reported to circulate in Chinese domestic pigs,while the epizootiology of these viruses in free-ranging wild boars in China remains unknown.In this study,tissue a...Four species of porcine circoviruses(PCV1–4)have been reported to circulate in Chinese domestic pigs,while the epizootiology of these viruses in free-ranging wild boars in China remains unknown.In this study,tissue and serum samples collected from diseased or apparently healthy wild boars between 2018 and 2020 in 19 regions of China were tested for the prevalence of PCV1–4 infections.Positive rates of PCV1,PCV2,and PCV3 DNA in the tissue samples of Chinese wild boars were 1.6%(4/247),58.3%(144/247),and 10.9%(27/247)respectively,with none positive for PCV4.Sequence analysis of viral genome showed that the four PCV1 strains distributed in Hunan and Inner Mongolia shared 97.5%–99.6%sequence identity with global distributed reference strains.Comparison of the ORF2 gene sequences showed that 80 PCV2 strains widely distributed in 18 regions shared 79.5%–100%sequence identity with reference strains from domestic pigs and wild boars,and were grouped into PCV2a(7),PCV2b(31)and PCV2d(42).For PCV3,17 sequenced strains shared 97.2%–100%nucleotide identity at the genomic level and could be divided into PCV3a(3),PCV3b(2)and PCV3c(12)based on the phylogeny of ORF2 gene sequences.Serological data revealed antibody positive rates against PCV1 and PCV2 of 11.4%(19/167)and 53.9%(90/167)respectively.The data obtained in this study improved our understanding about the epidemiological situations of PCVs infection in free-ranging wild boars in China and will be valuable for the prevention and control of diseases caused by PCVs infection.展开更多
Impact statementThis study identifies avian tuberculosis as a potential cause of mass mortality in wild migratory birds in Inner Mongolia,China.Combining meta-transcriptomic sequencing and histopathological analysis,it...Impact statementThis study identifies avian tuberculosis as a potential cause of mass mortality in wild migratory birds in Inner Mongolia,China.Combining meta-transcriptomic sequencing and histopathological analysis,it reveals one of the rare instances oftuberculosis-associated outbreaks in avian populations.Thesefindings underscore the importance of surveillance on wildlifediseases to mitigate the risk of interspecies transmission of the disease associated pathogens and their broader implicationsfor biodiversity and public health.展开更多
基金supported by the National Key Research and Development Project of China (2020YFA0509400)Guangdong Basic and Applied Basic Research Foundation(2019B030302012)+1 种基金National Natural Science Foundation of China (81821002, 82130082)1·3·5 project for disciplines of excellence (ZYGD22007,ZYGC21004)
文摘Oral squamous cell carcinoma (OSCC) develops on the mucosal epithelium of the oral cavity. It accounts for approximately 90% oforal malignancies and impairs appearance, pronunciation, swallowing, and flavor perception. In 2020, 377,713 OSCC cases werereported globally. According to the Global Cancer Observatory (GCO), the incidence of OSCC will rise by approximately 40% by2040, accompanied by a growth in mortality. Persistent exposure to various risk factors, including tobacco, alcohol, betel quid (BQ),and human papillomavirus (HPV), will lead to the development of oral potentially malignant disorders (OPMDs), which are oralmucosal lesions with an increased risk of developing into OSCC. Complex and multifactorial, the oncogenesis process involvesgenetic alteration, epigenetic modification, and a dysregulated tumor microenvironment. Although various therapeuticinterventions, such as chemotherapy, radiation, immunotherapy, and nanomedicine, have been proposed to prevent or treat OSCCand OPMDs, understanding the mechanism of malignancies will facilitate the identification of therapeutic and prognostic factors,thereby improving the efficacy of treatment for OSCC patients. This review summarizes the mechanisms involved in OSCC.Moreover, the current therapeutic interventions and prognostic methods for OSCC and OPMDs are discussed to facilitatecomprehension and provide several prospective outlooks for the fields.
基金supported by National Natural Science Foundation of China (NSFC) (81272415 and 81171993)NSFC Key Project (81130046)+1 种基金Guangxi Key Projects (2013GXNSFEA053004)Guangxi Projects (2014GXNSFDA118030)
文摘Prostate cancer preferentially metastasizes to the bone. However, the underlying molecular mechanisms are still unclear. To explore the effects of a bone-mimicking microenvironment on PC3 prostate cancer cell growth and metastasis, we used osteoblast differentiation medium（ODM; minimal essential medium alpha supplemented with L-ascorbic acid） to mimic the bone microenvironment. PC3 cells grown in ODM underwent epithelial-mesenchymal transition and showed enhanced colony formation, migration, and invasion abilities compared to the cells grown in normal medium. PC3 cells grown in ODM showed enhanced metastasis when injected in mice. A screening of signaling pathways related to invasion and metastasis revealed that the NF-κB pathway was activated, which could be reversed by Bay 11-7082, a NF-κB pathway inhibitor. These results indicate that the cells in different culture conditions manifested significantly different biological behaviors and the NF-κB pathway is a potential therapeutic target for prostate cancer bone metastasis.
基金supported by grants from the National Natural Science Foundation of China to Zhongzhong Tu(31902307)the National Key Research and Development Program of China to Changchun Tu and Na Feng(2017YFD0500104 and 2023YFF1305400)the Wildlife Borne Infectious Diseases Monitoring Project of the State Forestry and Grassland Administration of China.
文摘Dear Editor,Canine distemper virus(CDV)is the causal agent of a highly contagious viral infectious disease that affects domestic and wild carnivores globally.It is an enveloped,non-segmented negative sense RNA virus that belongs to the Morbillivirus genus in Paramyxoviridae family,which contains viruses of epidemiological relevance to humans and animals.Based on the variability of the hemagglutinin gene(H),CDV strains have been at least 21 major genetic lineages:America-1 to America-5,Canada-1 and-2,Asia-1 to Asia-6,Europe wild-life,Arctic,Africa-1/South Africa,Africa-2,South America-1 to South America-3 and Rockborn-like(Giacinti et al.,2022).Mutations in the binding sites of the H protein,which interact with viral entry receptors such as signaling lymphocytic activation molecule(SLAM)and nectin-4,are associated with the emergence of the disease in new host species(Beineke et al.,2015).
文摘The changes associated with malignancy are not only in cancer cells but also in environment in which cancer cells live.Metabolic reprogramming supports tumor cells’high demand of biogenesis for their rapid proliferation,and helps tumor cells to survive under certain genetic or environmental stresses.Emerging evidence suggests that metabolic alteration is ultimately and tightly associated with genetic changes,in particular the dysregulation of key oncogenic and tumor suppressive signaling pathways.Cancer cells activate HIF signaling even in the presence of oxygen and in the absence of growth factor stimulation.This cancer metabolic phenotype,described firstly by German physiologist Otto Warburg,ensures enhanced glycolytic metabolism for the biosynthesis of macromolecules.The conception of metabolite signaling,i.e.,metabolites are regulators of cell signaling,provides novel insights into how reactive oxygen species(ROS)and other metabolites deregulation may regulate redox homeostasis,epigenetics,and proliferation of cancer cells.Moreover,the unveiling of noncanonical functions of metabolic enzymes,such as the moonlighting functions of phosphoglycerate kinase 1(PGK1),reassures the importance of metabolism in cancer development.The metabolic,microRNAs,and ncRNAs alterations in cancer cells can be sorted and delivered either to intercellular matrix or to cancer adjacent cells to shape cancer microenvironment via media such as exosome.Among them,cancer microenvironmental cells are immune cells which exert profound effects on cancer cells.Understanding of all these processes is a prerequisite for the development of a more effective strategy to contain cancers.
基金supported by the National Nature Science Foundation of China (NSFC Nos.81773861 and 81773682)National Science and Technology Major Project (2017ZX09101001, China)+3 种基金Jiangsu Provincial National Science Foundation for Distinguished Young Scholars(No. BK20180027, China)Double First-Class University Projectthe Program for Jiangsu province Innovative Research Teamfunded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD, China)。
文摘Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestinal damage were commonly characterized by the sharp upregulation of tryptophan(Trp)àkynurenine(KYN)àkynurenic acid(KA) axis metabolism. Mechanistically,chemotherapy-induced intestinal damage triggered the formation of an interleukin-6(IL-6)àindoleamine2,3-dioxygenase 1(IDO1)àaryl hydrocarbon receptor(AHR) positive feedback loop, which accelerated kynurenine pathway metabolism in gut. Besides, AHR and G protein-coupled receptor 35(GPR35) negative feedback regulates intestinal damage and inflammation to maintain intestinal integrity and homeostasis through gradually sensing kynurenic acid level in gut and macrophage, respectively. Moreover, based on virtual screening and biological verification, vardenafil and linagliptin as GPR35 and AHR agonists respectively were discovered from 2388 approved drugs. Importantly, the results that vardenafil and linagliptin significantly alleviated chemotherapy-induced intestinal toxicity in vivo suggests that chemotherapeutics combined with the two could be a promising therapeutic strategy for cancer patients in clinic.This work highlights GPR35 and AHR as the guardian of kynurenine pathway metabolism and core component of defense responses against intestinal damage.
基金supported by project of the State Key Laboratory of Trauma,Burn and Combined Injury,Third Military Medical University(SKLJYJF20).
文摘Resistance to cancer therapy is a major barrier to cancer management.Conventional views have proposed that acquisition of resistance may result from genetic mutations.However,accumulating evidence implicates a key role of non-mutational resistance mechanisms underlying drug tolerance,the latter of which is the focus that will be discussed here.Such non-mutational processes are largely driven by tumor cell plasticity,which renders tumor cells insusceptible to the drug-targeted pathway,thereby facilitating the tumor cell survival and growth.The concept of tumor cell plasticity highlights the significance of re-activation of developmental programs that are closely correlated with epithelial–mesenchymal transition,acquisition properties of cancer stem cells,and transdifferentiation potential during drug exposure.From observations in various cancers,this concept provides an opportunity for investigating the nature of anticancer drug resistance.Over the years,our understanding of the emerging role of phenotype switching in modifying therapeutic response has considerably increased.This expanded knowledge of tumor cell plasticity contributes to developing novel therapeutic strategies or combination therapy regimens using available anticancer drugs,which are likely to improve patient outcomes in clinical practice.
基金funded by Guangdong Basic and Applied Basic Research Foundation(2019B030302012,China)National Key R&D Program of China(2020YFA0509400 and 2020YFC2002705)+1 种基金NSFC(81821002,81790251 and 82130082,China)1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYJC21042,China)。
文摘Pancreatic ductal adenocarcinoma(PDAC)is characterized by the highest mortality among carcinomas.The pathogenesis of PDAC requires elevated autophagy,inhibition of which using hydroxychloroquine has shown promise.However,current realization is impeded by its suboptimal use and unpredictable toxicity.Attempts to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessible approach.Here,using a patient-derived organoid model,we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents,through which econazole(ECON),an antifungal compound,emerged as the top candidate.Further testing in cell-line and xenograft models of PDAC validated this activity,which occurred as a direct consequence of dysfunctional autophagy.More specifically,ECON boosted autophagy initiation but blocked lysosome biogenesis.RNA sequencing analysis revealed that this autophagic induction was largely attributed to the altered expression of activation transcription factor 3(ATF3).Increased nuclear import of ATF3 and its transcriptional repression of inhibitor of differentiation-1(ID-1)led to inactivation of the AKT/mammalian target of rapamycin(m TOR)pathway,thus giving rise to autophagosome accumulation in PDAC cells.The magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated apoptosis.Furthermore,ECON,as an autophagy inhibitor,exhibited synergistic effects with trametinib on PDAC.This study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereby ECON inhibits PDAC growth.
基金This work was supported by National Key Research and Development Project of China(2020YFA0509400)Guangdong Basic and Applied Basic Research Foundation(2019B030302012)+2 种基金Chinese NSFC(81821002,82130082,81790251,82003098,82073246)1·3·5 project for disciplines of excellence(ZYGD22007)China Postdoctoral Science Foundation(2020TQ0214,2020M673252).The authors would like to thank Ping Fan of West China Biobanks,Department of Clinical Research,West China Hospital,Sichuan University,for biospecimen collection,processing,quality control,and storage.
文摘The single-nucleotide polymorphism(SNP)of p53,in particular the codon 72 variants,has recently been implicated as a critical regulator in tumor progression.However,the underlying mechanism remains elusive.Here we found that cancer cells carrying codon 72-Pro variant of p53 showed impaired metastatic potential upon serine supplementation.Proteome-wide mapping of p53-interacting proteins uncovered a specific interaction of the codon 72 proline variant(but not p5372R)with phosphoserine aminotransferase 1(PSAT1).Interestingly,p53^(72P)-PSAT1 interaction resulted in dissociation of peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α)that otherwise bound to p53^(72P),leading to subsequent nuclear translocation of PGC-1αand activation of oxidative phosphorylation(OXPHOS)and tricarboxylic acid(TCA)cycle.Depletion of PSAT1 restored p53^(72P)-PGC-1αinteraction and impeded the OXPHOS and TCA function,resulting in mitochondrial dysfunction and metastasis suppression.Notably,pharmacological targeting the PSAT1-p53^(72P)interaction by aminooxyacetic acid(AOA)crippled the growth of liver cancer cells carrying the p53^(72P)variant in both in vitro and patient-derived xenograft models.Moreover,AOA plus regorafenib,an FDA-proved drug for hepatocellular carcinoma and colorectal cancer,achieved a better anti-tumor effect on tumors carrying the p53^(72P)variant.Therefore,our findings identified a gain of function of the p53^(72P)variant on mitochondrial function and provided a promising precision strategy to treat tumors vulnerable to p53^(72P)-PSAT1 perturbation.
基金This work was supported by grants from the National Natural Science Foundation of China to Z Tu(31902307)National Key Research and Development Program of China to C Tu(2017YFD0500104)Wildlife Borne Infectious Diseases Monitoring Project of the State Forestry and Grassland Administration of China.
文摘Four species of porcine circoviruses(PCV1–4)have been reported to circulate in Chinese domestic pigs,while the epizootiology of these viruses in free-ranging wild boars in China remains unknown.In this study,tissue and serum samples collected from diseased or apparently healthy wild boars between 2018 and 2020 in 19 regions of China were tested for the prevalence of PCV1–4 infections.Positive rates of PCV1,PCV2,and PCV3 DNA in the tissue samples of Chinese wild boars were 1.6%(4/247),58.3%(144/247),and 10.9%(27/247)respectively,with none positive for PCV4.Sequence analysis of viral genome showed that the four PCV1 strains distributed in Hunan and Inner Mongolia shared 97.5%–99.6%sequence identity with global distributed reference strains.Comparison of the ORF2 gene sequences showed that 80 PCV2 strains widely distributed in 18 regions shared 79.5%–100%sequence identity with reference strains from domestic pigs and wild boars,and were grouped into PCV2a(7),PCV2b(31)and PCV2d(42).For PCV3,17 sequenced strains shared 97.2%–100%nucleotide identity at the genomic level and could be divided into PCV3a(3),PCV3b(2)and PCV3c(12)based on the phylogeny of ORF2 gene sequences.Serological data revealed antibody positive rates against PCV1 and PCV2 of 11.4%(19/167)and 53.9%(90/167)respectively.The data obtained in this study improved our understanding about the epidemiological situations of PCVs infection in free-ranging wild boars in China and will be valuable for the prevention and control of diseases caused by PCVs infection.
基金approved by the Animal Ethics Committee ofthe Institute of Microbiology,Chinese Academy of Sciences(Approval Number:APIMCAS2018034 and APIMCAS2021112).
文摘Impact statementThis study identifies avian tuberculosis as a potential cause of mass mortality in wild migratory birds in Inner Mongolia,China.Combining meta-transcriptomic sequencing and histopathological analysis,it reveals one of the rare instances oftuberculosis-associated outbreaks in avian populations.Thesefindings underscore the importance of surveillance on wildlifediseases to mitigate the risk of interspecies transmission of the disease associated pathogens and their broader implicationsfor biodiversity and public health.
