Epigenetic changes in colorectal cancer

合集下载

EMT有关基因

MINI REVIEW ARTICLEpublished:17September2013doi:10.3389/fonc.2013.00221 Role of epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma:is tumor budding the missing link? Eva Karamitopoulou1,2*1Clinical Pathology Division,Institute of Pathology,University of Bern,Bern,Switzerland2Translational Research Unit,Institute of Pathology,University of Bern,Bern,SwitzerlandEdited by:Inti Zlobec,University of Bern, SwitzerlandReviewed by:Parham Minoo,University of Calgary, CanadaQianghua Xia,The Children’s Hospital of Philadelphia,USA*Correspondence:Eva Karamitopoulou,Clinical Pathology Division,Institute of Pathology,University of Bern, Murtenstrasse31,CH-3010Bern, Switzerlande-mail:eva.diamantis@pathology.unibe.ch Pancreatic ductal adenocarcinoma(PDAC)ranks as the fourth commonest cause of cancer death while its incidence is increasing worldwide.For all stages,survival at5years is<5%. The lethal nature of pancreatic cancer is attributed to its high metastatic potential to the lymphatic system and distant ck of effective therapeutic options contributes to the high mortality rates of PDAC.Recent evidence suggests that epithelial-mesenchymal transition(EMT)plays an important role to the disease progression and development of drug resistance in PDAC.Tumor budding is thought to reﬂect the process of EMT which allows neoplastic epithelial cells to acquire a mesenchymal phenotype thus increasing their capacity for migration and invasion and help them become resistant to apoptotic signals. In a recent study by our own group the presence and prognostic signiﬁcance of tumor budding in PDAC were investigated and an association between high-grade budding and aggressive clinicopathological features of the tumors as well as worse outcome of the patients was found.The identiﬁcation of EMT phenotypic targets may help identifying new molecules so that future therapeutic strategies directed speciﬁcally against them could potentially have an impact on drug resistance and invasiveness and hence improve the prognosis of PDAC patients.The aim of this short review is to present an insight on the morphological and molecular aspects of EMT and on the factors that are involved in the induction of EMT in PDAC.Keywords:pancreatic cancer,epithelial-mesenchymal transition,tumor budding,prognosis,biomarkerPANCREATIC CANCERPancreatic ductal adenocarcinoma(PDAC)is a common can-cer with dismal prognosis(1)that escapes early detection and resists treatment(2).Most patients have advanced stage dis-ease at presentation with a median survival of less than1year (1,3).Surgical resection is the only potentially curative treat-ment of PDAC(3).Classical histomorphological features like tumor size,blood vessel,or lymphatic invasion,and presence of lymph node metastases constitute essential prognostic deter-minants in pancreatic cancer and are invariably included in the pathology reports,with tumor stage being the most important of all(3).The lethal nature of PDAC has been attributed to the propensity of PDAC cells to rapidly disseminate to the lym-phatic system and distant organs(4).However,even patients with completely resected,node-negative PDACs eventually die of their disease.Within this context and considering the fact that the management of PDAC remains suboptimal and that adjuvant therapy has resulted to limited progress,the identiﬁcation of addi-tional reliable and reproducible prognostic markers that would enable better patient stratiﬁcation and eventually provide a guide toward a more successful and individualized therapy,is mandatory (1,5).EPITHELIAL-MESENCHYMAL TRANSITIONEpithelial-mesenchymal transition is a biologic process that allows epithelial cells to undergo the biochemical changes that enable them to acquire a mesenchymal phenotype,including enhanced migratory capacity,invasiveness,elevated resistance to apoptosis, and increased production of extracellular matrix(ECM)compo-nents(6,7).EMT is characterized by loss of cell adhesion,down regulation of E-cadherin expression,acquisition of mesenchy-mal markers(including N-cadherin,Vimentin,and Fibronectin), and increased cell motility(6).Both EMT and mesenchymal-epithelial transition(MET),the reversion of EMT,are essential for developmental and repair processes like implantation,embryo for-mation,and organ development as well as wound healing,tissue regeneration,and organﬁbrosis(8).However,EMT also occurs in neoplastic cells that have undergone genetic and epigenetic changes.These changes affect both oncogenes and tumor sup-pressor genes that enable cancer cells to invade and metastasize. Moreover,some neoplastic cells may go through EMT retaining many of their epithelial properties while other cells are becoming fully mesenchymal(9).Many molecular processes are involved in the initiation of EMT including activation of transcription factors,expression of speciﬁc cell-surface proteins,reorganization and expression of cytoskeletal proteins,production of ECM-degrading enzymes,and changes in the expression of speciﬁc microRNAs(miRNAS).The above fac-tors can also be used as biomarkers to detect cells in EMT state(10). EMT has been linked to cellular self-renewal programs of cancer stem cells and apoptosis-anoikis resistance,which are features of therapeutic resistance(11).The zincﬁnger transcription factors Snail,Slug,Zeb1,and Twist repress genes responsible for the epithelial phenotype and represent important regulators of EMT(6,7,12).In PDAC Snail expression has been reported to be seen in nearly80%of the cases and Slug expression in50%(13).Snail expression was inversely correlated with E-cadherin expression and decreased E-cadherin expression was associated with higher tumor grade. Similarly,poorly differentiated pancreatic cancer cell lines showed higher levels of Snail and lower levels of E-cadherin compared with moderately differentiated cell lines(13)while silencing of Zeb1leaded to up-regulation of E-cadherin and restoration of an epithelial phenotype(14).Zeb1expression in PDAC also corre-lated with advanced tumor grade and worse outcomes(14–16) and was shown to be primarily responsible for the acquisition of an EMT phenotype,along with increased migration and inva-sion in response to NF-κB signaling in pancreatic cancer cells (16).EMT AND TUMOR BUDDINGTumor budding reﬂects a type of diffusely inﬁltrative growth con-sisting of detached tumor cells or small cell clusters of up toﬁve cells at the invasive front of gastrointestinal carcinomas(17–22). Tumor buds represent a non-proliferating,non-apoptotic,highly aggressive subpopulation of tumor cells that display migratory and invasive capacities(23).The aim of tumor buds seems to be the invasion of the peritumoral connective tissue,the avoidance of the host’s defense andﬁnally the inﬁltration of the lymphatic and blood vessels with the consequence of local and distant metastasis. The EMT process by allowing a polarized cell to assume a more mesenchymal phenotype with increased migratory capacity,inva-siveness,and resistance to apoptosis seems to play a major role in the development of tumor buds.In fact,tumor buds are thought to result from the process of EMT.Thus,although formally tumor budding cannot be equated with EMT,several similarities between the two processes,including activation in WNT signaling,can be shown(24).The detachment of tumor buds from the main tumor body is accomplished by loss of membranous expression of the adhesion molecule E-cadherin.Activation of WNT sig-naling is further suggested by nuclear expression of b-catenin in tumor-budding cells,as well as increase of laminin5gamma2and activation of Slug and Zeb1(24,25).The presence of high-grade tumor budding has been consis-tently associated with negative clinicopathologic parameters in gastrointestinal tumors(26–30).In a previous study from our group we could show that tumor budding occurs frequently in pancreatic cancer and is a strong,independent,and reproducible, highly unfavorable prognostic factor that may be used as a para-meter of tumor aggressiveness and as an indicator of unfavorable outcome,even within this group of patients with generally poor prognosis.Moreover,tumor budding was proven to have a more powerful prognostic ability than other more classic prognostic fac-tors including TNM stage,thus adding relevant and independent prognostic information(31).EMT AND miRNAsMicroRNAS are small non-coding RNAs of18–25nucleotides, excised from60to110nucleotide RNA precursor structures (32).MiRNAs are involved in crucial biological processes, including development,differentiation,apoptosis,and pro-liferation,through imperfect pairing with target messenger RNAs of protein-coding genes and the transcriptional or post-transcriptional regulation of their expression(33,34).Recent studies illustrate the role of miRNAs on the regula-tion of gene expression and proteins in metastasis.For exam-ple,it has been shown that miR-10b,which is up-regulated by EMT transcription factor Twist,is associated with increased invasiveness and metastatic potential(35,36).Furthermore,it was shown that the miR-200family(miR-200a,miR-200b,miR-200c,miR-141,and miR-429)and miR-205play critical roles in regulating EMT by directly targeting the mRNAs encoding E-cadherin repressors Zeb1and Zeb2(37).Moreover,recent studies showed that members of the miR-200family by induc-ing EMT can regulate the sensitivity to epidermal growth fac-tor receptor(EGFR)in bladder cancer cells and to gemcitabine in pancreatic cancer cells(38).Conversely,Zeb1represses the transcription of miR-200genes by directly binding to their promoter region,thereby forming a double-negative feedback loop(39).On the other hand,miR-200family can also pro-mote the conversion of mesenchymal cells to epithelial-like cells (MET)suggesting that these miRNAs may also favor metastatic outgrowth.Recent studies aiming at the evaluation of miRNAs in pan-creatic cancer have shown that speciﬁc miRNAs are dysregulated in PDAC while the higher expression of some miRNA species was able to distinguish between benign and malignant pancre-atic tissue(40).For example,miR-21was shown to be over-expressed in79%of pancreatic cancers as opposed to27%of chronic pancreatitis(41).In resected PDAC specimens high lev-els of miR-200c expression strongly correlated with E-cadherin levels and were associated with signiﬁcantly better survival rates compared with patients whose tumors had low levels of miR-200c expression(42).CHEMORESISTANCE AND EMTCells undergoing EMT become invasive and develop resistance to chemotherapeutic agents.Moreover,EMT can be induced by chemotherapeutic agents,and stress conditions such as exposure to radiation or hypoxia(43,44).Up-regulation of Twist has been shown to be associated with resistance to paclitaxel in nasopharyngeal,bladder,ovarian,and prostate cancers(45).In colorectal cancer cell lines,chronic expo-sure to oxaliplatin leaded to the development of the ability to migrate and invade with phenotypic changes resembling EMT(spindle-cell shape,loss of polarity,intercellular separa-tion,and pseudopodia formation)by the oxaliplatin-resistant cells(46).Pancreatic cancer remains today an extremely lethal disease largely because of its resistance to existing treatments(47).EMT has been shown to contribute signiﬁcantly to chemoresistance in several cancers,including pancreatic cancer(30,48,49).Induction of gemcitabine resistance in previously sensitive cell lines resulted in development of an EMT phenotype and was associated with an increased migratory and invasive ability compared to gemc-itabine sensitive cells(49).Moreover,gene expression proﬁling ofchemoresistant cells showed a strong association between expres-sion of the EMT transcription factors Zeb1,Snail,and Twist and decreased expression of E-cadherin(39,50).Silencing of Zeb1 with siRNA resulted to MET(51)and restored chemosensitivity (14).Interestingly,maintenance of chemoresistance in cell lines that have undergone EMT is dependent on Notch and NF-κB signaling(30).Inhibition of Notch-2down regulates Zeb1,Snail, and Slug expression,attenuates NF-κB signaling,and reduces the migratory and invasive capacity of the gemcitabine resistant cells(30).Epithelial-mesenchymal transition can also confer resistance to targeted agents.For example,lung cancer cell lines that have undergone EMT,became resistant to the growth inhibitory effects of EGFR kinase inhibition(erlotinib)in vitro and in xenografts(47)as well as other EGFR inhibitors such as geﬁtinib and cetuximab(48)Thus,EMT can lead to resis-tance to multiple agents and result to rapid progression of the tumor.Clarifying the correlation between EMT and drug resistance may help clinicians select an optimal treat-ment.CONCLUSIONPancreatic cancer remains an extremely lethal disease partly because of the poor response to existing treatments.Accumulat-ing evidence suggests that EMT plays an important role in PDAC progression,is associated with stem cell features of the PDAC cells and seems to signiﬁcantly contribute to the chemoresistance of pancreatic cancer.Moreover,is associated with more aggressive tumor characteristics and with poor patient survival.Because of its role in therapy response and tumor progression,targeting EMT could potentially reduce drug resistance and have a great impact in the survival of PDAC patients.Tumor budding thought to be the result of the EMT process is commonly observed in PDAC and high-grade tumor budding has been proven to have an independent adverse prognostic impact in the survival of PDAC patients.Figure1depicts tumor bud-ding as a possible transition between a fully epithelial and a fully mesenchymal phenotype of the tumor cells in PDAC.Moreover, cancer cells in tumor buds have been shown to have EMT and cancer stem cell characteristics.The further characterization of the budding cells at a protein and gene level in order to iden-tify a“molecular budding-promoting proﬁle”will lead to a better understanding of the tumor-stroma interaction at the area of the invasive front and help to further elucidate the similarities between budding cells,EMT process and cancer stem cells in pancreatic cancer.Investigating these issues will allow us to gain further insight into pancreatic carcinogenesis,and provide us with a platform on which to build future studies leading to the identiﬁcation of new therapeutic interventions.REFERENCES1.Hidalgo M.Pancreatic cancer.NEngl J Med(2010)362:1605–17.doi:10.1056/NEJMra09015572.Tuveson DA,Hingorani SR.Duc-tal pancreatic cancer in humans and mice.Cold Spring Harb Symp Quant Biol(2005)70:65–72.doi:10.1101/ sqb.2005.70.0403.Fernandez-del-Castillo C,JimenezRE,Steer ML.Surgery in the treatment of exocrine pancreas and prognosis.In:Tanabe KK,edi-tor(2013).Available from:www.4.Li Y,Kong D,Ahmad A,Bao B,Sarkar FH.Pancreatic cancer stem cells:emerging target for designing novel therapy.Cancer Lett(2012).Available from:/10.1016/j canlet.2012.03.018,5.Welsch T,Kleeff J,Friess H.Molecu-lar pathogenesis of pancreatic can-cer:advances and challenges.Curr Mol Med(2007)7:504–21.doi:10.2174/1566524077813870826.Kalluri R,Weinberg RA.The basicsof epithelial-mesenchymal transi-tion.J Clin Invest(2009)119:1420–8.doi:10.1172/JCI391047.Thiery JP,Acloque H,Huang RYJ,Nieto MA.Epithelial-mesenchymal transitions in development and dis-ease.Cell(2009)139:871–90.doi:10.1016/j.cell.2009.11.0078.Rasheed ZA,Yang J,Wang Q,Kowal-ski J,Freed I,Murter C,et al.Prog-nostic signiﬁcance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma.J Natl Cancer Inst(2010)102:340–51.doi:10.1093/jnci/djp5359.Iwatsuki M,Mimori K,YokoboriT,Ishi H,Beppu T,Nakamori S.Epithelial–mesenchymal transi-tion in cancer development and its clinical signiﬁcance.Cancer Sci (2010)101(2):293–9.doi:10.1111/j.1349-7006.2009.01419.x10.Kalluri R.EMT:when epithelial cellsdecide to become mesenchymal-like cells.J Clin Invest(2009)119:1417–9.doi:10.1172/JCI3967511.Krantz SB,Shields MA,Dangi-Garimella S,Munshi HG,Bentrem DJ.Contribution of epithelial-to-mesenchymal transition and cancer stem cells to pancreatic cancer progression.J Surg Res(2012)173: 105–12.doi:10.1016/j.jss.2011.09.02012.Lee JM,Dedhar S,Kalluri R,Thompson EW.The epithelial-mesenchymal transition:new insights in signaling,devel-opment,and disease.J Cell Biol(2006)172:973–81.doi:10.1083/jcb.20060101813.Hotz B,Arndt M,Dullat S,BhargavaS,Buhr HJ,Hotz HG.Epithelial tomesenchymal transition:expressionof the regulators snail,slug,andtwist in pancreatic cancer.ClinCancer Res(2007)13:4769–76.doi:10.1158/R-06-292614.Arumugam T,Ramachandran V,Fournier KF,Wang H,MarquisL,Abbruzzese JL,et al.Epithe-lial to mesenchymal transition con-tributes to drug resistance in pan-creatic cancer.Cancer Res(2009)69:5820–8.doi:10.1158/0008-5472.CAN-08-281915.Buck E,Eyzaguirre A,Barr S,Thompson S,Sennello R,Y oung D,et al.Loss of homotypic cell adhe-sion by epithelial-mesenchymaltransition or mutation limits sen-sitivity to epidermal growth factorreceptor inhibition.Mol CancerTher(2007)6:532–41.doi:10.1158/1535-7163.MCT-06-046216.Maier HJ,Schmidt-Strassburger U,Huber MA,Wiedemann EM,BeugH,Wirth T.NF-kappaB promotesepithelial-mesenchymal transition,migration and invasion of pancre-atic carcinoma cells.Cancer Lett(2010)295:214–28.doi:10.1016/j.canlet.2010.03.00317.Prall F.Tumour budding in col-orectal carcinoma.Histopathology(2007)50:151–62.doi:10.1111/j.1365-2559.2006.02551.x18.Brown M,Sillah K,Grifﬁths EA,Swindell R,West CM,Page RD,et al.Tumour budding and a lowhost inﬂammatory response areassociated with a poor progno-sis in oesophageal and gastro-oesophageal junction cancers.Histopathology(2010)56:893–9.doi:10.1111/j.1365-2559.2010.03559.x19.Koike M,Kodera Y,Itoh Y,Nakayama G,Fujiwara M,Hamajima N,et al.Multivariateanalysis of the pathologic featuresof esophageal squamous cell cancer:tumor budding is a signiﬁcantindependent prognostic factor.AnnSurg Oncol(2008)15:1977–82.doi:10.1245/s10434-008-9901-620.Miyata H,Y oshioka A,YamasakiM,Nushijima Y,Takiguchi S,Fujiwara Y,et al.Tumor bud-ding in tumor invasive front pre-dicts prognosis and survival ofpatients with esophageal squa-mous cell carcinomas receivingneoadjuvant chemotherapy.Cancer(2009)115:3324–34.doi:10.1002/cncr.2439021.Roh MS,Lee JI,Choi PJ.Tumorbudding as a useful prognosticmarker in esophageal squamous cellcarcinoma.Dis Esophagus(2004)17:333–7.doi:10.1111/j.1442-2050.2004.00436.x22.Ohike N,Coban I,Kim GE,Bas-turk O,Tajiri T,Krasinskas A,etal.Tumor budding as a strongprognostic indicator in invasiveampullary adenocarcinomas.Am JSurg Pathol(2010)34:1417–24.doi:10.1097/PAS.0b013e3181f0b05a23.Zlobec I,Lugli A.Epithelial mes-enchymal transition and tumorbudding in aggressive colorectalcancer:tumor budding as oncotar-get.Oncotarget(2010)1:651–61.24.Muto T,Mochizuki H,Masaki T edi-tors.Tumor Budding in ColorectalCancer:Recent Progress in ColorectalCancer Research(Horizons in Can-cer Research).(Vol.8).Tokyo:Nova(2006).25.Schmalhofer O,Brabletz S,Brabletz T.E-cadherin,beta-catenin,and ZEB1in malignantprogression of cancer.CancerMetastasis Rev(2009)28:151–66.doi:10.1007/s10555-008-9179-y26.Karamitopoulou E,Zlobec I,KölzerV,Kondi-Paﬁti A,Patsouris ES,Gen-natas K,et al.Proposal for a10-high-power-ﬁelds scoring methodfor the assessment of tumor bud-ding in colorectal cancer.ModPathol(2013)26:295–301.doi:10.1038/modpathol.2012.15527.Nakamura T,Mitomi H,KikuchiS,Ohtani Y,Sato K.Evaluationof the usefulness of tumor bud-ding on the prediction of metasta-sis to the lung and liver after cura-tive excision of colorectal cancer.Hepatogastroenterology(2005)52:1432–5.28.Ueno H,Mochizuki H,HashiguchiY,Hatsuse K,Fujimoto H,HaseK.Predictors of extrahepatic recur-rence after resection of colorectalliver metastases.Br J Surg(2004)91:327–33.doi:10.1002/bjs.442929.Ueno H,Murphy J,Jass JR,Mochizuki H,Talbot IC.Tumour‘budding’as an indexto estimate the potential ofaggressiveness in rectal cancer.Histopathology(2002)40:127–32.doi:10.1046/j.1365-2559.2002.01324.x30.Wang LM,Kevans D,Mulcahy H,O’Sullivan J,Fennelly D,Hyland J,et al.Tumor budding is a strong andreproducible prognostic marker inT3N0colorectal cancer.Am J SurgPathol(2009)33:134–41.doi:10.1097/PAS.0b013e318184cd5531.Karamitopoulou E,Zlobec I,BornD,Kondi-Paﬁti A,Patsouris E,Gen-natas K,et al.Tumor budding isa strong and independent prognos-tic factor in pancreatic cancer.EurJ Cancer(2013)49:1032–9.doi:10.1016/j.ejca.2012.10.02232.Calin GA,Croce CM.Micro RNAsignatures in human cancers.NatRev Cancer(2006)6:857–66.doi:10.1038/nrc199733.McShane L,Altman DG,SauerbreiW,Taube SE,Gion M,Clark GM,etal.REporting recommendations fortumor MARKer prognostic studies(REMARK).Eur J Cancer(2005)41:1690–6.doi:10.1016/j.ejca.2005.03.03234.Pasquinelli AE,Hunter S,BrachtJ.MicroRNAs:a developing story.Curr Opin Gen Dev(2005)15:200–5.doi:10.1016/j.gde.2005.01.00235.Peter ME.Let-7and miR-200microRNAs:guardians againstpluripotency and cancer progres-sion.Cell Cycle(2009)8:843–52.doi:10.4161/cc.8.6.790736.Preis M,Gardner TB,Gordon SR,Pipas JM,Mackenzie TA,Klein EE,et al.MicroRNA10b expression cor-relates with response to neoadju-vant therapy and survival in pan-creatic ductal adenocarcinoma.ClinCancer Res(2011)17:5812–21.doi:10.1158/R-11-069537.Gregory PA,Bert AG,Paterson EL,Barry SC,Tsykin A,Farshid G,et al.The miR-200family and miR-205regulate epithelial to mesenchymaltransition by targeting ZEB1andSIP1.Nat Cell Biol(2008)10:593–601.doi:10.1038/ncb172238.Burk U,Schubert J,Wellner U,Schmalhofer O,Vincan E,SpadernaS,et al.A reciprocal repressionbetween ZEB1and members of themiR-200family promotes EMT andinvasion in cancer cells.EMBO Rep(2008)9:582–9.doi:10.1038/embor.2008.7439.Wellner U,Schubert J,Burk UC,Schmalhofer O,Zhu F,Sonntag A,et al.The EMT-activator ZEB1pro-motes tumorigenicity by repress-ing stemness-inhibiting microR-NAs.Nat Cell Biol(2009)11:1487–95.doi:10.1038/ncb199840.Panarelli NC,Chen YT,ZhouXK,Kitabayashi N,Yantiss RK.MicroRNA expression aids thepreoperative diagnosis of pancre-atic ductal adenocarcinoma.Pan-creas(2012)41:685–90.doi:10.1097/MPA.0b013e318243a90541.Dillhoff M,Liu J,Frankel W,CroceC,Bloomston M.MicroRNA-21is overexpressed in pan-creatic cancer and a potentialpredictor of survival.J Gas-trointest Surg(2008)12:2171–6.doi:10.1007/s11605-008-0584-x42.Yu J,Ohuchida K,Mizumoto K,Sato N,Kayashima T,Fujita H, et al.MicroRNA,hsa-miR-200c, is an independent prognos-tic factor in pancreatic cancer and its upregulation inhibits pancreatic cancer invasion but increases cell prolifera-tion.Mol Cancer(2010)9:169.doi:10.1186/1476-4598-9-169 43.Li C,Heidt DG,Dalerba P,BurantCF,Zhang L,Adsay V,et al.Identiﬁcation of pancreatic can-cer stem cells.Cancer Res(2007) 67:1030–7.doi:10.1158/0008-5472.CAN-06-203044.Lee CJ,Dosch J,Simeone DM.Pan-creatic cancer stem cells.J Clin Oncol(2008)26:2806–12.doi:10.1200/JCO45.Hong SP,Wen J,Bang S,ParkS,Song SY.CD44-positive cells are responsible for gemc-itabine resistance in pancreatic cancer cells.Int J Cancer(2009)125:2323–31.doi:10.1002/ijc.2457346.Hermann PC,Huber SL,HerrlerT,Aicher A,Ellwart JW,GubaM,et al.Distinct populations ofcancer stem cells determine tumorgrowth and metastatic activity inhuman pancreatic cancer.Cell StemCell(2007)1:313–23.doi:10.1016/j.stem.2007.06.00247.Li Y,VandenBoom TG,Kong D,Wang Z,Ali S,Philip PA,et al.Up-regulation of miR-200and let-7bynatural agents leads to the reversalof epithelial-to-mesenchymal tran-sition in gemcitabine-resistant pan-creatic cancer cells.Cancer Res(2009)69:6704–12.doi:10.1158/0008-5472.CAN-09-129848.Yang AD,Fan F,Camp ER,vanBuren G,Liu W,Somcio R,etal.Chronic oxaliplatin resistanceinduces epithelial-to-mesenchymaltransition in colorectal cancercell lines.Clin Cancer Res(2006)12:4147–53.doi:10.1158/1078-R-06-003849.Shah AN,Summy JM,Zhang J,Park S,Parikh N,Gallick GE.Development and characterizationof gemcitabine-resistant pancre-atic tumor cells.Ann Surg Oncol(2007)14:3629–37.doi:10.1245/s10434-007-9583-550.Shimono Y,Zabala M,ChoRW,Lobo N,Dalerba P,QianD,et al.Downregulation ofmiRNA-200c links breast cancerstem cells with normal stemcells.Cell(2009)138:592–603.doi:10.1016/j.cell.2009.07.01151.Conroy T,Paillot B,Francois E,Bugat R,Jacob JH,Stein U,etal.Irinotecan plus oxaliplatin andleucovorin-modulatedﬂuorouracilin advanced pancreatic cancer–aGroupe Tumeurs Digestives of theFederation Nationale des Centres deLutte Contre le Cancer study.J ClinOncol(2005)23:1228–36.doi:10.1200/JCO.2005.06.050Conﬂict of Interest Statement:Theauthor declares that the research wasconducted in the absence of anycommercial orﬁnancial relationshipsthat could be construed as a potentialconﬂict of interest.Received:24July2013;accepted:11August2013;published online:17Sep-tember2013.Citation:Karamitopoulou E(2013)Role of epithelial-mesenchymal tran-sition in pancreatic ductal adenocar-cinoma:is tumor budding the miss-ing link?Front.Oncol.3:221.doi:10.3389/fonc.2013.00221This article was submitted to Gastroin-testinal Cancers,a section of the journalFrontiers in Oncology.Copyright©2013Karamitopoulou.Thisis an open-access article distributed underthe terms of the Creative CommonsAttribution License(CC BY).The use,distribution or reproduction in otherforums is permitted,provided the origi-nal author(s)or licensor are credited andthat the original publication in this jour-nal is cited,in accordance with acceptedacademic practice.No use,distribution orreproduction is permitted which does notcomply with these terms.。

甲基化中文

结果实验组孕鼠产下的仔鼠大多数在身体的不同部位出现了大小不等的棕色斑块，甚至出现了以棕褐色为主要毛色的小鼠。而对照组孕鼠的仔鼠大多数为黄色。分析表明喂以富甲基饲料的孕鼠所产仔鼠的IAP所含CpG岛的甲
基化平均水平远高于对照组，转录调控区的高甲基化使原该呈异位表达的基
因趋于沉默，毛色也趋于棕褐色。
2013年8月19日
23
一、DNA甲基化
DNA全新甲基化
DNA主动去甲基化
DNA甲基化状态的保持
2013年8月19日
24
二、组蛋白修饰
2013年8月19日
25
二、组蛋白修饰
组蛋白修饰是表观遗传研究的重要内容。组蛋白的 N端是不稳定的、无一定组织的亚单位，其
延伸至核小体以外，会受到不同的化学修饰，这种修
启动子区域的CpG岛一般是非甲基化状态的，其非甲基化状态对相关基因的转录是必须的。
目前认为基因调控元件（如启动子）的CpG岛中发生5mC 修饰会在空间上阻碍转录因子复合物与DNA的结合。因而DNA甲基化一般与基因沉默相关联。
2013年8月19日
18
一、DNA甲基化
2013年8月19日
19
2013年8月19日
3
概
Definition of Epigenetics
述
Any changes in gene expression resulting from either a DNA and chromatin modification or resulting from a post posttranscriptional mechanism. However, it does not reflect a difference in the DNA code。

Cancer Epigenetics From Mechanism to Therapy

Leading EdgeReviewCancer Epigenetics:From Mechanism to TherapyMark A.Dawson1,2and Tony Kouzarides1,*1Gurdon Institute and Department of Pathology,University of Cambridge,Tennis Court Road,Cambridge CB21QN,UK2Department of Haematology,Cambridge Institute for Medical Research and Addenbrooke’s Hospital,University of Cambridge,Hills Road, Cambridge CB20XY,UK*Correspondence:t.kouzarides@/10.1016/j.cell.2012.06.013The epigenetic regulation of DNA-templated processes has been intensely studied over the last15 years.DNA methylation,histone modiﬁcation,nucleosome remodeling,and RNA-mediated target-ing regulate many biological processes that are fundamental to the genesis of cancer.Here,we present the basic principles behind these epigenetic pathways and highlight the evidence suggest-ing that their misregulation can culminate in cancer.This information,along with the promising clin-ical and preclinical results seen with epigenetic drugs against chromatin regulators,signiﬁes that it is time to embrace the central role of epigenetics in cancer.Chromatin is the macromolecular complex of DNA and histone proteins,which provides the scaffold for the packaging of our entire genome.It contains the heritable material of eukaryotic cells.The basic functional unit of chromatin is the nucleosome. It contains147base pairs of DNA,which is wrapped around a histone octamer,with two each of histones H2A,H2B,H3, and H4.In general and simple terms,chromatin can be subdi-vided into two major regions:(1)heterochromatin,which is highly condensed,late to replicate,and primarily contains inac-tive genes;and(2)euchromatin,which is relatively open and contains most of the active genes.Efforts to study the coordi-nated regulation of the nucleosome have demonstrated that all of its components are subject to covalent modiﬁcation,which fundamentally alters the organization and function of these basic tenants of chromatin(Allis et al.,2007).The term‘‘epigenetics’’was originally coined by Conrad Wad-dington to describe heritable changes in a cellular phenotype that were independent of alterations in the DNA sequence. Despite decades of debate and research,a consensus deﬁnition of epigenetics remains both contentious and ambiguous(Berger et al.,2009).Epigenetics is most commonly used to describe chromatin-based events that regulate DNA-templated pro-cesses,and this will be the deﬁnition we use in this review. Modiﬁcations to DNA and histones are dynamically laid down and removed by chromatin-modifying enzymes in a highly regulated manner.There are now at least four different DNA modiﬁcations(Baylin and Jones,2011;Wu and Zhang,2011) and16classes of histone modiﬁcations(Kouzarides,2007;Tan et al.,2011).These are described in Table1.These modiﬁcations can alter chromatin structure by altering noncovalent interac-tions within and between nucleosomes.They also serve as docking sites for specialized proteins with unique domains that speciﬁcally recognize these modiﬁcations.These chromatin readers recruit additional chromatin modiﬁers and remodeling enzymes,which serve as the effectors of the modiﬁcation.The information conveyed by epigenetic modiﬁcations plays a critical role in the regulation of all DNA-based processes, such as transcription,DNA repair,and replication.Conse-quently,abnormal expression patterns or genomic alterations in chromatin regulators can have profound results and can lead to the induction and maintenance of various cancers.In this Review,we highlight recent advances in our understanding of these epigenetic pathways and discuss their role in oncogen-esis.We provide a comprehensive list of all the recurrent cancer mutations described thus far in epigenetic pathways regulating modiﬁcations of DNA(Figure2),histones(Figures3,4,and5), and chromatin remodeling(Figure6).Where relevant,we will also emphasize existing and emerging drug therapies aimed at targeting epigenetic regulators(Figure1).Characterizing the EpigenomeOur appreciation of epigenetic complexity and plasticity has dramatically increased over the last few years following the development of several global proteomic and genomic technol-ogies.The coupling of next-generation sequencing(NGS)plat-forms with established chromatin techniques such as chromatin immunoprecipitation(ChIP-Seq)has presented us with a previ-ously unparalleled view of the epigenome(Park,2009).These technologies have provided comprehensive maps of nucleo-some positioning(Segal and Widom,2009),chromatin confor-mation(de Wit and de Laat,2012),transcription factor binding sites(Farnham,2009),and the localization of histone(Rando and Chang,2009)and DNA(Laird,2010)modiﬁcations.In addi-tion,NGS has revealed surprising facts about the mammalian transcriptome.We now have a greater appreciation of the fact that most of our genome is transcribed and that noncoding RNA may play a fundamental role in epigenetic regulation(Ama-ral et al.,2008).Most of the complexity surrounding the epigenome comes from the modiﬁcation pathways that have been identiﬁed.12Cell150,July6,2012ª2012Elsevier Inc.Recent improvements in the sensitivity and accuracy of mass spectrometry (MS)instruments have driven many of these discoveries (Stunnenberg and Vermeulen,2011).Moreover,although MS is inherently not quantitative,recent advances in labeling methodologies,such as stable isotope labeling by amino acids in cell culture (SILAC),isobaric tags for relative and absolute quantiﬁcation (iTRAQ),and isotope-coded afﬁnity tag (ICAT),have allowed a greater ability to provide quantitative measurements (Stunnenberg and Vermeulen,2011).These quantitative methods have generated ‘‘protein recruit-ment maps’’for histone and DNA modiﬁcations,which contain proteins that recognize chromatin modiﬁcations (Bartke et al.,2010;Vermeulen et al.,2010).Many of these chromatin readers have more than one reading motif,so it is important to under-stand how they recognize several modiﬁcations either simulta-neously or sequentially.The concept of multivalent engagement by chromatin-binding modules has recently been explored by using either modiﬁed histone peptides (Vermeulen et al.,2010)or in-vitro-assembled and -modiﬁed nucleosomes (Bartkeet al.,2010;Ruthenburg et al.,2011).The latter approach in particular has uncovered some of the rules governing the recruit-ment of protein complexes to methylated DNA and modiﬁed histones in a nucleosomal context.The next step in our under-standing will require a high-resolution in vivo genomic approach to detail the dynamic events on any given nucleosome during the course of gene expression.Epigenetics and the Cancer ConnectionThe earliest indications of an epigenetic link to cancer were derived from gene expression and DNA methylation studies.These studies are too numerous to comprehensively detail in this review;however,the reader is referred to an excellent review detailing the history of cancer epigenetics (Feinberg and Tycko,2004).Although many of these initial studies were purely correl-ative,they did highlight a potential connection between epige-netic pathways and cancer.These early observations have been signiﬁcantly strengthened by recent results from the Inter-national Cancer Genome Consortium (ICGC).Whole-genomeTable 1.Chromatin Modiﬁcations,Readers,and Their Function Chromatin Modiﬁcation NomenclatureChromatin-Reader MotifAttributed Functionand Cit,citrulline.Reader domains:MBD,methyl-CpG-binding domain;PHD,plant homeodomain;MBT,malignant brain tumor domain;PWWP,proline-tryptophan-tryptophan-proline domain;BRCT,BRCA1C terminus domain;UIM,ubiquitin interaction motif;IUIM,inverted ubiquitin interaction motif;SIM,sumo interaction motif;and PBZ,poly ADP-ribose binding zinc ﬁnger.aThese are established binding modules for the posttranslational modiﬁcation;however,binding to modiﬁed histones has not been ﬁrmly established.Cell 150,July 6,2012ª2012Elsevier Inc.13sequencing in a vast array of cancers has provided a catalog of recurrent somatic mutations in numerous epigenetic regulators (Forbes et al.,2011;Stratton et al.,2009).A central tenet in analyzing these cancer genomes is the identiﬁcation of ‘‘driver’’mutations (causally implicated in the process of oncogenesis).A key feature of driver mutations is that they are recurrently found in a variety of cancers,and/or they are often present at a high prevalence in a speciﬁc tumor type.We will mostly concentrate our discussions on suspected or proven driver mutations in epigenetic regulators.For instance,malignancies such as follicular lymphoma contain recurrent mutations of the histone methyltransferase MLL2in close to 90%of cases (Morin et al.,2011).Similarly,UTX ,a histone demethylase,is mutated in up to 12histologi-cally distinct cancers (van Haaften et al.,2009).Compilation of the epigenetic regulators mutated in cancer highlights histone acetylation and methylation as the most widely affected epige-netic pathways (Figures 3and 4).These and other pathways that are affected to a lesser extent will be described in the following sections.Deep sequencing technologies aimed at mapping chromatin modiﬁcations have also begun to shed some light on the origins of epigenetic abnormalities in cancer.Cross-referencing of DNA methylation proﬁles in human cancers with ChIP-Seq data for histone modiﬁcations and the binding of chromatinregulators have raised intriguing correlations between cancer-associated DNA hypermethylation and genes marked with ‘‘bivalent’’histone modiﬁcations in multipotent cells (Easwaran et al.,2012;Ohm et al.,2007).These bivalent genes are marked by active (H3K4me3)and repressive (H3K27me3)histone modi-ﬁcations (Bernstein et al.,2006)and appear to identify transcrip-tionally poised genes that are integral to development and lineage commitment.Interestingly,many of these genes are targeted for DNA methylation in cancer.Equally intriguing are recent comparisons between malignant and normal tissues from the same individuals.These data demonstrate broad domains within the malignant cells that contain signiﬁcant alter-ations in DNA methylation.These regions appear to correlate with late-replicating regions of the genome associated with the nuclear lamina (Berman et al.,2012).Although there remains little mechanistic insight into how and why these regions of the genome are vulnerable to epigenetic alterations in cancer,these studies highlight the means by which global sequencing plat-forms have started to uncover avenues for further investigation.Genetic lesions in chromatin modiﬁers and global alterations in the epigenetic landscape not only imply a causative role for these proteins in cancer but also provide potential targets for therapeutic intervention.A number of small-molecule inhibitors have already been developed against chromatin regulators (Figure 1).These are at various stages of development,andthreeFigure 1.Epigenetic Inhibitors as Cancer TherapiesThis schematic depicts the process for epigenetic drug development and the current status of various epigenetic therapies.Candidate small molecules are ﬁrst tested in vitro in malignant cell lines for speciﬁcity and phenotypic response.These may,in the ﬁrst instance,assess the inhibition of proliferation,induction of apoptosis,or cell-cycle arrest.These phenotypic assays are often coupled to genomic and proteomic methods to identify potential molecular mechanisms for the observed response.Inhibitors that demonstrate potential in vitro are then tested in vivo in animal models of cancer to ascertain whether they may provide therapeutic beneﬁt in terms of survival.Animal studies also provide valuable information regarding the toxicity and pharmacokinetic properties of the drug.Based on these preclinical studies,candidate molecules may be taken forward into the clinical setting.When new drugs prove beneﬁcial in well-conducted clinical trials,they are approved for routine clinical use by regulatory authorities such as the FDA.KAT,histone lysine acetyltransferase;KMT,histone lysine methyltransferase;RMT,histone arginine methyltransferase;and PARP,poly ADP ribose polymerase.14Cell 150,July 6,2012ª2012Elsevier Inc.of these(targeting DNMTs,HDACs,and JAK2)have already been granted approval by the US Food and Drug Administra-tion(FDA).This success may suggest that the interest in epige-netic pathways as targets for drug discovery had been high over the past decade.However,the reality is that theﬁeld of drug discovery had been somewhat held back due to concerns over the pleiotropic effects of both the drugs and their targets. Indeed,some of the approved drugs(against HDACs)have little enzyme speciﬁcity,and their mechanism of action remains contentious(Minucci and Pelicci,2006).The belief and investment in epigenetic cancer therapies may now gain momentum and reach a new level of support following the recent preclinical success of inhibitors against BRD4,an acetyl-lysine chromatin-binding protein(Dawson et al.,2011; Delmore et al.,2011;Filippakopoulos et al.,2010;Mertz et al., 2011;Zuber et al.,2011).The molecular mechanisms governing these impressive preclinical results have also been largely uncovered and are discussed below.This process is pivotal for the successful progression of these inhibitors into the clinic. These results,along with the growing list of genetic lesions in epigenetic regulators,highlight the fact that we have now entered an era of epigenetic cancer therapies.Epigenetic Pathways Connected to CancerDNA MethylationThe methylation of the5-carbon on cytosine residues(5mC)in CpG dinucleotides was theﬁrst described covalent modiﬁca-tion of DNA and is perhaps the most extensively characterized modiﬁcation of chromatin.DNA methylation is primarily noted within centromeres,telomeres,inactive X-chromosomes,and repeat sequences(Baylin and Jones,2011;Robertson,2005). Although global hypomethylation is commonly observed in malignant cells,the best-studied epigenetic alterations in cancerare the methylation changes that occur within CpG islands, which are present in 70%of all mammalian promoters.CpG island methylation plays an important role in transcriptional regu-lation,and it is commonly altered during malignant transforma-tion(Baylin and Jones,2011;Robertson,2005).NGS platforms have now provided genome-wide maps of CpG methylation. These have conﬁrmed that between5%–10%of normally unme-thylated CpG promoter islands become abnormally methylated in various cancer genomes.They also demonstrate that CpG hypermethylation of promoters not only affects the expression of protein coding genes but also the expression of various noncoding RNAs,some of which have a role in malignant trans-formation(Baylin and Jones,2011).Importantly,these genome-wide DNA methylome studies have also uncovered intriguing alterations in DNA methylation within gene bodies and at CpG‘‘shores,’’which are conserved sequences upstream and downstream of CpG islands.The functional relevance of these regional alterations in methylation are yet to be fully deciphered, but it is interesting to note that they have challenged the general dogma that DNA methylation invariably equates with transcriptional silencing.In fact,these studies have established that many actively transcribed genes have high levels of DNA methylation within the gene body,suggesting that the context and spatial distribution of DNA methylation is vital in transcrip-tional regulation(Baylin and Jones,2011).Three active DNA methyltransferases(DNMTs)have been identiﬁed in higher eukaryotes.DNMT1is a maintenance methyl-transferase that recognizes hemimethylated DNA generated during DNA replication and then methylates newly synthesized CpG dinucleotides,whose partners on the parental strand are already methylated(Li et al.,1992).Conversely,DNMT3a and DNMT3b,although also capable of methylating hemimethylated DNA,function primarily as de novo methyltransferases to estab-lish DNA methylation during embryogenesis(Okano et al.,1999). DNA methylation provides a platform for several methyl-binding proteins.These include MBD1,MBD2,MBD3,and MeCP2. These in turn function to recruit histone-modifying enzymes to coordinate the chromatin-templated processes(Klose and Bird,2006).Although mutations in DNA methyltransferases and MBD proteins have long been known to contribute to developmental abnormalities(Robertson,2005),we have only recently become aware of somatic mutations of these key genes in human malig-nancies(Figure2).Recent sequencing of cancer genomes has identiﬁed recurrent mutations in DNMT3A in up to25%of patients with acute myeloid leukemia(AML)(Ley et al.,2010). Importantly,these mutations are invariably heterozygous and are predicted to disrupt the catalytic activity of the enzyme. Moreover,their presence appears to impact prognosis(Patel et al.,2012).However,at present,the mechanisms bywhich Figure2.Cancer Mutations Affecting Epigenetic Regulators of DNA MethylationThe5-carbon of cytosine nucleotides are methylated(5mC)by a family of DNMTs.One of these,DNMT3A,is mutated in AML,myeloproliferative diseases(MPD),and myelodysplastic syndromes(MDS).In addition to its catalytic activity,DNMT3A has a chromatin-reader motif,the PWWP domain, which may aid in localizing this enzyme to chromatin.Somatically acquired mutations in cancer may also affect this domain.The TET family of DNA hydroxylases metabolizes5mC into several oxidative intermediates,including 5-hydroxymethylcytosine(5hmC),5-formylcytosine(5fC),and5-carbox-ylcytosine(5caC).These intermediates are likely involved in the process of active DNA demethylation.Two of the three TET family members are mutated in cancers,including AML,MPD,MDS,and CMML.Mutation types are as follows:M,missense;F,frameshift;N,nonsense;S,splice site mutation;and T,translocation.Cell150,July6,2012ª2012Elsevier Inc.15these mutations contribute to the development and/or mainte-nance of AML remains elusive.Understanding the cellular consequences of normal and aber-rant DNA methylation remains a key area of interest,especially because hypomethylating agents are one of the few epigenetic therapies that have gained FDA approval for routine clinical use(Figure1).Although hypomethylating agents such as azaci-tidine and decitabine have shown mixed results in various solid malignancies,they have found a therapeutic niche in the myelo-dysplastic syndromes(MDS).Until recently,this group of disor-ders was largely refractory to therapeutic intervention,and MDS was primarily managed with supportive care.However,several large studies have now shown that treatment with azacitidine, even in poor prognosis patients,improves their quality of life and extends survival time.Indeed,azacitidine is theﬁrst therapy to have demonstrated a survival beneﬁt for patients with MDS (Fenaux et al.,2009).The molecular mechanisms governing the impressive responses seen in MDS are largely unknown. However,recent evidence would suggest that low doses of these agents hold the key to therapeutic beneﬁt(Tsai et al., 2012).It is also emerging that the combinatorial use of DNMT and HDAC inhibitors may offer superior therapeutic outcomes (Gore,2011).DNA Hydroxy-Methylation and Its Oxidation Derivatives Historically,DNA methylation was generally considered to be a relatively stable chromatin modiﬁcation.However,early studies assessing the global distribution of this modiﬁcation during embryogenesis had clearly identiﬁed an active global loss of DNA methylation in the early zygote,especially in the male pronucleus.More recently,high-resolution genome-wide mapping of this modiﬁcation in pluripotent and differentiated cells has also conﬁrmed the dynamic nature of DNA methylation, evidently signifying the existence of an enzymatic activity within mammalian cells that either erases or alters this chromatin modiﬁcation(Baylin and Jones,2011).In2009,two seminal manuscripts describing the presence of5-hydroxymethylcyto-sine(5hmC)offered theﬁrst insights into the metabolism of 5mC(Kriaucionis and Heintz,2009;Tahiliani et al.,2009).The ten-eleven translocation(TET1–3)family of proteins have now been demonstrated to be the mammalian DNA hydroxy-lases responsible for catalytically converting5mC to5hmC. Indeed,iterative oxidation of5hmC by the TET family results in further oxidation derivatives,including5-formylcytosine(5fC) and5-carboxylcytosine(5caC).Although the biological signiﬁ-cance of the5mC oxidation derivatives is yet to be established, several lines of evidence highlight their importance in transcrip-tional regulation:(1)they are likely to be an essential intermediate in the process of both active and passive DNA demethylation,(2) they preclude or enhance the binding of several MBD proteins and,as such,will have local and global effects by altering the recruitment of chromatin regulators,and(3)genome-wide mapping of5hmC has identiﬁed a distinctive distribution of this modiﬁcation at both active and repressed genes,including its presence within gene bodies and at the promoters of bivalently marked,transcriptionally poised genes(Wu and Zhang,2011). Notably,5hmC was also mapped to several intergenic cis-regu-latory elements that are either functional enhancers or insulator elements.Consistent with the notion that5hmC is likely to have a role in both transcriptional activation and silencing, the TET proteins have also been shown to have activating and repressive functions(Wu and Zhang,2011).Genome-wide mapping of TET1has demonstrated it to have a strong prefer-ence for CpG-rich DNA and,consistent with its catalytic function, it also been localized to regions enriched for5mC and5hmC. The TET family of proteins derive their name from the initial description of a recurrent chromosomal translocation, t(10;11)(q22;q23),which juxtaposes the MLL gene with TET1in a subset of patients with AML(Lorsbach et al.,2003).Notably, concurrent to the initial description of the catalytic activity for the TET family of DNA hydroxylases,several reports emerged describing recurrent mutations in TET2in numerous hematolog-ical malignancies(Cimmino et al.,2011;Delhommeau et al., 2009;Langemeijer et al.,2009)(Figure2).Interestingly,TET2-deﬁcient mice develop a chronic myelomonocytic leukemia (CMML)phenotype,which is in keeping with the high prevalence of TET2mutations in patients with this disease(Moran-Crusio et al.,2011;Quivoron et al.,2011).The clinical implications of TET2mutations have largely been inconclusive;however,in some subsets of AML patients,TET2mutations appear to confer a poor prognosis(Patel et al.,2012).Early insights into the process of TET2-mediated oncogenesis have revealed that the patient-associated mutations are largely loss-of-function muta-tions that consequently result in decreased5hmC levels and a reciprocal increase in5mC levels within the malignant cells that harbor them.Moreover,mutations in TET2also appear to confer enhanced self-renewal properties to the malignant clones (Cimmino et al.,2011).Histone ModiﬁcationsIn1964,Vincent Allfrey prophetically surmised that histone modiﬁcations might have a functional inﬂuence on the regulation of transcription(Allfrey et al.,1964).Nearly half a century later, theﬁeld is still grappling with the task of unraveling the mecha-nisms underlying his enlightened statement.In this time,we have learned that these modiﬁcations have a major inﬂuence, not just on transcription,but in all DNA-templated processes (Kouzarides,2007).The major cellular processes attributed to each of these modiﬁcations are summarized in Table1.The great diversity in histone modiﬁcations introduces a remarkable complexity that is slowly beginning to be ing transcription as an example,we have learned that multiple coexisting histone modiﬁcations are associated with activation,and some are associated with repression. However,these modiﬁcation patterns are not static entities but a dynamically changing and complex landscape that evolves in a cell context-dependent fashion.Moreover,active and repres-sive modiﬁcations are not always mutually exclusive,as evi-denced by‘‘bivalent domains.’’The combinatorial inﬂuence that one or more histone modiﬁcations have on the deposition, interpretation,or erasure of other histone modiﬁcations has been broadly termed‘‘histone crosstalk,’’and recent evidence would suggest that crosstalk is widespread and is of great bio-logical signiﬁcance(Lee et al.,2010).It should be noted that the cellular enzymes that modify histones may also have nonhistone targets and,as such,it has been difﬁcult to divorce the cellular consequences of individual histone modiﬁcations from the broader targets of many of these16Cell150,July6,2012ª2012Elsevier Inc.enzymes.In addition to their catalytic function,many chromatin modiﬁers also possess‘‘reader’’domains allowing them to bind to speciﬁc regions of the genome and respond to information conveyed by upstream signaling cascades.This is important, as it provides two avenues for therapeutically targeting these epigenetic regulators.The residues that line the binding pocket of reader domains can dictate a particular preference for speciﬁc modiﬁcation states,whereas residues outside the binding pocket contribute to determining the histone sequence speciﬁcity.This combination allows similar reader domains to dock at different modiﬁed residues or at the same amino acid displaying different modiﬁcation states.For example,some methyl-lysine readers engage most efﬁciently with di/tri-methyl-ated lysine(Kme2/3),whereas others prefer mono-or unmethy-lated lysines.Alternatively,when the same lysines are now acet-ylated,they bind to proteins containing bromodomains(Taverna et al.,2007).The main modiﬁcation binding pockets contained within chromatin-associated proteins is summarized in Table1. Many of the proteins that modify or bind these histone modiﬁ-cations are misregulated in cancer,and in the ensuing sections, we will discuss the most extensively studied histone modiﬁca-tions in relation to oncogenesis and novel therapeutics. Histone Acetylation.The Nε-acetylation of lysine residues is a major histone modiﬁcation involved in transcription,chromatin structure,and DNA repair.Acetylation neutralizes lysine’s posi-tive charge and may consequently weaken the electrostatic interaction between histones and negatively charged DNA.For this reason,histone acetylation is often associated with a more ‘‘open’’chromatin conformation.Consistent with this,ChIP-Seq analyses have conﬁrmed the distribution of histone acetyla-tion at promoters and enhancers and,in some cases,throughout the transcribed region of active genes(Heintzman et al.,2007; Wang et al.,2008).Importantly,lysine acetylation also serves as the nidus for the binding of various proteins with bromodo-mains and tandem plant homeodomain(PHD)ﬁngers,which recognize this modiﬁcation(Taverna et al.,2007).Acetylation is highly dynamic and is regulated by the competing activities of two enzymatic families,the histone lysine acetyltransferases(KATs)and the histone deacetylases (HDACs).There are two major classes of KATs:(1)type-B,which are predominantly cytoplasmic and modify free histones,and(2) type-A,which are primarily nuclear and can be broadly classiﬁedinto the GNAT,MYST,and CBP/p300families.KATs were theﬁrst enzymes shown to modify histones.The importance of theseﬁndings to cancer was immediately apparent,as one of these enzymes,CBP,was identiﬁed by its ability to bind the transforming portion of the viral oncoprotein E1A(Bannister and Kouzarides,1996).It is now clear that many,if not most,of the KATs have been implicated in neoplastic transformation,and a number of viral oncoproteins are known to associate with them.There are numerous examples of recur-rent chromosomal translocations(e.g.,MLL-CBP[Wang et al., 2005]and MOZ-TIF2[Huntly et al.,2004])or coding mutations (e.g.,p300/CBP[Iyer et al.,2004;Pasqualucci et al.,2011]) involving various KATs in a broad range of solid and hematolog-ical malignancies(Figure3).Furthermore,altered expression levels of several of the KATs have also been noted in a range of cancers(Avvakumov and Coˆte´,2007;Iyer et al.,2004).In some cases,such as the leukemia-associated fusion gene MOZ-TIF2,we know a great deal about the cellular conse-quences of this translocation involving a MYST family member. MOZ-TIF2is sufﬁcient to recapitulate an aggressive leukemia in murine models;it can confer stem cell properties and reacti-vate a self-renewal program when introduced into committed hematopoietic progenitors,and much of this oncogenic potential is dependent on its inherent and recruited KAT activity as well as its ability to bind to nucleosomes(Deguchi et al.,2003;Huntly et al.,2004).Despite these insights,the great conundrum with regards to unraveling the molecular mechanisms by which histone acetyl-transferases contribute to malignant transformation has been dissecting the contribution of altered patterns in acetylation on histone and nonhistone proteins.Although it is clear that global histone acetylation patterns are perturbed in cancers(Fraga Figure 3.Cancer Mutations Affecting Epigenetic Regulators Involved in Histone AcetylationThese tables provide somatic cancer-associated mutations identiﬁed in histone acetyltransferases and proteins that contain bromodomains(which recognize and bind acetylated histones).Several histone acetyltransferases possess chromatin-reader motifs and,thus,mutations in the proteins may alter both their catalytic activities as well as the ability of these proteins to scaffold multiprotein complexes to chromatin.Interestingly,sequencing of cancer genomes to date has not identiﬁed any recurrent somatic mutations in histone deacetylase enzymes.Abbreviations for the cancers are as follows: AML,acute myeloid leukemia;ALL,acute lymphoid leukemia;B-NHL,B-cell non-Hodgkin’s lymphoma;DLBCL,diffuse large B-cell lymphoma;and TCC, transitional cell carcinoma of the urinary bladder.Mutation types are as follows:M,missense;F,frameshift;N,nonsense;S,splice site mutation;T, translocation;and D,deletion.Cell150,July6,2012ª2012Elsevier Inc.17。

tpo35三篇阅读原文译文题目答案译文背景知识

tpo35三篇阅读原文译文题目答案译文背景知识阅读-1 (1)原文 (2)译文 (5)题目 (8)答案 (17)背景知识 (18)阅读-2 (21)原文 (21)译文 (24)题目 (27)答案 (36)背景知识 (36)阅读-3 (39)原文 (39)译文 (43)题目 (46)答案 (54)背景知识 (55)阅读-1原文Earth’ s Age①One of the first recorded observers to surmise a long age for Earth was the Greek historian Herodotus, who lived from approximately 480 B.C. to 425 B.C. He observed that the Nile River Delta was in fact a series of sediment deposits built up in successive floods. By noting that individual floods deposit only thin layers of sediment, he was able to conclude that the Nile Delta had taken many thousands of years to build up. More important than the amount of time Herodotus computed, which turns out to be trivial compared with the age of Earth, was the notion that one could estimate ages of geologic features by determining rates of the processes responsible for such features, and then assuming the rates to be roughly constant over time. Similar applications of this concept were to be used again and again in later centuries to estimate the ages of rock formations and, in particular, of layers of sediment that had compacted and cemented to form sedimentary rocks.②It was not until the seventeenth century that attempts were madeagain to understand clues to Earth's history through the rock record. Nicolaus Steno (1638-1686) was the first to work out principles of the progressive depositing of sediment in Tuscany. However, James Hutton (1726-1797), known as the founder of modern geology, was the first to have the important insight that geologic processes are cyclic in nature. Forces associated with subterranean heat cause land to be uplifted into plateaus and mountain ranges. The effects of wind and water then break down the masses of uplifted rock, producing sediment that is transported by water downward to ultimately form layers in lakes, seashores, or even oceans. Over time, the layers become sedimentary rock. These rocks are then uplifted sometime in the future to form new mountain ranges, which exhibit the sedimentary layers (and the remains of life within those layers) of the earlier episodes of erosion and deposition.③Hutton's concept represented a remarkable insight because it unified many individual phenomena and observations into a conceptual picture of Earth’s history. With the further assumption that these geologic processes were generally no more or less vigorous than they are today, Hutton's examination of sedimentary layers led him to realize that Earth's history must be enormous, that geologic time is anabyss and human history a speck by comparison.④After Hutton, geologists tried to determine rates of sedimentation so as to estimate the age of Earth from the total length of the sedimentary or stratigraphic record. Typical numbers produced at the turn of the twentieth century were 100 million to 400 million years. These underestimated the actual age by factors of 10 to 50 because much of the sedimentary record is missing in various locations and because there is a long rock sequence that is older than half a billion years that is far less well defined in terms of fossils and less well preserved.⑤Various other techniques to estimate Earth's age fell short, and particularly noteworthy in this regard were flawed determinations of the Sun's age. It had been recognized by the German philosopher Immanuel Kant (1724-1804) that chemical reactions could not supply the tremendous amount of energy flowing from the Sun for more than about a millennium. Two physicists during the nineteenth century both came up with ages for the Sun based on the Sun's energy coming from gravitational contraction. Under the force of gravity, the compressionresulting from a collapse of the object must release energy. Ages for Earth were derived that were in the tens of millions of years, much less than the geologic estimates of the lime.⑥It was the discovery of radioactivity at the end of the nineteenth century that opened the door to determining both the Sun’s energy source and the age of Earth. From the initial work came a suite of discoveries leading to radio isotopic dating, which quickly led to the realization that Earth must be billions of years old, and to the discovery of nuclear fusion as an energy source capable of sustaining the Sun's luminosity for that amount of time. By the 1960s, both analysis of meteorites and refinements of solar evolution models converged on an age for the solar system, and hence for Earth, of 4.5 billion years.译文地球的年龄①希腊历史学家希罗多德是最早有记录的推测地球年龄的观察家之一，他生活在大约公元前480年到公元前425年。

【高三二模】上海市浦东新区2023届高三英语二模及答案

上海市浦东新区2023届高三英语二模Listening Comprehension Section ADirections: In Section A, you will hear ten short conversations between two speakers. At the end of each conversation, a question will be asked about what was said. The conversations and the questions will be spoken only once. After you hear a conversation and a question about it, read the four possible answers on your paper, and decide which one is the best answer to the question you have heard.1. A. His suit is too old to wear. B. He doesn’t want to wear a suit.C. He’ll go shopping with the woman.D. He doesn’t want to buy new clothes.2. A. He will look at the timetable first.B.10:30 is a perfect time for the reservation.C.The barber shop is fully booked on Saturday.D.No other customers plan to make appointments at 10:30.3. A. She didn’t buy the ticket. B. The ticket was expensive.C. There are still a few tickets left.D. She doesn’t know how much the ticket cost.4. A. He is quitting the orchestra for academic reasons.B.He is blamed for being a member of the orchestra.C.He doesn’t enjoy being a member of the orchestra.D.He prefers to study rather than travel and perform.5. A. Have a bigger breakfast. B. Make time for lunch in her schedule.C. Take only morning classes next semester.D. Change her schedule after she eats lunch.6. A. She doesn’t know where the calculator is.B.She expects the man to have the calculator repaired.C.She’d like the man to return the calculator by tonight.D.She’s angry for the man forgetting to bring the calculator.7. A. She has lost the credit card. B. They can’t buy meals at a low price.C. None of the restaurants is worth a try.D. The meals are less expensive than expected.8. A. The location of the session has been changed.B.She will definitely go to the session this evening.C.She’ll probably be too tired to walk to the session.D.The session might be canceled because of a heavy snow.9. A. He is usually not bad-tempered. B. He doesn’t like the man.C. He started the semester in a bad mood.D. He has few responsibilities.10. A. The girl may realize her dream with social media.B.The girl can present and record fashion on social media.C.The girl should first learn to make proper use of social media.D.The girl isn’t qualified as an influencer for her lack of taste in fashion.Section BDirections: In Section B, you will hear two short passages and one longer conversation, and you will be asked several questions on each of the passages and the conversation. The passages and the conversation will be read twice, but the questions will be spoken only once. When you hear a question, read the four possible answers on your paper and decide which one would be the best answer to the question you have heard.Questions 11 through 13 are based on the following passage.11. A. A different angle. B. A sharp mind.C. Various ways of workout.D. Exposure to different cultures.12. A. He will accept the new environment easily.B.He is likely to struggle with the travel budget.C.He will have to organize different daily routine.D.He may find road trips more appealing than beach views.13. A. To show travelling may bring health risks.B.To show travelling allows you to meet new people.C.To show travelling can change a person’s outlook on life.D.To show travelling gives you a chance to challenge new things.Questions 14 through 16 are based on the following passage.14. A. To detect potential danger in cold places.B.To generate more heat within their bodies.C.To keep their babies warm in breeding seasons.D.To get rid of extra heat with bigger skin surface.15. A. Wood mice. B. Bats in warm climates.C. Bird species.D. Kangaroos in Australia.16. A. Animals cope with body changes. B. Joel Allen’s rule is out of date.C. Climate change poses threat to species.D. Animals adapt to a warmer world.Questions 17 through 20 are based on the following conversation.17. A. By using cash. B. By entering a password.C. By scanning the code.D. By using a tap-and-go card.18. A. Because it touches the card reader.B.Because it uses the password.C.Because it has a built-in signal receiver.D.Because it receives the flying data.19. A. The bank will cover its clients against the loss.B.Every transaction is completed within half a second.C.People must enter their ID card number for continual use.D.Each payment is restricted to a certain amount of money.20. A. Look for his wallet. B. Apply for a tap-and-go card.C. Borrow cash from the woman.D. Stick to buying things in cash.I.Grammar and Vocabulary Section ADirections: After reading the passage below, fill in the blanks to make the passage coherent and grammatically correct. For the blanks with a given word, fill in each blank with the proper form of the given word; for the other blanks, use one word that best fits each blank.Emily Dobek is a seventh-grader at East Prairie Elementary School. Recently she (21) (win) a national prize by designing a space station for travelling to Mars.Dobek traces her interest in space and the universe back (22) Grade Three when she and her father watched a blood moon — a total lunar eclipse ( 月食 ) — on the roof of their house. She says that night watching the lunar eclipse awakened her passion (23) has yet to run out of fuel.So (24) her teacher, Andrew Smeeton, received information about the national challenge, she immediately had one student in mind.“I knew she would love the challenge and that she would go way beyond in her research,” Smeeton said. “When she started, bone density (骨密度) of astronauts (25) (research) immediately to figure out how to survive on Mars.”According to Dobek’s design, the Mars Storage Station (MSS) will be built (26) (accommodate) the need for sufficient supplies. She explains how her spacecraft —the Adventure —will be joined to a space station before flying to the MSS to load supplies. Her design includesthe Self Growing Farm, and she details (27) it would work with elements on Mars.Then there is physical and leisure activity for the astronauts under Dobek’s design. A simulator( 模拟器) allows astronauts to choose their exercise machine and virtual reality environment. Rooms with circular ceilings allow astronauts to watch (28) (download) shows and even see places on Earth, such as their homes.Chief among her immediate goals, she said, is to inspire (29) with this project. “I want to tell other kids to follow their passions,” Dobek said, “(30)they want to do, they should kind ofjust push for it. They should always try their best.”Section BDirections: Complete the following passage by using the words in the box. Each word can only be used once. Note that there is one word more than you need.Japan saw 799,728 births in 2022, the lowest number on record. That number has nearly halved in the past 40 years; by contrast, Japan recorded more than 1.5 million births in 1982. Japan also reported a(n) 31 high for post-war deaths last year, at more than 1.58 million. Deaths have 32 births in Japan for more than a decade, posing a growing problem for leaders of the world’s third-largest economy. They now face a ballooning elderly population, along with a shrinking workforce to 33 pensions and health care as demand from the aging population increases. Japan’s population has been in 34 decline since its economic boom of the 1980s and stood at 125.5 million in 2021. Its death rate of 1.3 is far below the rate of 2.1 required to maintain a stable population, in the 35 of immigration.The country also has one of the highest life expectancies in the world; in 2020, nearly one in 1,500 people in Japan were aged 100 or older. These concerning trends resulted in a warning from Prime Minister that Japan is “on the edge of not being able to maintain social 36 ” and Japan “simply cannot wait any longer” in solving the problem of its low birth rate. A new government agency will be set up to focus on the issue, with Prime Minister saying that he wants the government to 37 its spending on child-related programs.But money alone might not be able to solve the complex problem, with various social factors contributing to the low birth rate. Japan’s high cost of living, limited space and lack of child care support in cities make it difficult to raise children, meaning fewer couples are having kids. Urban couples are also often far from 38 family in other regions, who could help provide support. In 2022, Japan was ranked one of the world’s most expensive places to raise a child. And yet, thecountry’s economy has slowed down since the early 1990s, meaning frustratingly low wages and little 39 mobility.The average real annual household income declined from $50,600 in 1995 to $43,300 in 2020. Attitudes toward marriage and starting families have also 40 in recent years, with more couples putting off both during the pandemic.II.Reading ComprehensionSection ADirections: For each blank in the following passage there are four words or phrases marked A, B, C and D. Fill in each blank with the word or phrase that best fits the context.A recent series of studies examined the role of talent in the sports world. They focused on three different sports: World Cup soccer, professional basketball, and professional baseball. The results were mixed. For soccer and basketball, the studies revealed that adding talented players to a team is indeed a(n) 41 strategy, but only up to a point. Performance 42 when about 70% of the players were considered top talent. Above that level, the team’s performance began to decline. Interestingly, this trend was not evident in baseball, where additional 43 talent continued to enhance the team’s performance. (Figure 1 and 2)In looking for an explanation for the different results for different sports, the researchers 44 one important factor — the extent to which a good performance by a team requires its members to coordinate (协调) their actions. This task 45 distinguishes baseball from basketball and soccer.In baseball, the performance of individual players is 46 teammates than in soccer and basketball. The researchers concluded that when, during the course of play, task interdependence is high, team performance will47 when there is too much talent in the group. When task interdependence is lower, 48 , individual talent will have a positive effect on team performance.One explanation for this phenomenon is not so far from the pecking order (等级排序) situation among chickens. If a basketball star is pursuing his own personal goals, 49 , trying to gather a high personal point total, he may be less 50 as a team player. He may take a shot himself when it would be better to pass the ball to a teammate, thus making the team’s overall performance suffer. “There is no51 in TEAM,” young children learning to play team sports are often told. Apparently stars 52 follow this basic principle of sportsmanship.Another possibility is that when there is a lot of talent on a team, some players may begin to 53 . This is referred to as the Ringelmann effect. Ringelmann conducted an experiment in which he asked two, three, four, and up to 28 people to participate in a game of tug-of-war. He measured how much force each person used to pull the rope. He found that whenever he added a person to the team, everyone else pulled with less force.54 the ideal team — for sports, business, science, or entertainment — is more complicated than simply hiring the best talent. An A-team may require a 55 — not just A players, but a few generous B players as well.41. A. sensible B. partial C. alarming D. attainable42. A. faded B. peaked C. evolved D. proceeded43. A. team B. creative C. academic D. individual44. A. identified B. overlooked C. considered D. concealed45. A. explanation B. conclusion C. discussion D. interdependence46. A. more suitable for B. more critical to C. less dependent on D. less involved in47. A. swing B. suffer C. endure D. function48. A. in principle B. in a sense C. in other words D. on the other hand49. A. as a rule B. by contrast C. for example D. as a matter of fact50. A. stressed B. genuine C. sensitive D. generous51. A. I B. HE C. THEY D. WE52. A. closely B. rarely C. humbly D. jointly53. A. make less effort B. cause more trouble C. take less advantage D. attach more importance54. A. Inspiring B. Intensifying C. Gathering D. Training55. A. exploration B. balance C. stability D. flexibilitySection BDirections: Read the following three passages. Each passage is followed by several questions or unfinished statements. For each of them there are four choices marked A, B, C and D. Choose the one that fits best according to the information given in the passage you have just read.(A)It was a winter afternoon when, rushing to attend the final show of my art school degree, I caught the heel of my boot on the edge of a pavement. Suddenly, I was flying through the air. Ifthe past two years studying photography had taught me anything, it was an appreciation of how things can change in a thousandth of a second. Light, shadow, colours, all are in a constant state of flux (不断的变动) — as is life. And since crash-landing onto my left shoulder, I have been living through the truth of this wisdom.That day, doctors diagnosed a cracked bone. It was only the next morning when, instinctively, I tried to capture some spectacular sunlight streaming into my kitchen, that I had to face the harsh reality: I could no longer lift my camera, let alone use it. Later that week, a hospital appointment confirmed my worst fear — the arm needed total rest.Soon, I became cantankerous and impatient. I couldn’t travel, I couldn’t go anywhere much. Surfing online, I came across the concept of gratitude interventions and their role in boosting mood and wellbeing. A Californian psychologist, Sonja Lyubomirsky, has pioneered research into using a daily photography practice as a tool for enhanced gratitude. Her instructions are simple, but not necessarily easy. Take photographs throughout the day of things that are central to who you are. Take at least five photos a day. Initially, it felt like a demanding task. But reading how participants assigned to the gratitude interventions had experienced enhanced positive emotions, I decided to persevere.Pain forced me to slow down, because capturing a single iPhone photo was painful. And, yet, the struggle to find anything to feel grateful about, and then to record it, started to dramatically improve both my mood and my images. I began to photograph the most boring details of my days, from my breakfast cup to a red pepper reflected in the window. Despite everything, I found I could find magic in the ordinary. “Life seems repetitive and boring when you don’t notice the uniqueness of each moment and the constant subtle changes that are going on all around you,” writes Andy Karr in a wonderful book o n photography. I agree, but don’t just take my word for it — experience it for yourself.56.What happened to the writer on the winter afternoon?A.She went to her classmate’s degree show in a hurry.B.She tripped over and broke her shoulder bone.C.She was taught an unforgettable lesson on photography.D.She took a photo of a tragic crash-landing to be on show.57.The underlined word “cantankerous” in paragraph 3 is closest in meaning to .A.suspicious of the hospital diagnosisB. desperate to have my injury treatedC. enthusiastic about boosting wellbeingD. bad-tempered and always complaining58.The writer photographed the boring life routine because .A.underlying magic consisted in daily affairsB.gratitude fuelled a struggle against boredomC.it was central to the essence of photographyD.she felt like being assigned demanding tasks59.Which of the following might be the best title for the passage?A.Express Gratitude to WinterB. Become a Master of PhotographyC. Witness Rebirth out of InjuryD. Picture this Beauty in the OrdinaryReviewsFilter byMost commentsRating Newest ENTERTAINMENT | RESTAURANTS | THEATRE | FILM | MUSIC | EXHIBITIONSA notable highlight of the show was the real confidence of the singing. Sam Hall was ajoy to watch, with perfect comic timing, as was Emma Williams, thoroughlybelievable and convincing in her role. These two young talents stole the show , inmy opinion. The only disappointments were the dancing, which showed a lack of originality, and the opening scene, which fell a little flat. Despite the occasional technical flaws, this was a highly enjoyable and greatly impressive production, which the company should be proud of.I was really looking forward to Jonathan Baker’s latest, which is set in an imagined,but realistic, London of the near future. But I found this new effort was let down by theslightly one-dimensional characterization, and the writing is below standard forthe most part: some of the early scenes between Martha and her husband are slightly boring. The superb characterization and ambition that Baker demonstrated in his previous novels seem to be missing here. Baker’s commitment to describing the lives of ordinary people is admirable, but the whole thing is lacking in energy.This is episode number three in the nearly twenty-year-old series, delivering a very attractive andinteresting story and loads of comedy. There is some strong writing and voice acting, but the newepisode chooses to go for a linear (线性的) narrative, with some puzzles included along the way,which is less involving than the theme of exploration and conversation which previous episodes havedepended on. Besides, the puzzles are not particularly engaging, and many of them have been seenbefore in other adventure games. The visuals are extremely impressive, of course, as we have come to expect, this time featuring venues in Catalonia. But overall, a slight disappointment.60. The underlined phrase “stole the show ” most probably means .A. disappointed the producerB. ruined the whole performanceC. attracted the most attentionD. exhibited excessive confidence61. Which of the following statements about Jonathan Baker is TRUE ?A. He excels in one-dimensional characterization.B. His novels center around ordinary people’s lives.C. His novels show consistent super characterization and ambition.D. He is passionate about presenting realistic images of future London.62. The puzzles in episode number three .A. are integrated in the narrativeB. are appealing to the audienceC. deal with the theme of explorationD. are absent in other adventure gamesPlugs across AmericaThe United States has around 150,000 fuel stations to refill fossil-fuel-burning vehicles. Despite the rapid growth of all-electric vehicles in America — 400,000 of them were sold in 2021, up from barely 10,000 in 2012 — the country has only 6,000 fast electric charging stations, the kind that can rapidly charge a battery-powered car.A glance at America’s charging map reveals a lot of charging deserts. This makes sense, as EVs (electric vehicles) still represent less than 3% of new car sales. Large cities have a growing number of fast chargers, but not nearly enough to accommodate so many EVs. Away from cities, these chargers are along interstate highways closely enough to allow electric cars safe passage. Otherwise, they are nearly nonexistent in rural America. And EV stations have a problem that gas stations don’t: “Even the fastest T esla supercharger is still going to take 15 minutes to put a couple hundred miles on the vehicle,” says Jeremy Michalek, a professor at Carnegie Mellon University.Michalek says American charging facilities fall far behind what’s needed for the whole count ry to transition to electric driving. On the bright side, there is time to catch up, because not all Americans will embrace EVs at once. Most early adopters were those with access to a charger at home in their garage or parking space. Those owners can wake up with a full battery and only need to rely on public chargers when they leave town on an extended trip. But as the country gets to higher levels of EV adoption, the current facilities won’t be enough. That is why Michalek says the US needs to prioritize increasing the number of chargers at rest stops along well-traveled highways, especially as more people use electric cars for summer-time road trips.“As we get to higher levels of EV adoption, if we don’t have enough chargers for peak demand, the wait ti mes are going to be unlike what we see with gas stations,” he says.Charging dead zones will be larger as more Americans consider an EV. Renters who do not have the option to install a home charger will be hesitant to go fully electric until they can feel confident a public plug will be there when they need it. And as more households drive only electric vehicles, it will be crucial that people can get to all the places they want to go.In the best case, Michalek envisions public-private cooperation to build a national charging network. The US government has promised to install plugs throughout rural areas, while companies constructing charging stations across America will have a strong motivation to fill in the country’s biggest cities. After all, companies like Electrify America, EVgo, and ChargePoint charge customers of energy they use.63.It can be learned from the 2nd paragraph that .A.there is a shortage of charging stations in the rural areas ofAmericaB.it takes about 15 minutes for an average charger to charge a battery-powered carC.more electric vehicles are sold than fossil-fuel burning cars in large cities in AmericaD.there are enough chargers in America considering the limited sales ofnew electric vehicles64.Which of the following statements would Michalek most probably agree with?panies setting up charging stations are hesitant to go electric.B.Those who already have a home charger don’t have to find a public plug.C.Top priority needs to be given to adding more charging stations across the country.D.There is enough time to establish a charging network, because not many EVs are used.65.What can be inferred about the renters?A.Some renters don’t have the intention to go electric.B.Some renters might not be authorized to install a home charger.C.As more renters are unwilling to use public plugs, the charging dead zones are growing.D.Some renters might not have enough confidence in the public plugs for the safety reasons.66.Who does Michalek expect to work together to establish the charging network nationwide?A.The government and some companies.B. The local government and every household.C. The charging facility providers and every family.D. The federal government and the local rural government.Section CDirections: Read the following passage. Fill in each blank with a proper sentence given in the box. Each sentence can be used only once. Note that there are two more sentences than you need.A.In reality gardens are anything but natural.B.What are the things they have been attracted to?C.They are idealized landscapes with all the mud, pests and dead plants edited out.D.How much better a place the planet would be if gardening was our outlet for this need!E.Much like agriculture, gardening is a universal human desire coded into our cultural DNA.F.The calmness created by owning a tiny green space under my control has a powerful effect on my mind.As a botanist who studies our cultural relationship with plants, I am forever fascinated with what draws people to gardening.Admittedly, connecting with the natural world might seem like an obvious motivation,and undoubtedly it is a key part of the attraction. 67 If they were, we’d abandon anyattempts at design, planting or care and watch how walls of weeds slowly gave way to themass of bushes. But that wouldn’t be gardening, of course, because for all their diversity, theone thing that all gardens have in common is how unnatural they are. 68 Dazzlingplants, water features and glorious blooms is all interconnected well beyond what would naturally occur. Whether it is green lawns created in the driest deserts or a tropical paradise on a stormy North Atlantic island, they are all about shaping the natural world to fit our idea of what it “should” be.As I work on my tiny terrariums ( 玻璃花园) on dark February nights, something magical happens to my brain.69 In a world that has become increasingly uncertain, people are often fuelled by the same psychological desire: the instinctive need to have a bit of control amid chaos.As our world becomes more and more unpredictable and often frightening, gardening seems to be able to appeal to and reach out to a whole new generation, often against all odds.Of course, gardening isn’t the only thing people turn to. The rise of culture conflict s and fixation on body image have also been widely documented as being driven by a psychological need to feel a degree of certainty, control and safety. However, I can’t help but think of these alternatives: 70III.Summary WritingDirections: Read the following passage. Summarize the main idea and the main point(s) of the passage in no more than 60 words. Use your own words as far as possible.71.A plan to restore green spacesThe UK government has revealed a plan to protect and restore England’s wildlife. It focuses on at-risk species by making canals, rivers and streams cleaner and expanding green spaces.The new Environmental Improvement Plan sets goals to create or restore more than 5,000 square kilometres of wildlife habitats across England and restore 400 miles of rivers. It will create or expand 25 national nature reserves. New woodland will also be planted alongside rivers. At the moment, access to green spaces is not equal across the UK. Around 4% of people live more than 10 minutes away from their nearest park. The Environmental Improvement Plan aims to make sure households in England are within a 15-minute walk to a green space.As well as helping more people to get close to nature, the plan should increase England’s biodiversity. A Species Survival Fund will be set up to help some of England’s most endangered animals, such as red squirrels (松鼠) and water rats. The Government has set targets to boost these species by 2030. There are also targets to reduce food waste, glass, metal, paper and plastic by 2028, and to improve the quality of water in rivers.New rules mean that the Government will have to consider the environmental effects of any policy it puts forward. These goals are part of a 25-year plan that was launched in 2018. The aim of the plan is to improve the environment “within a generation”, which is roughly 25 years.Although lots of people have welcomed the plan, not everyone is impressed. Paul de Zylva, from the charity Friends of the Earth, said it wasn’t clear enough how the goals would be met and that many of them were like promises the Government had already made but not yet delivered.IV.TranslationDirections: Translate the following sentences into English, using the words given in the brackets.72.有了无人机，救援人员就可以安全地评估灾区的受灾状况。

epigenetics文献抄读PPT精品文档

.
23
Third, inflammation—a driver of the formation, progression, and rupture of atherosclerotic plaques—has also been associated with hypermethylation.
.
24
Whether epigenetic changes are causally related to the pathogenetic features in the lesions, or whether they merely represent a consequence of the ongoing pathological process remains unclear.
The genomic information is the same in all our cells and during our entire lifespan, the epigenomic information varies from cell to cell and during the lifetime of the individual.
.
18
An Intreresting Study
Phenotypic alterations during adulthood may be explained by exposure to adverse environmental conditions in utero. Groundbreaking work elucidating this mechanism in humans came from Heijmans and coworkers, who studied individuals prenatally exposed to famine during the Dutch Hunger Winter in 1944/45.

细胞视黄酸结合蛋白与肿瘤相关研究.pdf

异常甲基化与周期蛋白D1(cyclin D1)的高表达存在良
好的相关性[19]。CRABP1基因异常甲基化随后产生
的表达缺失，最先报道出现在乳突性甲状腺癌组织、
一株结肠癌细胞和食道鳞状细胞癌组织[20,21]。通过
用甲基转移酶抑制剂5-脱氧氮杂胞苷(5-Aza-CdR)干
预而食管鳞状细胞癌发生CRABP1表达逆转。同时
衍生物，是重要的核受体家族成员的配体，是目前
发现的诱导分化剂中最重要的一种，对多种组织、
细胞均有很强的诱导分化作用，被广泛用于肿瘤的
化学治疗。由于视黄酸的化学性质不够稳定且为脂
溶性，因此在其吸收、转运和分泌的过程中必须和
特殊的蛋白质相结合。其生理功能主要由两类蛋白
质介导，即：视黄酸受体和视黄酸结合蛋白。视黄
有时延伸到第一或第二内含子[12]。
由于在许多肿瘤中存在CRABP基因异常甲基
化，CRABP1和CRABP2成为常见的分子靶标.. [13-15]。
文献报道[13,16-18]，在甲状腺肿瘤、卵巢癌、结肠癌、
食道磷癌中普遍存在CRABP1基因启动子异常甲基
化，可能为候补抑癌基因。在结肠癌中.. CRABP1的
食管鳞状细胞癌组织也检测到CRABP1基因CpG位
点甲基化。通过对食道磷癌细胞诱导CRABP1表达，
肿瘤细胞增殖受到抑制[14]。肝细胞癌.. CRABP1基因
CpG 位点异常甲基化与患者低生存率存在相关性，
可以作为肝细胞癌的诊断和预后判别的一个生物学
指标[22]。相似地，在缺乏CRABP1蛋白的食管鳞癌
上视黄酸核受体之间互相作用的重要物质。本文主
要讨论视黄酸结合蛋白与肿瘤相关的研究进展。

Cancer Epigenetics_ A Brief Review

AbstractCancer is a disease that results from the successive accumu-lation of genetic and epigenetic alterations. Despite intense study, many unanswered questions about the nature of the contribution of epigenetic changes to carcinogenesis remain. In this review, we describe principles of epigenetics as they relate to our current understanding of carcinogenesis. There are a number of in vivo models of speciﬁ c pathways of car-cinogenesis that are very useful for the characterization of epigenetic mechanisms that link environmental exposures or genetic susceptibility and cancer progression. Because epi-genetic alterations are thought to be reversible, they offer great promise for treatment of cancer. The use of animal models to evaluate the effects of decitabine and zebularine has elucidated the mechanisms of action and indicated the potential for these types of treatment. Ultimately, the great-est challenge lies in the integration of laboratory and epide-miologic data to best prevent and treat this deadly disease.Key Words: cancer; chromatin; epigenetics; histones; mechanisms; methylationIntroductionThe ﬁ eld of cancer epigenetics has thrived on discover-ies from in vitro, in vivo, and human clinical and epi-demiologic studies. Results from these complimentary approaches have challenged the classic view of cancer, which has traditionally been hypothesized as a disease that results from the successive accumulation of genetic altera-tions in oncogenes and tumor-suppressor genes, which leads to uncontrolled cell growth. It is now appreciated that epi-genetic alterations contribute to carcinogenesis and a mechanis-tic link exists between environmental and dietary exposures and disease. Despite the rapidly developing breadth ofknowledge in this ﬁ eld, many questions remain to under-stand the contribution of epigenetics to the carcinogenic pro-cess. Do environmental toxicants induce epigenetic changes to inﬂ uence the initiation or promotion of cancer? Can epigenetic changes be initiators in the carcinogenic process, or are they a consequence of cellular transformation and genetic alterations? Most important, because epigenetic changes are largely thought to be reversible, can epigenetic therapy offer an avenue for cancer treatment? In this review, we will describe epigenetic changes in the context of carci-nogenesis and offer examples of models of cancer progres-sion and treatment that allow for the elucidation of the role epigenetics plays in cancer progression and treatment. First, we will introduce principles of epigenetic mecha-nisms in light of carcinogenesis. Then we will discuss how animal models contribute to our understanding of the contri-bution of epigenetics to understanding distinct pathways of carcinogenesis.DNA MethylationOne of the most extensively studied epigenetic mechanisms is the methylation of the ﬁ fth carbon of a cytosine nucleotide to create 5-methylcytosine (5mC 1). The methyl group of 5mC lies in the major groove of the double helix and can interfere with transcription factor binding to prevent gene expression. Additionally, there is a class of methylated DNA-binding proteins, speciﬁ cally MECP2 and the MBD family of proteins, which bind to methylated cytosines and repress gene transcription by blocking transcription factors. Cytosine pairs with guanine by means of a phosphate group, and this dinucleotide (CpG) has been a major focus of epi-genetic research because of its capacity to directly silence gene expression, particularly with respect to tumor-suppressor genes in carcinogenesis. CpG sites are unevenly distributed throughout the genome, concentrating in repetitive sequences such as tandem and interspersed repeats, distal gene regula-tory regions, and CpG islands (Bird 2002; Ehrlich 2009; Ehrlich et al. 1982). DNA methylation is highly dysregu-lated in cancer. Aberrant patterns of methylation arise, leading to hypomethylation of distal regulatory regions and repeti-tive elements along with hypermethylation of CpG islandsShami Virani, Justin A. Colacino, Jung H. Kim, and Laura S. RozekCancer Epigenetics: A Brief Review1Abbreviations that appear ≥3x throughout this article: 5mC,5-methylcytonsine; DNMT, DNA methyltransferase; H DAC, histone deacetylase.Shama Virani, BS, is a graduate student; Justin A. Colacino, MPH , is a graduate student; Jung H. Kim, PhD, is a postdoctoral fellow; and Laura S. Rozek, PhD, is an assistant professor, all at the Department of Environmental H ealth Sciences, University of Michigan School of Public H ealth, Ann Arbor.Address correspondence and reprint requests to Dr. Laura Rozek, University of Michigan School of Public Health, Department of Environmental Health Sciences, 6630 SPH Tower, 1415 Washington Heights, Ann Arbor, MI 48109 or email rozekl@.(Bird 2002; Ehrlich 2009). It has been known for some time that tumors from different sites display distinct CpG meth-ylation proﬁles (Esteller et al. 2001) and exhibit distinct pathways of carcinogenesis within tumor sites (Sartor et al. 2011; Shen et al. 2007). However, how CpG methylation re-lates to epidemiologic and clinical characteristics is not yet fully understood.Loss of DNA methylation was one of the ﬁ rst epigenetic changes described in human cancer. The ﬁ rst study of DNA methylation in human tumor tissue, using methylation-sensitive restriction enzyme digestion paired with Southern blotting, re-vealed that tumor tissues had a lower proportion of methylated cytosine than normal tissues (Feinberg and V ogelstein 1983). Shortly thereafter, whole genome enzymatic digests paired with high-performance liquid chromatography were used to show that overall 5mC content was inversely associated with tumor progression (Gama-Sosa et al. 1983). Since the publi-cation of these seminal studies, almost every type of cancer has been shown to have an overall deﬁ ciency of 5mC com-pared with normal tissue, occurring speciﬁ cally in intergenic repetitive regions, which increases genomic instability and promotes the progression of tumorigenesis.Repetitive ElementsRepetitive elements make up about half of the genome and are normally heavily methylated. In cancer, hypomethyl-ation of these genomic regions make up a large percentage of 5mC loss in cancers (Ehrlich 2009; Lander et al. 2001). Centromeric tandem repeats, adjacent-centromeric (juxta-centromeric) tandem repeats, and short- (Alu) and long-interspersed elements (LINE-1) are the most frequently studied repetitive elements in cancer that are found to be hypometh-ylated. Tandem repeats at and near the centromere play a role in keeping the DNA packaged into heterochromatin at the point of sister chromatid association, allowing for chromo-some stability. Hypomethylation of these regions can lead to chromatin decondensation and chromosome rearrangements through unstable translocations, leading to widespread ge-nomic instability (Eden et al. 2003). For example, in vitro experiments conducted to knock out DnmtI, a DNA methyl-transferase (DNMT1), in murine embryonic stem cells showed an increase in chromosomal translocations (Chen et al. 1998). Additionally, loss of heterochromatin can affect the copy number of genes involved in tumorigenesis (Eden et al. 2003; Ehrlich 2009; Kokalj-V okac et al. 1993). Hypometh-ylation of tandem repeats at or near centromeric regions contributes to tumorigenesis by unraveling the structure of the genome and amplifying genomic rearrangements (Kokalj-V okac et al. 1993). H owever, chromosomal abnormalities are not the only process that occurs in tumor cells, and this is signiﬁ ed by other repetitive elements that are found to be hypomethylated in cancer.Alu and LINE-1 elements are retrotransposons—that is, genetic elements that have the ability to amplify themselves by means of RNA intermediates. These elements together make up about 30% of the genome (Chen et al. 1998). There are more than 500,000 LINE-1 elements in the ge-nome, although because of truncations, mutations, and dele-tions, only about 100 copies are functional. There are more than 1 million copies of Alu (Batzer and Deininger 2002). Both elements contain promoter sequences, which indicates their capacity for gene transcription if unregulated (Cordaux and Batzer 2009; Kazazian and Goodier 2002). In normal tissues, LINE-1 and Alu elements are silenced through DNA methylation; these elements are hypomethylated in cancer (Bird 2002; Thayer 1993). For example, it has been shown that hypomethylation of LINE-1 elements occurs in colorec-tal cancer early in tumorigenesis, disrupting normal patterns of gene expression (Suter et al. 2004). Hypomethylation of LINE-1 sequences has also been shown in urothelial and hepatocellular cancers (Jurgens et al. 1996; Takai et al. 2000). Alu elements, although less studied, have been shown to be hypomethylated with LINE-1 elements in prostate adenocarcinomas (Cho et al. 2007), pancreatic endocrine tumors, and carcinoid tumors (Choi et al. 2007). H ypo-methylation of LINE-1 and Alu elements was found to be strongly linked to genomic instability early in non-small-cell lung cancer, playing a potential role in the formation of lung neoplasias (Daskalos et al. 2009).Hypomethylation of these elements and their consequent activation has many implications for tumorigenesis. They can cause insertional mutagenesis and potentially disperse processed pseudogenes, which occur when spliced messen-ger RNA is reverse transcribed by L1 reverse transcriptase and reinserted into the genome. Transduction can occur when LINE-1 elements mobilize their 3’ and 5’ ends sepa-rately and carry them to new genomic locations. Rearrange-ments also take place when Alu and LINE-1 elements insert to potentially cause deletions or inversions in the genome (Kazazian 2004; Kazazian and Goodier 2002). This results in chromosomal abnormalities, aberrant gene expression, and overall genomic instability.Other targets of hypomethylation are the CpG sites found in promoter regions that are outside CpG islands. These are found in promoter regions of normally repressed genes and are methylated in normal cells (Bird 2002; Ehrlich 2002, 2009). In cancer cells, these regions are found to be hypo-methylated, affecting repression of normally silenced genes. For example, imprinted genes are normally monoallelically expressed; however, hypomethylation of CpG sites in pro-moter regions of these genes leads to their biallelic expres-sion and is linked to carcinogenesis (H olm et al. 2005). Hypomethylation of promoter regions leads to activation of otherwise silenced genes, promoting aberrant gene expres-sion, disruption of normal cellular processes, and overall ge-nomic instability.DNA MethyltransferasesAlthough cancer genomes are globally hypomethylated, some regions of the genome are found to be hypermethylated. Themechanism through which this occurs is DNMT overex-pression. DNA methylation is regulated by DNMTs that act as the methyl donors to the cytosine residue. Although ﬁ ve members of the DNMT family have been discovered, only DNMT1, DNMT3a, and DNMT3b are known to contribute to the global pattern of cytosine methylation (Kulis and Esteller 2010; Okano et al. 1999). DNMT1 is classiﬁ ed as a mainte-nance protein and appears to be involved in methylation of CpG sites in newly synthesized daughter DNA strands to match the methylation pattern of the parental strand. It also directly binds histone deacetylases to promote heterochroma-tin formation and silence gene activity (Bird 2002; Kulis and Esteller 2010; Li et al. 1992). DNMT3a and DNMT3b are classiﬁ ed as de novo enzymes that are essential for establish-ment of mammalian development methylation patterns during embryogenesis and germ-cell development (Kulis and Esteller 2010).DNMT overexpression seems to be a common character-istic of tumors, although only DNMT1 and DNMT3a/b are implicated in tumorigenesis (Issa et al. 1993). It has been proposed that these enzymes cooperate to initiate and main-tain de novo methylation in cancer cells (Rhee et al. 2002). DNMT1 and DNMT3b have been shown to form a complex with oncogenic transcription factors to induce de novo meth-ylation of CpG islands in promoter regions (Di Croce et al. 2002). Patients with DNMT3a mutations had signiﬁ cantly worse prognosis in acute myeloid leukemia (Ley et al. 2010). Therefore, DNMTs in cancer have a crucial role in the hy-permethylation that is found on CpG islands and its subse-quent downstream effects.The genomic regions that are targeted for hypermethyl-ation tend to be CpG islands. Contrary to individual CpG sites throughout the genome in intergenic regions, CpG is-lands are usually unmethylated in normal cells, regardless of gene expression (Jones and Laird 1999). However, there are very speciﬁ c instances in which CpG islands are methylated in normal cells, such as in imprinted genes and X-chromosome inactivation.CpG Islands and Gene ExpressionCpG islands occupy approximately 60% of human gene pro-moters, most of which are constitutively expressed genes (Vu et al. 2000). A CpG island is generally deﬁ ned as a 1000-kb stretch of DNA with GC content greater than 50%. The normal hypomethylated pattern of CpG islands is found to be consistent across various types of somatic tis-sues despite tissue-speciﬁc differences, illustrating that DNA methylation of these islands is not used as a regula-tory mechanism of gene expression (Cotton et al. 2011). Therefore, when a CpG island becomes aberrantly methyl-ated, it can have detrimental effects by stably silencing the associated gene (Cotton et al. 2011). The cancer cell ge-nome is characterized by hypermethylation of CpG islands in promoter regions (Edwards and Ferguson-Smith 2007; Jones and Laird 1999; Meehan et al. 1992; Riggs and Pfeifer 1992). In contrast with hypomethylation of intergenic CpG sites in cancer that lead to genomic instability, hyper-methylation of CpG islands promotes the progression of tumorigenesis by silencing tumor-suppressor genes. For example, PTEN, a protein that prevents rapid proliferation, is commonly hypermethylated in brain and thyroid cancers, whereas APC, a protein involved in cell-cycle regulation, cell–cell adhesion, and cell mobility, is inactivated by hyper-methylation in many lung, breast, and colorectal cancers (Fan and Zhang 2009; Hatziapostolou and Iliopoulos 2011; Illingworth and Bird 2009). Suppression of p16, a cell-cycle regulator, occurs in essentially all common human cancers (Ligget and Sidransky 1998). Inactivating these tumor sup-pressors directly promotes tumorigenesis due to lack of con-trol over cellular processes.In addition to tumor-suppressor genes, hypermethylation of other classes of genes such as DNA repair genes and tran-scription factors can indirectly lead to tumorigenesis through silencing of further downstream targets or accumulation of genetic errors. For example, GATA-4 and GATA-5 are tran-scription factors silenced in colorectal and gastric cancers (Alvarez-Nunez et al. 2006). Inactivation of DNA repair genes, such as O-6-methylguanine-DNMT, is commonly found in primary neoplasias (Esteller et al. 2000). Therefore, hypermethylation of CpG islands in cancers can affect mul-tiple pathways to promote carcinogenesis.Promoter hypermethylation is often an early event in tumorigenesis. Several mechanisms have been proposed for targeting CpG islands for hypermethylation. One explana-tion is that the location of these islands in genomic regions that have potentially undergone massive epigenetic repro-gramming leads to hypermethylation as a byproduct or for prevention of error (Bird 2002). Another explanation is that some gene promoters are targeted speciﬁ cally by DNMTs complexed to oncogenic transcription factors (Okano et al. 1999). Finally, it has been proposed that hypermethylation is a result of histone marks created in a tumor-speciﬁ c manner (Hatziapostolou and Iliopoulos 2011).Although it may appear that hypomethylation and hyper-methylation in cancer are opposing forces, the patterns usu-ally coexist within the same tumor, although they occur in different genomic regions. Further, the epigenetic abnormal-ities that occur because of hypo- and hypermethylation can interact in various ways to produce distinct subtypes of cancer. However, these patterns are stable but not irre-versible and remain ﬂ exible as the cellular environment changes, contributing to the complexity of the cancer cell epigenome.The dysregulation of DNA methylation patterns ob-served in cancer does not occur independent of other epige-netic changes. Methylated DNA-binding proteins, which are attracted to methylated cytosine residues and contribute in gene silencing, have been shown to interact with a number of other partners involved in epigenetic regulation. In particu-lar, methylated DNA-binding proteins have been shown to interact with proteins that are involved in controlling the in-teraction between DNA and histones, the proteins involved in DNA packaging.Chromatin Remodeling in CancerThe estimated 1.8 linear meters of DNA in the human cell are organized into a 3-dimensional structure and compacted within the cell nucleus by means of associations with his-tones, the major DNA packaging proteins. These DNA–histone complexes are the primary components of chromatin, which makes up the bulk of the material in the nucleus. The basic chromatin unit is the nucleosome, which consists of a protein octamer containing pairs of each of the four core his-tone proteins (H2A, H2B, H3, H4). Nucleosome structures are highly conserved and repetitive throughout the genome, forming a “beads-on-a-string” structure. Nucleosomes are organized by histone protein H1, a linker protein found out-side the main histone octamer complex that binds to linker DNA at the entry and exit points of the nucleosome (Allan et al. 1980).There are two common higher levels of nucleosome or-ganization that are deﬁ ned by the level of compaction of the nucleosome structures euchromatin and heterochromatin. Euchromatin is loosely packed and typically represents transcriptionally active genic regions due to the increased accessibility of the DNA in the nucleosome structure. Het-erochromatin is densely packed, with intense cytological nuclear staining due to the high density of nuclear proteins. Heterochromatin is further classiﬁ ed into constitutive het-erochromatin, or permanently silenced chromatin, and fac-ultative heterochromatin, which is silenced chromatin that can become reactivated in response to appropriate genetic or environmental cues. Thus, throughout an organism’s lifetime, chromatin conformation is a ﬂ uid, cell type–spe-ciﬁ c process, and it is prone to restructuring in response to environmental or physiologic signals. Altered or abnormal chromatin conformation has also now been recognized as an epigenetic hallmark of many cancers.Chromatin conformation is controlled by chemical mod-iﬁ cations, mainly covalent modiﬁ cations, of the N-terminus tails of the histone proteins that form the core of the nucleo-some. H istone modiﬁ cations can affect the interaction be-tween histone proteins and DNA as well as between adjacent histone proteins. Histone modiﬁ cation is a dynamic process, with enzymes catalyzing the addition of covalent modiﬁ ca-tions (“writers”), their removal (“erasers”), and recognition of marks previously laid down (“readers”) (Wang et al. 2007). Dysregulation of each of these classes of enzymes has been associated with a variety of cancer types. Here, we will detail the functional consequences of aberrant control of these enzymes during the carcinogenic process for histone methylation and acetylation, the two best-characterized his-tone modiﬁ cations.Histone MethylationHistone methylation has been widely shown to regulate tran-scription; methylation at speciﬁ c histone tail residues is asso-ciated with both transcriptional activation and repression. Histone methylation occurs at both arginine and lysine resi-dues on the tails of histone proteins H3 and H4. A summary of enzymes that modify or read histone methylation marks that have been shown to be dysregulated in cancer is shown in Table 1. Lysine methylation is catalyzed by histone-lysine-N-methyltransferases, also known as K-methyltransferases, and involves the transfer of methyl groups from the cofactor S-adenosyl methionine. A key protein involved in control of stem cell maintenance and differentiation, EZH2 (enhancer of Zeste 2), is a K-methyltransferase that catalyzes the tri-methylation of H3K27 (Cao et al. 2002). EZH2 is a member of the polycomb repressive complex 2, a protein complex that involves both a K-methyltransferase and “reader” pro-teins that recognize H3K27me3. The H3K27me3 mark is normally involved in silencing genes related to development and stem cell differentiation, including the Hox gene cluster (Lewis 1978). In many cancers, however, EZH2 is overex-pressed both at the transcriptional and protein levels. EZH2 overexpression has been described as important in prostate cancer, where an increase in EZH2 protein staining in the cell nucleus was observed with a progression from benign to metastatic disease (Varambally et al. 2002). Further studies have identiﬁ ed overexpression of EZH2 as a key feature in breast cancer, lymphomas, and glioblastomas, among other cancers (Kleer et al. 2003; Suvà et al. 2009; van Kemenade et al. 2001). In cancer cells, H3K27me3 has also been shown to repress gene expression independent of gene-promoter DNA methylation (Kondo et al. 2008), whereas in normal cells, EZH2 has been shown to control DNA methylation by interacting with DNMTs (Vire et al. 2006). Additionally, dysregulation of other members of the polycomb repressive complex, including proteins that interact with polycomb repressive complex 2 proteins following the transfer of the H3K27me3 mark by EZH2, have also been recently described. In contrast with the silencing histone modiﬁ cation H3K27me3, histone methylation can also be a mark associated with tran-scriptional activation. The mixed lineage leukemia (MLL) is a K-methyltransferase that catalyzes the methylation of H3K4. MLL acts in opposition to polycomb repressive com-plex proteins, activating genes involved in development and differentiation (Milne et al. 2002). MLL genetic events, par-ticularly gene fusions and overampliﬁ cation, have been shown to be an important characteristic of leukemia. An experimental mouse model with an MLL–AF9 gene fusion introduced by homologous recombination led to the development of acute leukemia in all chimeric mice (Corral et al. 1996). A study of acute lymphoblastic leukemia patients with MLL transloca-tions found a unique gene expression proﬁ le when compared with patients with conventional B-precursor acute lympho-blastic leukemia (Armstrong et al. 2002). Speciﬁ cally, patients with MLL translocations were found to have multilineage gene expression, aberrantly overexpressing genes associated with early-stage hematopoiesis.H istone methylation marks are removed by a variety of enzymes, with marks at speciﬁc histone tail residues interacting with distinct histone lysine demethylases, or K-demethylases. JMJD2C is a K-demethylase that catalyzesthe removal of methylation marks from H3K9, a mark typi-cally associated with gene repression (Snowden et al. 2002). Ampliﬁ cation of JMJD2C has been observed in a variety of cancers, including breast and esophageal cancer (Liu et al. 2009; Yang et al. 2000). Lysine speciﬁ c demethylase 1, a K-demethylase that targets H3K9 and H3K4 methylation, has recently shown to be overexpressed in estrogen recep-tor–negative breast cancer (Lim et al. 2010), mesenchymal tumors (Schildhaus et al. 2011), and bladder cancers (Hayami et al. 2011). Although more research is necessary to fully understand the functional consequences of dysregulation of histone methylation, it is clear that K-demethylases and K-methyltransferases are important in the carcinogenic process and represent novel targets for therapy.Histone AcetylationUnlike histone methylation, which can be associated with transcriptional activation or repression based on the speciﬁ c residue methylated, histone acetylation is strongly associ-ated with transcriptional activation. Histone acetylation oc-curs on lysine residues and is thought to enhance transcription by charge neutralization of the positively charged histones, decreasing their interaction with the negatively charged DNA phosphate backbone. Maintenance of histone acetylation marks and the dynamic state of chromatin conformation are controlled by histone acetyltransferases (HATs), also known as K-acetyltransferases, and histone deacetylases (HDACs1). HA Ts catalyze the addition of acetyl groups to histone lysinesHistone-modifying enzyme Targetmodiﬁ cation Cellular function/related cancers ReferencesLysine methyltransferases (KMTs)MLL H3K4T ranscriptional activation; gene fusionsidentiﬁ ed in leukemia Armstrong et al. 2002; Corral et al. 1996SETDB1H3K9T ranscriptional repression; ampliﬁ ed in melanoma Ceol et al. 2011EZH2H3K27T ranscriptional repression; associatedwith tumor aggressivenessUpregulated in breast cancer, prostatecancer, lymphoma, glioblastoma Kleer et al. 2003; Suvà et al. 2009; van Kemenade et al. 2001; Varambally et al. 2002NSD1H3K36, H4K20T ranscriptional activation; gene fusionsin leukemia, multiple myeloma T aketani et al. 2009; Wang et al. 2007DOT1H3K79DNA damage repair; involved in leukemia Chang et al. 2010; Okada et al.2005; Tatum and Li 2011 Lysine demethylases (KDMs)LSD1H3K4, H3K9T ranscriptional repression; dysregulatedin breast cancer, upregulated in aggressiveprostate cancer Kahl et al. 2006; Lim et al. 2010; Wang et al. 2009JMJD2C H3K9T ranscriptional activation; rearrangedin lymphoma, ampliﬁ ed in breast cancer andesophageal cancer Liu et al. 2009; Vinatzer et al. 2008; Y ang et al. 2000JMJD3H3K27T ranscriptional activation; upregulatedin aggressive prostate cancerXiang et al. 2007 Lysine methylation readersING4H3K4T umor suppressor; deleted in headand neck cancer and breast cancer,reduced expression in glioma Garkavtsev et al. 2004;Gunduz et al. 2005; Kim, Chin, et al. 2004; T apia et al. 2011BMI-1H3K27Oncogene; overexpressed in lymphoma,leukemia, colorectal and breast cancer Beà et al. 2001; Kim, Y oon, Kim, et al. 2004; Kim, Y oon, Jeong, et al. 2004; Lessard et al. 2003; Pietersen et al. 2008Table 1 Examples of histone methylation dysregulation in cancerusing acetyl coenzyme A as a cofactor and induce an open or permissive chromatin state, whereas HDACs remove acetyl groups and induce a closed or repressive state (Roth et al. 2001). The normal in vivo role of HATs and HDACs is often obfuscated in cancer, leading to an abnormal chromatin phenotype.There are three distinct families of H ATs: The Gcn5 family, the p300/CBP family, and the MYST family (Lee and Workman 2007). HATs from each of these families have been shown to play a role in carcinogenesis, from either inappropriate activation or repression of target gene activity. The Wnt signaling pathway, previously shown to be com-monly dysregulated in cancers, particularly those with a stem cell phenotype, has been shown to be augmented by the HAT Gcn5 in breast cancer (Chen et al. 2010). CBP (cyclic AMP response element-binding [CREB] protein) and p300, have been shown to be capable of acetylation of all four core histones as well as a number of other nonhistone proteins, including p53, Rb, E2F, and myb (Iyer et al. 2004). Loss of heterozygosity at either p300 or CBP has been detected in a large proportion of cancer cell lines examined, with 51% of cell lines experiencing loss at p300 and 35% experiencing loss at CBP (Tillinghast et al. 2003). These ﬁ ndings suggest that both p300 and CBP are important tumor-suppressor genes that may be lost through loss of heterozygosity in a number of different cancers. MYST family HATs have been identiﬁ ed as important in hematopoesis and, as such, also identiﬁ ed as dysregulated in acute myeloid leukemia (Yang and Ullah 2007). In the M4/M5 subset of leukemia cases, a stable and recurrent translocation t(8;16)(p11;p13) causes a fusion between MOZ, a MYST family acetyltransferase, and CBP, leading to aberrant chromatin acetylation (Borrow et al. 1996). Similarly, MOZ is found fused to p300 following a t(8;22)(p11;q13) translocation observed in a subset of acute monocytic leukemia cases (Chaffanet et al. 2000).HDACs are enzymes that catalyze the removal of histone acetyl marks and are involved in transcriptional repression. HDACs, like HATs, also have nonhistone proteins as poten-tial substrates and are involved in the deacetylation of a number of proteins identiﬁ ed as important in carcinogenesis, including p53, YY1, and STAT3 (Glozak et al. 2005). The 18 human proteins identiﬁ ed with HDAC activity suggest that there is likely some redundancy in function between HDACs as well as the potential for different histone tail residues or other nonhistone proteins as targets.Studies of multistage models of carcinogenesis have identiﬁ ed histone deactylation as an early step in the process (Fraga et al. 2005). Speciﬁ cally, early loss of monoactylation of histone H4K16 was observed in a mouse model of multi-stage skin carcinogenesis. Additionally, a number of cancer cell lines, as well as primary lymphomas and colorectal ad-enomas, were also found to be hypoacetylated compared with normal cells, suggesting that histone deacetylation is a widespread event in cancer. HDACs are often overexpressed in many different tumor types, including breast (Krusche et al. 2005), prostate (Weichert, Röske, Niesporek, et al. 2008), and colorectal cancer (Weichert, Röske, Gekeler, et al. 2008). A study of the function of HDAC3, a class 1 HDAC, in cancer cells, found that long term knockdown by means of RNA interference led to inhibition of ␤-catenin’s transloca-tion to the nucleus (Godman et al. 2008). In addition to dis-rupting Wnt signaling, H DAC3 inhibition also increased expression of the vitamin D receptor, rendering those cells more sensitive to the effects of vitamin D. The common pat-tern of H DAC deregulation in cancer cells has provided a novel target for chemotherapeutic intervention—the HDAC inhibitor. HDAC inhibitors, both natural and synthetic, have been widely used in the treatment of a number of diseases, including psychiatric diseases and cancer. There are two H DAC inhibitors currently approved by the US Food and Drug Administration for the treatment of cutaneous T-cell lymphoma—suberoylanilide hydroxaminc acid (vorinostat) and romidepsin. Additionally, there are a number of other HDAC inhibitors under investigation in early- and late-stage clinical trials, which may provide novel epigenetic therapies for cancer treatment.Animal Models of CarcinogenesisFindings from in vivo models of carcinogenesis can be used to predict how the most susceptible humans in the popula-tion may respond to genetic lesions or exposure to environ-mental carcinogens. Additionally, these studies can identify epigenetic biomarkers and provide insight into the speciﬁ c mechanisms of tumor progression.There are a number of in vivo models of carcinogenesis that allow for the characterization of epigenetic mechanisms that link environmental exposures or genetic susceptibility and cancer progression. These models typically involve the induction of tissue-speciﬁc cancer through toxicant expo-sure or transgenic manipulation. A carefully designed ani-mal model can speciﬁ cally characterize molecular pathways of carcinogenesis, providing evidence for a sequential series of epigenetic and genetic effects as a malignancy progresses from carcinoma in situ to metastatic disease. Often these models are particularly useful for elucidating the contribu-tion of epigenetic dysregulation of speciﬁ c pathways in car-cinogenesis in a temporal fashion. Lung cancer is an example of a cancer where epidemiologic studies have identiﬁ ed rel-evant exposures, but the early events in carcinogenesis are not well characterized (Betancourt et al. 2010; Jenkins et al. 2009). Exposure to 3-methylcholanthrene and diethylnitro-samine has been known for at least two decades to induce lung tumors in animal models (Henry et al. 1981; Schuller et al. 1988). These models have proven useful to understand the basic processes that underlie neoplastic lung adenocarci-noma initiation and progression. More recently, researchers have extended the use of these lung carcinogenesis models to understand the speciﬁ c epigenetic mechanisms involved in lung cancer progression, including increases in promoter methylation of the cell-cycle regulator genes p27 and p57 (Liu et al. 2010). Epidemiologic studies have consistently identiﬁ ed inﬂ ammation as an important initiator and promoter。

基于人工智能的冠状动脉易损斑块腔内影像学研究进展

基于人工智能的冠状动脉易损斑块腔内影像学研究进展陈远兴综述韩韦钰，赵然尊审校遵义医科大学附属医院心血管内科，贵州遵义563000【摘要】斑块的不稳定导致冠状动脉的血栓性闭塞是大多数急性冠脉综合征(ACS)的原因。

尽管罪犯血管得以及时开通，但非罪犯血管的易损斑块对患者远期预后仍存在较大威胁。

因此，动态评估易损斑块的变化，对冠心病患者格外重要。

冠状动脉血管腔内成像技术，如血管内超声(IVUS)、光学相干断层扫描(OCT)、近红外光谱(NIRS)以及其多模态融合技术等，因其可视化、准确度高，可以揭示易损斑块的不同特征，常用于检测易损斑块。

而IVUS 、OCT 等图像解释需有经验的心血管临床医生逐帧判断，需要大量的时间成本，且图像的解读存在的观察者内及观察者间的差异，这推动了人工智能(AI)在冠状动脉血管腔内影像学应用的发展。

由于电子医疗系统的广泛应用、临床大数据的日益暴增，AI 已在医疗行业获得了极大的进展。

人工智能结合腔内影像学在斑块的识别、干预、预后等诸多方面广泛应用，未来将不断优化诊疗系统，提高精准医疗水平，实现对易损斑块的早期诊断及合理干预。

【关键词】动脉粥样硬化；急性冠脉综合征；腔内成像；易损斑块；人工智能【中图分类号】R541.4【文献标识码】A【文章编号】1003—6350（2023）03—0445—05Research progress of intravascular imaging of vulnerable coronary plaque based on artificial intelligence.CHEN Yuan-xing,HAN Wei-yu,ZHAO Ran-zun.Department of Cardiovascular Medicine,Affiliated Hospital of Zunyi Medical University,Zunyi 563000,Guizhou,CHINA【Abstract 】Plaque vulnerability leading to thrombotic occlusion of coronary arteries is the main cause of majori-ty of acute coronary syndrome (ACS).Despite the criminal vessels can be opened in time,the vulnerable plaques of non-criminal vessels still cause a great threat to the long-term prognosis of patients.Thus,dynamic assessment of vulner-able plaque changes is particularly important for patients with coronary heart disease.Intravascular imaging techniques in coronary arteries,such as intravascular ultrasound (IVUS),Optical Coherence Tomography (OCT),Near Infrared Spectrum Instrument (NIRS),and its multi-mode fusion technology,are often used to detect vulnerable plaques due to their high visualization and accuracy,which can reveal different characteristics of vulnerable plaques.However,IVUS,OCT and other image interpretation requires experienced cardiovascular clinicians to judge frame by frame,which re-quires a large amount of time cost,and there are intra-observer and inter-observer differences in image interpretation,which all promotes the development of AI in the application of intravascular coronary imaging.Artificial intelligence (AI)has made great progress in the medical field due to the wide application of electronic medical information system and the increasing explosion of clinical big data.Artificial intelligence combined with intravascular imaging has been widely ap-　·综述·doi:10.3969/j.issn.1003-6350.2023.03.035第一作者：陈远兴(1995—)，男，住院医师，主要研究方向为冠状动脉粥样硬化性心脏病腔内影像学图像分析。

肿瘤基因检测：Septin9甲基化检测-结直肠癌

肿瘤的预防和筛查
• WHO：三分之一可以预防，三分之一可以治愈，三分之一可以改善症状、延长生命（1985）
• WHO：恶性肿瘤40%可以预防，40%可以治愈，20%可以长期带瘤生存（2011）
• 肿瘤预防的关键：肿瘤的检测和筛查
癌症可防、可治： • 癌前阶段：可实现近100%预防 • 早期癌症：可以实现80%治愈率 • 晚期癌症：仅30%人活过5年。
有些检测辐射极大
理想的结直肠癌筛查技术
• 易采样，无创无辐射无痛苦 • 灵敏度高，最好能够发现早期癌前阶段 • 特异性高，具有肿瘤特异性 • 对设备要求低，适于推广
为真医药
为真医药
甲基化——5`甲基胞嘧啶
基因启动子区甲基化
为真医药
效应：基因表达下降或失活，蛋白水平下降
为真医药
甲基化是肿瘤发生的早期事件
查
为真医药
结直肠癌的筛查方式
• 血清肿瘤标志物是指和肿瘤发病相关的蛋白质 • 无创快速检测 • 临床上用于肿瘤的监控，也用于肿瘤的初步诊断 • 缺点：检测灵敏度低，器官特异性、肿瘤特异性差
• 医学影像通过占位效应发现肿瘤 • 检测便捷无创 • 临床上应用于肿瘤发病全程 • 缺点：检测灵敏度低，一般不能判定良恶性，
为真医药
Septin9甲基化检测
结直肠癌筛查技术
目录
• 肿瘤发病流行病学概述 • 结直肠癌的筛查和预防 • SEPTIN9 – 甲基化检测及其在临床上的应用 • DNA甲基化检测技术及送检流程
为真医药
为真医药
中国结直肠癌发病率与死亡率呈急剧上升趋势
2000-2012年中国结直肠癌发病率与死亡率
发病率（1/10^5）
- Glockner, S.C., et al., Cancer Research, 2009, 69:4691-9

Edexcel GCE General Studies 高级单选题模块3：变化与进步（2010年版）

.................................................................................................................................................................................................................................................................................
.................................................................................................................................................................................................................................................................................
Advice
Read each question carefully before you start to answer it.
• Keep an eye on the time. •• Check your answers if you have time at the end.
H37049A
©2010 Edexcel Limited.
(Total for Question 1 = 4 marks)
2

识别变化的重要性英语作文

识别变化的重要性英语作文Change is an inevitable part of life. It keeps things fresh and prevents monotony. Without change, life would be stagnant and boring.Change pushes us out of our comfort zones and helps us grow. It challenges us to adapt and learn new things, which ultimately makes us more resilient and capable.Change also brings about new opportunities. It opens doors to different experiences and perspectives, allowing us to explore and expand our horizons.Embracing change is essential for personal development. It forces us to confront our fears and insecurities, pushing us to become the best versions of ourselves.Change fosters innovation and progress. It encourages us to think outside the box and find creative solutions to problems, driving society forward.Change is a natural part of the world around us. Seasons change, technology advances, and people evolve. Adapting to these changes is crucial for our survival and success.Change keeps things interesting. It adds excitement and unpredictability to life, making each day a new adventure.Change is necessary for breaking habits and routines. It forces us to reevaluate our lives and make necessary adjustments for improvement.Change is essential for achieving balance and harmony. It allows us to let go of the past and embrace the present, leading to a more fulfilling and meaningful life.。

高一英语6月月考试题高一全册英语试题22

照对市爱民阳光实验学校高一英语6月月考试题说明：答题时间120分钟，总分150分。

第I卷第一听力〔共两节，总分值30分〕第一节〔共5小题；每题分，总分值分〕听下面5段对话。

每段对话后有一个小题，从题中所给的A、B、C三个选项中选出最正确选项，并标在试卷的相位置。

听完每段对话后，你都有10秒钟的时间来答复有关小题和阅读下一小题。

每段对话仅读一遍。

1．Where does the woman want to go?A. To the main entrance.B. To the cash desk.C. To the food counter.2. What will the man probably do?A. Use the woman’s phone.B. Go and look for a pay phone.C. Get some change from the woman.3. What does the man think of the movie?A. It tells about a touching story.B. The acting is overdone.C. It is wonderful.4. How much did the man pay for the camera?A. $ 150.B. $ 175.C. $ 200.5. What are the speakers talking about?A. Beth’s bike.B. Beth’s injury.C. A basketball game.第二节〔共15小题；每题分，总分值2分〕听下面5段对话或独白。

每段对话或独白后有几个小题，从题中所给的A、B、C三个选项中选出最正确选项，并标在试卷的相位置。

听每段对话或独白前，你将有时间阅读各个小题, 每题5秒钟；听完后，各小题将给出5秒钟的作答时间。

每段对话或独白读两遍。

AnticipatingChange

O ne thing is for sure…the world we live in doesn’tstand still. The need to carry power and data hasdeveloped into the world’s lifeline. Fifty years ago, who would have dreamt that telecommunications would be as portable and common as a wristwatch? Who would have dreamt that a physician would be able to check a patient’s vital sign information from anywhere in the world in real time? Who would have dreamt that every form of data would be able to be transmitted anyplace in seconds? The need for speed and clarity of data transmission has become our way of life. The need for products which will carry the data and power we all depend on has always been the focus of our company.A willingness to constantly re-focus on the future, to embrace new technologies, and to rapidly identify changing market and consumer trends has kept Whitney Blake in the forefront of the global need for data and power interconnect devices for more than 100 years. By respecting the tremendous power of change, we have not only become a prime source for finished product, but an invaluable source for the depth of technological expertise required by the many marketswhich we serve.Whatever the future brings, Whitney Blake will be there with the total cable connection solution. Y ou can count on that!WHITNEY BLAKE COMPANYMaking The Connection. • plastic and rubber extrusion, insulating and jacketing • shielding, helically wrapped and braided • plastic injection molding • cabling • taping • coiling • vulcanizing • rubber compression moldingF Over-mold and compression molded connections are available.Whitney Blake design engineers are with you throughout theentire cable design process to assure your cable assembly productsperform to your specifications and beyond.On-site testing assures certification to military and agency performancespecifications. Flex testing, sub-zero and high temperature materialperformance, ozone and oxidation testing, advanced circuit analyzersand lab rheometers are examples of our quality assurance capabilities.Connecting with our customers’ needs also means providing the widestrange of capabilities in both materials and manufacturing in order tooffer complete design to finished product possibilities.T oday’s markets demand that a supplier have an organizational culture whichresponds to customer needs, not only out of necessity, but also out of a desireto work in partnership with them to accomplish their goals.Whitney Blake has not had to change with respect to these needs.Our original business philosophy still works as well as it did over acentury ago…customer first.Y our success is our success.or us, making the connection means connecting with ourcustomers’ needs. Responding to our customers’ desires forsingle sourcing complete cable products, Whitney Blake offerscomplete cable assembly from design to finished product.P ushing the envelope of product design in areas of critical performance and rapidly changing technologies isbusiness as usual for Whitney Blake.We work hand-in-hand with design engineers in all fields to achieve excellence in a myriad of applications from super-tech communications to power tools.The requirements and specifications vary but the goal is always the same…performance.Many of the “smart” products we help develop encompass the full range of Whitney Blake capabilities such as miniaturization, complete module sub-assemblies, small resistors, plastic housings with PCB assemblies, flex circuits and switching circuitry to name a few.Thinking outside of the box is often required for innovation and creating solutions.Whitney Blake engineers were initially involved in the design and development of many of the military standards in operation today.We supply cordage to various military specifications including:In addition to many other stringent testing and specification requirements, all Whitney Blake products are manufactured under the quality assurance guidelines of ISO 9001:2000.The message is clear…we can make it happen.MIL-W-3795MIL-C-3849MIL-W-3885MIL-I-3930MIL-C-10392MIL-C-11997MIL-C-13273MIL-C-22442MIL-C-55040MIL-C-55668MIL-STD-45662AMIL-C-83501Federal Test Methods / STD. 228.TELECOMMUNICATION / TRANSPORTATION / MEDICAL DATA AND NETWORKING / CELLULAR MILITARY COMMUNICATION/ TELEMARKETING/ COMMERCIAL AND INDUSTRIALC onnecting with our customers really meansconnecting with “your” customers. We realizethe reliability of your cable products directlyrelates to the satisfaction and performance needs of theend user. The levels of performance andsatisfaction required range fromcomfort and convenience to the highestlevel of life dependency on dataand power transmission.It’s much more thanproducts that get packedin a box and put on atruck to go “somewhere.”Whitney Blake cableproducts are made toexceed both your customers’and your expectations. Quitefrankly, that’s the only way we knowhow to do it.As your markets and productdevelopment expand, our expertise indealing with a diverse customer basebecomes a valuable resource for you toanswer the challenges you face indelivering innovative and high qualityproducts to the world marketplace.Attention to detail shows in all aspects of the way we dobusiness with you. One example is the development ofeffective supply chain scenarios to satisfy inventoryrequirements for the benefit of customers who require thistype of control in their manufacturing process.And our “rapid response” design and engineering teamworks to bring new ideas and changes to existingproducts from concept to prototype to finished goodsexpeditiously so you can keep pace with your market.Once a design is finalized, our manufacturing teamassures that your cable product is made to your exactingspecifications. Throughout the entire process, our worldclass customer service team keeps you in the loop andcurrent on your order.We use the word “team” a lot because that’s the way wework. And our team of seasoned cableproduct professionals willbecome a part of your“team” to get the job doneto yourrequirements…fromconcept to delivery.Keeping in touch with ourcustomers and the marketsthey serve is how we stay currentwith rapidly changing technologies andconsumer trends. Y ou’ll find WhitneyBlake personnel at trade shows, industryseminars, and anywhere else that affectsthe markets we serve.The desire to be ahead of the game is what makes ustick. That’s why you’ll find more and more WhitneyBlake products showing up in exciting and innovativeapplications every day.An example of Whitney Blake’s constantlyexpanding role of leadership in the developmentof high-tech cable products is our developmentalrole in designing a data interconnect device forthe forthcoming M.I.B. project which will play acentral role in transmitting patient data frombedside monitors to physicians or care providersvia a hospital LAN.A s with all of our products, our electricalcoil cord assemblies for trucks areengineered from the ground up to assurethat we cover every detail. Truck electrical cordassemblies have to perform in a ruggedenvironment...day after day, week after week,mile after mile. That’s why features such assuperior extension life, sag-resistant coil memoryand super resistance to road salt are built rightinto our truck cables.Truck cables are subjected to dailyabuse by battery acid, brake fluid, dieselfuel, engine coolants, power steeringfluid and a host of other oils that couldbe a problem for other cables. We’vetaken the time and effort to build aproduct that delivers excellentresistance to fluids of all types. It’s justanother pre-engineered feature of ourtruck cables that assures long life andreliability for those who relyand depend on them.One thing is for sure, truck cablesaren’t stationary. Truck cables arecontinually moving, swinging andbanging into each other. That’s why special attention has been given to developing an especially tough and durable jacket for abrasion resistance, such as ours, which is second to none.The best cable in the world is only asgood as the connectors on each end.Our connecting devices are speciallydesigned to handle the rough conditionsrequired of them. Our truck electricalcoil cords are built for endurance andwill provide you with confident service over the long haul.•Applicable Specifications: SAE J1067 Type F (Flexible) Coiled Cords Or Type S (Stationary) Straight Cables SAE J2394 Type F Or S SAE J2222•Superior Extension Life•Sag Resistant Coil Memory•Excellent Fluid Resistance:Fluids Such As: Battery Acid, Brake Fluid,Diesel Fuel, Engine Coolants, Engine Oil,Power Steering, Transmission Oil •Excellent Resistance To Road Salt •Tough, Durable Jacket ProvidesExcellent Abrasion ResistanceDesigned and built for the real e after mile.T he pulse of the world’s cablemarket can be measuredby Whitney Blake’s Koiled Kord business.Koiled Kord has become a known brand name throughout the entire wire and cable industry as the cord of choice for a myriad of applications.Our in-stock Koiled Kords deliver product consistency and reliability right off the shelf whether you are manufacturing or distributing wire and cable products. In-stock cords are being used in computers, bar code readers, medical equipment,material handling equipment,production line tools, virtually all types of commercial vehicles, and in a wide variety of instrumentation and testing devices throughout many markets.Imagine an application…we just might have an in-stock KoiledKord waiting for it. If we don’t, we can custom build to meet yourrequirements in record time.Features such as serial or parallel interface cables with conductors color coded to your specifications, tinsel or stranded wire, wire sizesranging from8 AWG to 32 AWG,stranded tinned softcopper or cadmium-copper wire,to name just a few, arecapabilities available to you.Getting product the wayyou want it and when you want isquicker and easier than everbefore. Custom or in-stock,material options for Koiled Kordsare practically endless… naturalrubber, EPDM, SBR, PVC, TPR,Nylon, Polyethylene, Santoprene ®,Polypropylene, Hytrel, Neopreneand T eflon to name a few.Our in-stock cords offer a widevariety of sizes and gauges ofwire, a variety of insulation and jacketingoptions, a variety of terminationchoices, a variety of fillers, and avariety of shielding possibilities to fit manyapplications“right off the shelf.” Stock or custom, all Koiled Kords pass the same high stringent quality standards that every Whitney Blake product must meet.Many distributors across the country stock our cords because of the availability and consistent quality that only Whitney BlakeWhen the world goes shopping for stock cords, Whitney Blake delivers.In-stock or custom designed, design engineers specifyKoiled Kords ™for almost any application.M ore and more companies are turning to WhitneyBlake for their assembly needs. The reasons are clear.We have our own, in-house, highly sophisticatedcontract manufacturing facilities that provide our customerswith total fulfillment from manufacturing parts to final assemblyand packaging.We offer more than just hands to put the pieces together. Our team ofcontract manufacturing professionals will guide you through thewhole process and will often find a better and more efficient way todo the job. This means that our customers can lower their total overallcosts, get a better handle on their asset and overhead utilization, andkeep their inventory levels low while having the ability to meetmarket demand in a timely fashion.While issues of product cost and inventory are important, thisservice offers another side that may have a dramatic effect onyour total marketing strategy. Utilizing our facilities for assemblyactually expands your production capacity without incurring allthe extra costs which normally go along with expansion of yourown facilities. This means the potential of a “shorter time tomarket” and the ability to respond to market demands andfluctuations as they occur and not be constrained by yourmanufacturing capabilities.Our customers collaboration with Whitney Blake in this area hasbecome an integral part of their global supply strategy in meetingthe ever changing demands of the business world we live in.Whitney Blake is strategically positioned with NAFTA manufacturing in Mexico and the United States to offer the best solution for you and your products.A Strategy That EncompassesTotal Fulfillment.S ince 1899, Whitney Blake has been pioneeringthe design, development, and manufacturing ofretractile cable and wire products. In fact,Whitney Blake was a leader in the manufacture ofrubber insulated wire and cable right from thebeginning with the first commercial patents forretractile cords. It’s clear that our focus and heritagewill dictate our future for many years to come as wemove into the new century.Since day one, we have been looking aheadand preparing ourselves for the future of the manymarkets that we serve. Whitney Blake retractile cords,wire, and cord assemblies will continue to be anintegral part of the process of moving communicationsdata and electrical power from here to there just as wehave been for the past 100 years.We are looking forward to the many exciting developments that will come as data and power transmission needs continue to grow and are prepared to meet those needs, whatever form they may take, now and in the future. Whitney Blake Manufacturing Facilities:Vermont P .O. Box 579, Industrial Drive Bellows Falls, VT 05101Mexico Calle Obrero Mundial y Blvd. Garcia Morales #9Parque Industrial DYNATECH Hermosillo, Sonora 83170 MexicoWe would be pleased to hear from you.。

Epigenetic Regulation in Cancer

Epigenetic Regulation in CancerCancer is a complex disease that arises from genetic and epigenetic changes in cells. Epigenetic regulation refers to the modifications in gene expression that occur without altering the underlying DNA sequence. In cancer, epigenetic changes can lead to the activation of oncogenes or the silencing of tumor suppressor genes. Understanding the role of epigenetics in cancer is crucial for the development of new therapies and diagnostic tools.One perspective on epigenetic regulation in cancer is that it provides a mechanism for cells to adapt to changing environments. Epigenetic modifications can be influenced by factors such as diet, stress, and exposure to toxins. By altering gene expression, cells can respond to these environmental cues and maintain homeostasis. However, in cancer, these adaptations can become maladaptive, leading to uncontrolled growth and metastasis.Another perspective is that epigenetic changes in cancer are driven by mutations in genes that regulate epigenetic modifications. For example, mutations in genes encoding histone-modifying enzymes or DNA methyltransferases can lead to aberrant gene expression patterns. These mutations can be inherited or acquired during the course of the disease. Understanding the genetic basis of epigenetic changes in cancer is important for developing targeted therapies.A third perspective is that epigenetic changes in cancer are reversible and therefore represent a potential target for therapy. Unlike genetic mutations, which are difficult to reverse, epigenetic modifications can be modified by drugs that target the enzymes responsible for these modifications. Several epigenetic drugs have been developed and are currently in clinical trials for the treatment of cancer. These drugs have the potential to restore normal gene expression patterns and halt the progression of the disease.However, there are also concerns about the use of epigenetic drugs in cancer therapy. One concern is that these drugs may have off-target effects, leading to unintended consequences. For example, drugs that inhibit DNA methyltransferases may also affect the methylation of non-cancerous cells, leading to toxicity. Another concern is that epigenetic drugs may not be effective in all types of cancer or in all patients. The heterogeneity ofcancer means that different tumors may have different epigenetic profiles, making it difficult to develop drugs that are effective for all patients.Finally, there is a growing recognition that epigenetic changes in cancer are not only driven by genetic mutations but also by changes in the tumor microenvironment. The tumor microenvironment includes cells such as immune cells, fibroblasts, and endothelial cells, as well as extracellular matrix components and signaling molecules. These cells and molecules can influence epigenetic modifications in cancer cells, leading to changes in gene expression and tumor behavior. Understanding the role of the tumor microenvironment in epigenetic regulation is important for developing new therapies that target both cancer cells and the surrounding tissue.In conclusion, epigenetic regulation plays a critical role in cancer development and progression. Understanding the mechanisms underlying epigenetic changes in cancer is important for developing new therapies and diagnostic tools. While there are concerns about the use of epigenetic drugs in cancer therapy, these drugs represent a promising avenue for treatment. Further research is needed to fully understand the role of epigenetics in cancer and to develop effective therapies that target both cancer cells and the tumor microenvironment.。

Epigenetics Understanding Gene Expression

Epigenetics Understanding Gene Expression Epigenetics is a fascinating field of study that has revolutionized our understanding of gene expression and inheritance. It delves into the molecular mechanisms that control gene activity without altering the DNA sequence, shedding light on how environmental factors and lifestyle choices can influence our genetic predispositions. This emerging discipline has far-reaching implications for human health, disease prevention, and personalized medicine, making it a topic of great interest and significance.At the core of epigenetics is the concept of epigenetic marks, which are chemical modifications to the DNA and its associated proteins that can activate or silence genes. These marks can be influenced by various factors, including diet, stress, and exposure to toxins, and can be passed down from one generation to the next. This means that our experiences and choices can have a lasting impact on the expression of our genes, potentially affecting not only our own health but also that of our offspring.One of the most well-studied epigenetic marks is DNA methylation, which involves the addition of a methyl group to the DNA molecule. This modification typically leads to gene silencing, effectively turning off the expression of the associated gene. While DNA methylation patterns are largely established during early development, they can also be influenced by environmental factors throughout life. For example, studies have shown that certain dietary components, such as folate and other B vitamins, can affect DNA methylation patterns, highlighting the link between nutrition and epigenetic regulation.Another key player in epigenetic regulation is histone modification, which involves chemical alterations to the histone proteins around which DNA is wrapped. These modifications can either loosen or tighten the DNA-histone interaction, thereby influencing gene expression. Histone modifications are highly dynamic and responsive to environmental cues, providing a mechanism through which external stimuli can shape gene activity. For instance, chronic stress has been shown to induce specific histone modifications in the brain, contributing to changes in gene expression that are associated with mood disorders and other mental health conditions.Beyond its role in individual health and disease, epigenetics has also raised important ethical and social considerations. The idea that our lifestyle choices and environmental exposures can impact not only our own health but also that of future generations challenges traditional notions of genetic determinism and personal responsibility. It underscores the interconnectedness of human health and the environment, emphasizing the need for collective action to create healthier living conditions for all. Moreover, epigenetic research has the potential to uncover novel approaches for disease prevention and treatment, offering new hope for individuals at risk of inherited conditions.In conclusion, epigenetics represents a paradigm shift in our understanding of gene expression and inheritance, highlighting the intricate interplay between genetics, environment, and lifestyle. By elucidating the mechanisms through which external factors can influence gene activity, this field has opened up new avenues for personalized medicine, disease prevention, and public health interventions. As we continue to unravel the complexities of epigenetic regulation, it is crucial to consider the broader implications of this knowledge and work towards harnessing it for the benefit of current and future generations.。

血清甘油三酯水平对结直肠癌患者术后并发症的影响

血清甘油三酯水平对结直肠癌患者术后并发症的影响罗昭锋;崔小兵;吴万庆;郭晓磊;杨战锋;郭魁元【摘要】目的探讨结直肠癌患者血清甘油三酯水平对结直肠癌患者术后并发症的影响.方法选取郑州大学第五附属医院2015年1月至2017年12月接受开腹结直肠癌根治术治疗的240例患者,根据术前甘油三脂水平将患者分为高甘油三酯组和正常甘油三酯组,对比分析两组患者手术时间、术后恢复时间和术后并发症(切口感染、吻合口瘘、肺部感染、泌尿系感染、肠梗阻等)发生情况.结果高甘油三酯组患者术后切口感染、吻合口瘘发生率高于甘油三酯正常组,术后恢复时间较甘油三酯正常组长,差异有统计学意义(P<0.05).两组手术时间和肺部感染、泌尿系感染、肠梗阻发生率比较,差异无统计学意义(P>0.05).结论术前甘油三酯水平高的患者较甘油三酯水平正常患者术后恢复时间长,切口感染及吻合口瘘的发生率均较高,术前应给予重视.【期刊名称】《河南医学研究》【年(卷),期】2018(027)012【总页数】3页(P2186-2188)【关键词】甘油三酯;结直肠癌;并发症【作者】罗昭锋;崔小兵;吴万庆;郭晓磊;杨战锋;郭魁元【作者单位】郑州大学第五附属医院河南郑州 450052;郑州大学第五附属医院河南郑州 450052;郑州大学第五附属医院河南郑州 450052;郑州大学第五附属医院河南郑州 450052;郑州大学第五附属医院河南郑州 450052;郑州大学第五附属医院河南郑州 450052【正文语种】中文【中图分类】R735.3结直肠癌是我国常见的恶性肿瘤之一。

近年来，我国结直肠癌的发病率也呈现出较为明显的上升趋势。

虽然外科手术可以有效治疗和改善患者的病情和生存质量，但在临床病例中不难发现，患者在围手术期往往会发生伤口感染、吻合口瘘、肠梗阻等影响疾病预后的情况，这些也直接影响到康复效果。

本研究旨在分析术前患者甘油三酯水平对结直肠癌患者围手术期并发症的影响。

济南2024年统编版小学五年级下册C卷英语第6单元期末试卷

济南2024年统编版小学五年级下册英语第6单元期末试卷考试时间：100分钟（总分:110）A卷考试人：_________题号一二三四五总分得分一、综合题(共计100题共100分)1. 填空题：My ________ (玩具) is a great way to bond with friends.2. 填空题：The __________ (历史的反响) influences perspectives.3. 听力题：The chemical symbol for sulfur is ____.4. 听力题：It is _____ (sunny/rainy) today.5. 听力题：A chemical change can be identified by changes in color, temperature, or the formation of _____.6. 填空题：The __________ (历史的探讨过程) invites inquiry.7. 选择题：How many bones are there in the adult human body?A. 206B. 210C. 202D. 200答案: A8. 听力题：A ______ can jump very high.A chemical reaction can be sped up by increasing the ______.10. 填空题：I enjoy playing ________ (视频游戏) on my console.11. 选择题：What is the first month of the year?A. JanuaryB. FebruaryC. MarchD. April答案:A12. 选择题：What do you use to write on paper?A. PaintB. PencilC. WaterD. Glue答案:B13. 选择题：Which insect is known for making honey?A. AntB. FlyC. BeeD. Mosquito14. 填空题：The owl has excellent ______ (夜视能力).15. 填空题：The _______ (The age of Imperialism) was marked by the expansion of European empires.16. 听力题：I have _____ (one/two) pet cats.17. 填空题：A garden can provide a habitat for various ______ and wildlife.(花园可以为各种动植物和野生动物提供栖息地。

Evolutionary Genetics of Epigenetic Regulation

Evolutionary Genetics of EpigeneticRegulationOh, the evolutionary genetics of epigenetic regulation! Now there's a topic that gets my neurons firing! It's like peeking into the secret language of our genes, where whispers of past environments and experiences echo through generations. It's a dance between nature and nurture, a story written in molecules that control how our genes are expressed. Imagine this: DNA is the book of life, but epigenetic marks are like Post-it notes stuck between the pages. They don't change the words themselves, but they can highlight certain passages, making them louder or softer, or even completely covering them up. These marks can be influenced by all sorts of things – what we eat, how much we exercise, even the stress we experience. It's like our environment is leaving its own commentary on our genetic code, and the fascinating part is that these notes can sometimes be passed down to our children, carrying whispers of our own lives into the next generation. Think about it! A famine experienced by your grandmother might leave epigenetic marks on her genes, which could then influence your own metabolism and susceptibility to disease. It's a humbling thought, isn't it? We are not just products of our own choices, but also inheritors of the experiences of those who came before us. But here's where the evolutionary puzzle gets even more intricate. These epigenetic changes, while influenced by the environment, are not always random. Natural selection, the driving force of evolution, can actually favor certain epigenetic modifications that increase an organism's chances of survival and reproduction. It's like evolution is learning to anticipate future environments and preparing the next generation for what's to come. Take the case of plants, for example. Some plants have evolved epigenetic mechanisms that allow them to "remember" past exposure to drought conditions. These memories are passed down to their seeds, making the offspring more resistant to drought even if they haven't experienced it themselves. It's a remarkable adaptation that gives these plants a head start in challenging environments. And it's not just plants! Studies in animals, including humans, suggest that epigenetic inheritance may play a role in a variety of traits, from behavior and stress responses tosusceptibility to certain diseases. It's a rapidly evolving field, and we're just beginning to scratch the surface of understanding the complex interplay between genes, environment, and evolution. But one thing is clear: the evolutionary genetics of epigenetic regulation is rewriting our understanding of heredity and evolution. It's a story that's still being written, and I, for one, can't wait to see what the next chapter holds.。

1、下载文档前请自行甄别文档内容的完整性，平台不提供额外的编辑、内容补充、找答案等附加服务。
2、"仅部分预览"的文档,不可在线预览部分如存在完整性等问题,可反馈申请退款(可完整预览的文档不适用该条件!)。
3、如文档侵犯您的权益，请联系客服反馈,我们会尽快为您处理(人工客服工作时间：9:00-18:30)。