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2013 Long interspersed nuclear element-1 hypomethylation in cancer biology and clinical application

2013 Long interspersed nuclear element-1 hypomethylation in cancer biology and clinical application
2013 Long interspersed nuclear element-1 hypomethylation in cancer biology and clinical application

REVIEW

Long interspersed nuclear element-1hypomethylation in cancer:biology and clinical applications

Nakarin Kitkumthorn &Apiwat Mutirangura

Received:6December 2010/Accepted:20March 2011/Published online:10April 2011#Springer-Verlag 2011

Abstract Epigenetic changes in long interspersed nuclear element-1s (LINE-1s or L1s)occur early during the process of carcinogenesis.A lower methylation level (hypomethylation)of LINE-1is common in most cancers,and the methylation level is further decreased in more advanced cancers.Conse-quently,several previous studies have suggested the use of LINE-1hypomethylation levels in cancer screening,risk assessment,tumor staging,and prognostic prediction.Epi-genomic changes are complex,and global hypomethylation influences LINE-1s in a generalized fashion.However,the methylation levels of some loci are dependent on their locations.The consequences of LINE-1hypomethylation are genomic instability and alteration of gene expression.There are several mechanisms that promote both of these con-sequences in cis .Therefore,the methylation levels of different sets of LINE-1s may represent certain phenotypes.Furthermore,the methylation levels of specific sets of LINE-1s may indicate carcinogenesis-dependent hypomethylation.LINE-1methylation pattern analysis can classify LINE-1s into one of three classes based on the number of methylated CpG dinucleotides.These classes include hypermethylation,

partial methylation,and hypomethylation.The number of partial and hypermethylated loci,but not hypomethylated LINE-1s,is different among normal cell types.Consequent-ly,the number of hypomethylated loci is a more promising marker than methylation level in the detection of cancer DNA.Further genome-wide studies to measure the methyl-ation level of each LINE-1locus may improve PCR-based methylation analysis to allow for a more specific and sensitive detection of cancer DNA or for an analysis of certain cancer phenotypes.

Keywords Long interspersed nuclear element-1s .DNA methylation .Hypomethylation .Partial methylation .Cancer .LINE-1

Because of the retrotransposition events that have occurred during evolution,the human genome contains more than 500,000long interspersed nuclear element-1(LINE-1or L1)copies (Lander et al.2001).Most LINE-1s are truncated.More than 10,000LINE-1s are longer than 4.5kb and consist of a 5′untranslated region (UTR),two open reading frames,and a 3′UTR containing a polyadenylation signal (Penzkofer et al.2005).The DNA methylation levels of LINE-15′UTRs in cancer have been extensively evaluated for potential use as an epigenomic marker for cancer (Chalitchagorn et al.2004).The mean level of LINE-1methylation in most cancer types is lower than in normal cells (Table 1).The degree of LINE-1hypomethylation increases in more advanced cancers (Table 2and Electronic supplementary material (ESM)Table 1).The methylation of other interspersed repetitive sequences (IRSs),such as Alu elements and human endogenous retrovirus (HERV)sequen-ces,has been evaluated to a lesser extent (Tables 1and 2and ESM Table 1).LINE-1and other IRS methylation levels have the potential to be used as universal tumor markers for

Electronic supplementary material The online version of this article (doi:10.1007/s13148-011-0032-8)contains supplementary material,which is available to authorized users.

A.Mutirangura (*)

Center of Excellence in Molecular Genetics of Cancer and Human Diseases,Department of Anatomy,Faculty of Medicine,Chulalongkorn University,Bangkok 10330,Thailand e-mail:mapiwat@chula.ac.th

N.Kitkumthorn

Department of Oral and Maxillofacial Pathology,Faculty of Dentistry,Mahidol University,Bangkok 10400,Thailand

Clin Epigenet (2011)2:315–330DOI 10.1007/s13148-011-0032-8

Table1Interspersed repetitive sequence hypomethylation in cancer

Type of cancer Repeated

sequence

Hypomethylation Reference

Abdominal

paragangrioma

LINE-1Yes Geli et al.(2008)

Breast cancer Alu Yes Cho et al.(2010)

LINE-1Yes Cho et al.(2010)

Cervical cancer LINE-1Yes Shuangshoti et al.(2007)

Cholangiocarcinoma LINE-1Yes Kim et al.(2009a)

Colorectal cancer Alu Yes Kwon et al.(2010;Rodriguez et al.(2008)

LINE-1Yes Chalitchagorn et al.(2004;Suter et al.(2004);Matsuzaki et al.(2005);Estecio

et

al.(2007);Iacopetta et al.(2007);Ogino et al.(2008a);Nosho et al.(2009a,

b);

An et al.(2010);Baba et al.(2010);Ibrahim et al.(2011);Irahara et al.

(2010);

Kawakami et al.(2011);Kwon et al.(2010)

Ependymoma Alu Yes Xie et al.(2010)

Esophagus cancer LINE-1Yes Chalitchagorn et al.(2004)

Gastric cancer Alu Yes Yoo et al.(2008);Park et al.(2009);Hou et al.(2010);Xiang et al.(2010);

Yoshida et al.(2011)

LINE-1Yes Chalitchagorn et al.(2004;Yoo et al.(2008);Park et al.(2009);Yoshida et al.

(2011)

Germ cell tumor LINE-1Yes Alves et al.(1996)

Fibrolamellar carcinoma

of liver

LINE-1No Trankenschuh et al.(2010)

Head and neck squamous cell cancer LINE-1Yes Chalitchagorn et al.(2004);Hsiung et al.(2007);Smith et al.(2007);

Subbalekha

et al.(2009)

Hepatoma Alu Yes Lee et al.(2009)

LINE-1Yes Takai et al.(2000);Chalitchagorn et al.(2004);Tangkijvanich et al.(2007);

Lee et

al.

(2009);Kim et al.(2009b);Formeister et(al.2010);Trankenschuh et al.

(2010)

Leukemia(acute promyelocytic leukemia)Alu Yb8No Choi et al.(2009) LINE-1No Choi et al.(2009)

Leukemia(chronic myelogenous leukemia)Alu Yes Roman-Gomez et al.(2008);Fabris et al.(2011)

LINE-1Yes Roman-Gomez et al.(2008);Roman-Gomez et al.(2005);Fabris et al.(2011)

Leukemia(plasma

cell leukemia)

LINE-1Yes Bollati et al.(2009)

Lung cancer(non-small cell lung

cancer)Alu Yes Daskalos et al.(2009)

LINE-1Yes Chalitchagorn et al.(2004);Daskalos et al.(2009);Jin et al.(2009);Saito et

al.

(2010)

Lymphoma LINE-1No Chalitchagorn et al.(2004) Malignant

peripheral

nerve sheath

tumor

LINE-1No Feber et al.(2011)

Melanoma LINE-1Yes Tellez et al.(2009) Multiple myeloma Alu Yes Bollati et al.(2009)

LINE-1Yes Bollati et al.(2009)

Neuroendocrine tumor Alu Yes Choi et al.(2007) LINE-1Yes Choi et al.(2007)

Neurofibromatosis LINE-1No Feber et al.(2011)

the detection of cancer DNA and to predict prognosis (Watanabe and Maekawa2010).

LINE-1s have often been referred to as parasitic or junk DNA sequences.However,many LINE-1s play a role in gene regulation,and this control is regulated by the5′UTR methylation level(Aporntewan et al.2011). As a result,changes in the methylation status of different sets of LINE-1loci may lead to different cellular phenotypes(Phokaew et al.2008;Aporntewan et al. 2011).These differences may be an underlying reason why LINE-1methylation levels in normal cells show so much variation(Chalitchagorn et al.2004).Lower methylation levels can also be found in many non-malignant conditions.Current PCR-based techniques were designed to measure LINE-1methylation level and cannot distinguish between malignant-and non-malignant-associated LINE-1hypomethylation(Xiong and Laird 1997;Laird2010;Weisenberger et al.2005;Yang et al. 2004).Therefore,a technique that measures not only the level but also the pattern of LINE-1methylation should improve detection specificity and sensitivity and broaden the applications of this tumor marker.The topics of this review therefore include the following:(1)an up-to-date review of studies on LINE-1and other IRS methylation levels in cancer;(2)the characteristics of LINE-1hypomethylation in cancer;(3)the locus-dependent roles of LINE-1hypomethylation in cancer development;and (4)the improvement in cancer DNA identification by LINE-1methylation classification.

LINE-1and other IRS methylation levels in cancer The methylation levels of LINE-1s,Alu elements,and some types of HERVs have been studied(Table1).LINE-1 is the IRS element that is most frequently studied,and its hypomethylation has been found in many cancers.In a few cancer types,including cancer of the kidney,thyroid,and lymph nodes;acute promyelocytic leukemia;malignant peripheral nerve sheath tumor;and parathyroid adenoma, LINE-1hypomethylation had not been found(Table1). LINE-1hypomethylation is also found in premalignant lesions of the cervix(Shuangshoti et al.2007),extrahepatic bile duct(Kim et al.2009a),and stomach(Park et al.2009). Unexpectedly,LINE-1hypermethylation was observed in some lesions that possess a high potential for malignant transformation,including lesions associated with myelodys-plastic syndrome(Romermann et al.2007)and liver cirrhosis(Takai et al.2000).Interestingly,LINE-1hyper-methylation is found in partial hydatidiform moles,whereas

Table1(continued)

Type of cancer Repeated

sequence

Hypomethylation Reference

Ovarian cancer AluHER Yes Watts et al.(2008)

V-W Yes Menendez et al.(2004)

LINE-1Yes Menendez et al.(2004);Pattamadilok et al.(2008);Woloszynska-Read et al.

(2008);

Dammann et al.(2010)

Parathyroid

adenoma

LINE-1No Juhlin et al.(2010)

Pheochromocytoma LINE-1Yes Geli et al.(2008)

Prostate cancer Alu Yes Kim et al.(2011)

LINE-1Yes Santourlidis et al.(1999;Schulz et al.(2002);Chalitchagorn et al.(2004);

Florl et al.

(2004);Kindich et al.(2006);Yegnasubramanian et al.(2008);Cho et al.

(2009)

Renal cell

carcinoma

LINE-1No Florl et al.(1999);Chalitchagorn et al.(2004)

Thyroid cancer

(follicular type)

LINE-1No Lee et al.(2008)

Thyroid cancer

(papillary type)

LINE-1No Chalitchagorn et al.(2004)

Urothelial cancer HERV-K Yes Florl et al.(1999)

Alu Yb8Yes Choi et al.(2009)

LINE-1Yes Jurgens et al.(1996);Florl et al.(1999);Neuhausen et al.(2006);Choi et al.

(2009);

Wilhelm et al.(2010);Wolff et al.(2010)

LINE-1hypomethylation is seen in triploid diandric embryos.Both lesions originate from dispermic fertilization of an oocyte,suggesting that LINE-1hypermethylation in moles is directly linked to the neoplastic process and is not a consequence of growth control(Perrin et al.2007).

As shown in Table2and ESM Table1,LINE-1 hypomethylation is associated with advanced tumor stage, higher histological grade,and poor prognosis.LINE-1 hypomethylation increases with tumor size(Tangkijvanich et al.2007)and with higher tumor stage(Florl et al.1999; Kindich et al.2006;Pattamadilok et al.2008;Lee et al. 2009;Baba et al.2010).With increasing histological grade, according to multistep carcinogenesis,LINE-1hypomethy-lation levels are increased in many cancer types(Florl et al. 1999;Shuangshoti et al.2007;Cho et al.2007;Park et al. 2009;Iramaneerat et al.2011;Pattamadilok et al.2008). Furthermore,LINE-1hypomethylation is correlated with chromosomal aberrations(Schulz et al.2002;Cho et al. 2007;Choi et al.2007;Ogino et al.2008a;Bollati et al. 2009),the hypermethylation of tumor suppressor genes (Choi et al.2007;Kim et al.2009a),mutations of tumor suppressor genes(Iacopetta et al.2007;Kim et al.2009a), the alternate transcription of oncogenes(Wolff et al.2010), and the deregulation of cancer genes(Woloszynska-Read et al.2008).Therefore,LINE-1hypomethylation is associated with malignant phenotypes in human cells,deregulating gene expression and accelerating DNA rearrangement. Interestingly,the LINE-1hypomethylation level is inversely associated with microsatellite instability(Estecio et al.2007; Iacopetta et al.2007;Ogino et al.2008a;Goel et al.2010; Kawakami et al.2011).This finding may indicate that microsatellite instability and LINE-1hypomethylation are characteristics of different genomic instability mechanisms.

From a clinical point of view,LINE-1hypomethy-lation is associated with tumor metastasis(Schulz et al. 2002;Choi et al.2007),the recurrence rate(Formeister et al.2010),and the mortality rate(Ogino et al.2008b;Ahn et al.2011).LINE-1hypomethylation has been reported to be a prognostic marker in several types of cancer including the stage IA subgroup of non-small cell lung cancer(Saito et al.2010),ovary(Pattamadilok et al. 2008),and colon(Ogino et al.2008b;Baba et al.2010). LINE-1hypomethylation has been proposed to be used as a screening tool for cancer detection.LINE-1hypome-thylation is observed in blood leukocyte DNA(Hsiung et al.2007;Wilhelm et al.2010),serum(Chalitchagorn et al.2004;Tangkijvanich et al.2007),and oral rinse samples(Subbalekha et al.2009).Moreover,LINE-1 hypomethylation has also been demonstrated to be a surrogate marker for predicting tumor treatment response and prognosis(Aparicio et al.2009;Sonpavde et al.2009; Bernstein et al.2010;Fang et al.2010;Kawakami et al. 2011).

Alu elements and HERV genomes have been studied less frequently(Table1).Hypomethylation of Alu sequences was reported in nine cancers,whereas hypomethylation of HERV-K and HERV-W genomes was found in urothelial cancer(Florl et al.1999)and ovarian cancer(Menendez et al.2004),respectively.All of the Alu-and HERV-hypomethylated cancers also possess LINE-1hypomethy-lation.Certain cancer phenotypes are associated with the methylation levels of certain IRS types.For example, HERV-K,but not LINE-1and HERV-E,methylation levels are associated with poor prognosis and platinum resistance of ovarian clear cell carcinoma(Iramaneerat et al.2011). Characteristics of LINE-1and global hypomethylation in cancer

Transgenic mice with hereditary defects in DNA methyl-transferase show increased risk of developing cancer (Gaudet et al.2003).Therefore,global hypomethylation may be one of the mechanisms that promote carcinogenesis and is unlikely to be just a consequence of cancer development.However,lower genome-wide methylation levels have also been found in many conditions,such as embryogenesis(Migeon et al.1991;Kremenskoy et al. 2003),aging(Lutz et al.1972;Gonzalo2010),congenital malformation(Wang et al.2010),exposure to certain environments(Bollati et al.2007),nutrition(Brunaud et al.2003),and autoimmune diseases(Richardson et al. 1990).There is no report of increased cancer development risk in individuals with some of these conditions.There-fore,it is reasonable to hypothesize that the genomic distribution of IRS methylation levels is different in global hypomethylation-related conditions.Interestingly,in some conditions,the loss of genome-wide methylation is IRS type-specific.For example,hypomethylation of Alu ele-ments and HERV-K,but not LINE-1,was found in aging cells(Jintaridth and Mutirangura2011).However,LINE-1 hypomethylation has been demonstrated in many other conditions(Schulz et al.2006).Because LINE-1methyla-tion levels can regulate host gene expression in cis (Aporntewan et al.2011),it is reasonable to hypothesize that the reduction in LINE-1methylation is the result of epigenomic heterogeneity.A simpler explanation is that even though two different cells possess the same number of LINE-1loci and methylation levels,each LINE-1locus may have a different level of LINE-1methylation in these cells(Phokaew et al.2008).Therefore,LINE-1hypome-thylation is a cancer biomarker that may be a diagnostic tool for many cancer types.However,LINE-1hypomethy-lation is not specific to cancer.The inclusion of information regarding the genomic LINE-1methylation distribution pattern should therefore be a promising way to improve and

Table2Interspersed repetitive sequence hypomethylation and cellular,molecular phenotype

Cancer IRS Cellular phenotype Molecular association Reference

Higher clinical stage Poorer

histological

grade

Survival

Cervical cancer L1NR PE NR NR Shuangshoti et al.

(2007) Cholangiocarcinoma L1NR PE NR PE for CIMP and TSG mutation Kim et al.(2009a) Colorectal cancer L1NR PE NR NR Chalitchagorn et

al.(2004) L1NR NR NR PE for MSS Matsuzaki et al.

(2005) L1NR NR NR PE for MSI and CIN Deng et al.(2006)

L1NR NR NR NE for MSI Estecio et al.

(2007)

L1PE PE in mucinous

histology NR NE for MSI and TSG mutation Iacopetta et al.

(2007)

L1NR NR NR NE for MSI and CIMP Ogino et al.

(2008a)

PE for chromosomal alteration in

non-MSI tumor

L1NR NR PE NR Ogino et al.

(2008b)

L1NR NR NR NE for SNPSs in one-carbon

pathway genes.

Hazra et al.(2010)

L1NR NR NR LINE-1methylation level

correlated between synchronous

cancer pairs from the same

individuals.Nosho et al. (2009a)

L1NR NR NR NE for DNMT3B-positive tumors Nosho et al.

(2009b) L1NR NR NR PE for CIMP An et al.(2010)

L1NR NR PE in proximal

colon cancer NE

in distal colon

cancer

NR Ahn et al.(2010)

L1NR NR PE PE for MSI,CIMP,CIN,TSG

mutation and TSG expression

Baba et al.(2010)

L1NR NR NR NE for MSI and methylation index Goel et al.(2010)

PE for MSS HNPCC

L1NR PE NR NR Ibrahim et al.

(2011) L1NR NR PE NE for MSI and CIMP Kawakami et al.

(2011) Alu,L1NE PE NR NR Kwon et al.(2010) Ependymoma Alu NR PE NR NR Xie et al.(2010) Gastric cancer Alu NR PE NR NR Park et al.(2009) L1NR PE NR NR Park et al.(2009)

L1NR NR NR PE for folate metabolizing gene

polymorphisms

Hou et al.(2010)

Gastrointestinal stromal cancer L1PE NR NR NR Igarashi et al.

(2010)

Head and neck cancer L1PE NR NR NR Smith et al.(2007) L1NR NR PE especially HPV

16negative SCC

NR Furniss et al.

(2008)

L1NS NS NR NR Subbalekha et al.

(2009)

Higher clinical stage Poorer

histological

grade

Survival

Hepatocellular carcinoma L1PE PE NR NR Tangkijvanich et

al.(2007)

Alu NE PE NR NR Lee et al.(2009) L1PE PE NR NR Lee et al.(2009) L1NR PE NR NR Kim et al.(2009b) L1NR NR PE NR Formeister et al.

(2010)

Multiple myeloma (MM)Alu NR PE NR NE for hyperdiploid MM Bollati et al.

(2009)

L1NR PE NR PE for chromosomal translocation Bollati et al.

(2009)

Nerve tumor L1NR NE NR NR Feber et al.(2011)

Neuroendocrine tumor Alu NR NE PE PE for TSG methylation Choi et al.(2007) L1NR NE PE PE for chromosomal alteration and

gene methylation

Choi et al.(2007)

Non-small cell lung cancer(NSCLC)L1NR SCC>

adenocarcinoma

(P<0.001)

NR NR Jin et al.(2009) L1NR NR PE NR Saito et al.(2010)

Odontogenic tumor L1NR Ameloblastoma

>KCOT

(P=0.001)NR NR Kitkumthorn and

Mutirangura

(2010)

Ovarian cancer L1NS NE PE NR(Pattamadilok et

al.2008) L1NR NR NR PE with TSG expression Woloszynska-

Read et al.

(2008) L1NR NR NR PE for follow-up patients treated

with decitabine(P<0.001)

Fang et al.(2010)

L1PE NR NR PE for TSG methylation Woloszynska-

Read et al.

(2011)

Ovarian clear cell carcinoma L1PE NR NR NR Iramaneerat et al.

(2011)

HERV-

E

PE NR NR NR Iramaneerat et al.

(2011)

HERV-

K

PE NR PE NR Iramaneerat et al.

(2011)

Pancreatic cancer L1NR NR NR PE for MTHFR polymorphisms Matsubayashi et

al.(2005) Prostate cancer L1PE NR NR NR Santourlidis et al.

(1999) L1PE NR PE PE with chromosomal aberration Schulz et al.

(2002) L1PE NR NR NR Kindich et al.

(2006) Alu PE PE NR NR Cho et al.(2007)

L1PE PE NR NR Cho et al.(2007)

L1NR NR PE NR Yegnasubramanian

et al.(2008) L1NR PE NR NR Cho et al.(2009)

widen the applications of LINE-1methylation as a tumor marker(Pobsook et al.2011).

Although LINE-1methylation levels are variable in both cancer and normal cells,the mechanisms that alter methyla-tion levels may be different.Normal cells possess several patterns of LINE-1methylation levels.The levels of some cell types are precise and limited to within a specific range.In other cases,such as in the esophagus and thyroid,the ranges are expanded(Chalitchagorn et al.2004).Similar patterns can be observed when the methylation status of each LINE-1 locus is observed(Phokaew et al.2008).Different loci possess different methylation levels.Some are limited in range and others have wider ranges.Levels of LINE-1locus methylation between different cell types are usually different, but each locus reveals similar patterns regarding the range of methylation levels(Phokaew et al.2008).

Comparison of methylation levels between LINE-1loci in normal cells showed no significant correlation.This result suggests that the methylation level is locus-dependent(Fig.1; Phokaew et al.2008).In contrast,significant associations of methylation levels between LINE-1loci were frequently found in cancer.Therefore,the mechanism causing LINE-1 hypomethylation in cancer occurs generally and in a genome-wide manner(Fig.1;Phokaew et al.2008). However,this mechanism may be biased toward some IRS https://www.wendangku.net/doc/ca134952.html,ing microarray analysis,Szpakowski et al. (2009)reported that primate-specific LINE-1elements and most of the younger,primate-specific retroelements were preferentially hypomethylated in samples of squamous cell carcinoma of the head and neck in comparison to non-tumor adjacent tissue and normal controls.The association of the methylation level between two LINE-1loci was found to be highest if they were located in the same gene(Phokaew et al. 2008).Therefore,in addition to evolutionarily derived classifications,LINE-1hypomethylation in cancer can be influenced by genomic location.LINE-1methylation regulates gene expression in cis The notion that LINE-1is methylated to prevent the process of retrotransposition should be reevaluated.First,in the human genome,less than100LINE-1s are retrotransposi-tion competent,and only a few LINE-1s have been shown to be responsible for retrotransposition events during human evolution(Sassaman et al.1997).Although a recent study showed that LINE-1retrotransposition may be common(Lupski2010;Beck et al.2010),this evidence fails to explain the methylation of the vast majority of retrotransposition-incompetent LINE-1s.The human ge-nome possesses thousands of5′UTR-containing LINE-1s, and most of them are methylated to a certain degree (Chalitchagorn et al.2004).It is unlikely that

this

Fig.1Effect of global hypomethylation in cancer.a Normal genomes contain hypermethylated,partially methylated,and hypomethylated LINE-1s.The methylation levels of each locus are regulated in a location-dependent manner.b The cancer genome contains more hypomethylated LINE-1s.Global hypomethylation decreases the methylation status of many LINE-1loci.However,there are some loci that are not influenced and some loci that show increased methylation levels.Local mechanisms are also present in cancer cells, and some locations are affected by the process of carcinogenesis

Higher clinical stage Poorer

histological

grade

Survival

Urothelial cancer L1PE PE NR NR Florl et al.(1999) L1PE PE NE NR Neuhausen et al.

(2006) L1NR NR NR PE for Met oncogene alternate

transcript

Wolff et al.(2010)

IRS interspersed repetitive sequence,L1long interspersed nucleotide element-1,NR no report,NS non-significant,PE positive evidence, NE negative evidence,TSG tumor suppressor gene,CIMP CpG island methylator phenotype,MSS microsatellite stable,MSI microsatellite instability, CIN chromosomal instability,SNP single nucleotide polymorphism,DNMT3B DNA methyltransferase-3B,HNPCC hereditary nonpolyposis colorectal cancer,MM multiple myeloma,HCC hepatocellular carcinoma,SCC squamous cell carcinoma,KCOT keratocystic odontogenic tumor, HERV-E human endogenous retrovirus E,HERV-K human endogenous retrovirus K,MTHFR methylenetetrahydrofolate reductase

methylation provides a selective advantage to the cells by preventing retrotransposition.The significant differences in LINE-1methylation levels between loci or cell types suggests that LINE-1methylation may be important to maintain normal cellular function and that this function may be altered by the global hypomethylation process that occurs in cancer.

The location-dependent LINE-1methylation pattern in normal cells suggests a role for epigenetic regulation.Currently,there are at least two reported mechanisms for how LINE-1methylation regulates gene expression in cis .Both mechanisms are dependent on the transcriptional activity of the LINE-1promoter.Moreover,similar to other promoters,the LINE-15′UTR promoter is controlled by DNA methylation,and the transcription activity of a LINE-1element is directly correlated with its hypomethylation level (Aporntewan et al.2011).The first mechanism is that LINE-1-mediated control of gene expression is through the production of unique RNA sequences (Fig.2).The other mechanism is that intragenic LINE-1RNAs repress host gene expression via the nuclear RNA-induced silencing complex (RISC;Fig.3).

There are two ways for the LINE-1promoter to produce unique RNA sequences (Fig.2).The 5′UTR of LINE-1is a promoter that transcribes in both the forward and reverse directions (Matlik et al.2006;Weber et al.2010;Speek 2001;Wolff et al.2010;Rangwala et al.2009).If the transcription is in the forward orientation,then the promoter produces LINE-1RNA.However,the poly-A addition signal of LINE-1does not always function.Consequently,many LINE-1transcripts can continue beyond the end of the LINE-1sequence,therefore resulting in 3′transduction (Moran et al.1999;Rangwala et al.2009).These transduction sequences are unique RNA sequences gener-ated by the LINE-1promoter.On the other hand,LINE-15′transduction that occurs by reverse transcription will also produce unique RNA sequences.A large number of these transduction sequences have been reported (Rangwala et al.2009);however,there are currently only two examples that prove that these sequences are increased by LINE-1hypomethylation (Weber et al.2010;Wolff et al.2010;Aporntewan et al.2011).

Intragenic LINE-1regulation of host gene expression was revealed by the finding that in vitro insertion of a full-length LINE-1disrupted host gene expression (Han et al.2004).In vivo,this gene regulation is tuned by LINE-1methylation levels (Aporntewan et al.2011).When LINE-1methylation levels were reduced by chemical treatment or by carcinogenesis,a significant number of genes containing LINE-1s were repressed (Fig.3a –c ).The degree of this repression was inversely correlated with the intragenic LINE-1methylation level.The role of LINE-1methylation is to prevent the formation of a pre-mRNA –LINE-1–RNA complex.If the complex is formed,then the RISC protein AGO2will bind and prevent mRNA production (Fig.3;Aporntewan et al.2011).

Comparative sequence analysis between intragenic and intergenic LINE-1s showed multiple conserved nucleotides in intragenic LINE-1s that are crucial for maintaining LINE-1transcription and methylation (Aporntewan et al.2011).Moreover,many LINE-1s are excluded from genomic regions containing housekeeping genes (Eller et al.2007;Graham and Boissinot 2006).Therefore,locations of LINE-1s yield a selective advantage for human evolu-tion.It is important to note that the diploid human genome contains an extensive amount of structural variation due to retrotransposition events (Huang et al.2010;Ewing and Kazazian 2011).Consequently,variation in the expression of many genes may be due to the distinctive locations of heritable LINE-1s,and similar to other DNA polymorphisms,some LINE-1insertions are polymorphisms that lead to certain disease-related phenotypes.LINE-1hypomethylation may also control gene expression in trans .In some cancer cells,inhibition of LINE-1reverse transcriptase can alter the expression of many genes (Carlini et al.2010).

LINE-1hypomethylation and genomic instability in cancer

In addition to a number of association studies (Ji et al.1997;Lu and Randerath 1984;Daskalos et al.2009),the high risk of chromosomal abnormalities in individuals with hereditary mutations in DNA methyltransferase genes indicates that global hypomethylation promotes genomic instability (Hansen et al.1999;Eden et al.2003).However,the underlying mechanisms of how DNA

methylation

Fig.2LINE-1can produce two types of unique RNA sequences.One type of unique sequence is the result of LINE-1RNA tran-scription proceeding beyond the LINE-1sequence.The other type occurs when the reverse LINE-1promoter transcribes unique DNA sequences located beyond the 5′end of LINE-1

maintains genomic integrity are not yet known.Current reports suggest that LINE-1hypomethylation leads to several events that promote genomic instability,including retrotransposition,endogenous DNA double-strand break (EDSB)repair,and the dysregulation of DNA repair genes.The process of LINE-1retrotransposition includes RNA transcription,protein translation,DNA restriction,reverse transcription,and integration (Moran 1999).This retrotrans-position usually produces large DNA rearrangements (Huang et al.2010;Gilbert et al.2002).Recently,an advanced LINE-1junction sequencing technique showed that somatic L1insertions occur at high frequency in human lung cancer genomes (Iskow et al.2010).Therefore,LINE-1hypome-thylation in cancer may increase the retrotransposition activity of some LINE-1s and consequently cause a faster rate of DNA rearrangement.However,many DNA rear-rangements occur in cancer cells that are not LINE-1retrotransposition events.Therefore,LINE-1retrotransposi-tion contributes to only a small proportion of mutations in cancer.Moreover,there are only a few reports that retrotransposition events can produce clonal expansion mutations (Miki et al.1992).Finally,the loss of the methylation of non-retrotransposable repeats,such as satellite DNA,also promotes chromosome translocation (Maraschio et al.1988;Ji et al.1997).Therefore,LINE-1retrotranspo-sition may not be the major mechanism causing somatic mutation in cancer by global hypomethylation.

The second mechanism is the differential repair of methylated and unmethylated replication-independent EDSBs (RIND-EDSBs;Kongruttanachok et al.2010).RIND-EDSBs are different from replication-dependent EDSBs and environmental-or radiation-induced DSBs.Replication-dependent EDSBs and radiation-induced DSBs,if unre-paired,lead to cell death.In contrast,RIND-EDSBs are ubiquitously present in all cells and always involve hyper-methylation (Pornthanakasem et al.2008).This occurrence indicates a time lag between methylated RIND-EDSB production and repair (Kongruttanachok et al.2010).RIND-EDSBs can be produced within both methylated and unmethylated genomes.Methylated RIND-EDSBs are selec-tively repaired by the more precise ataxia telangiectasia mutated (ATM)-dependent non-homologous end joining repair process (Kongruttanachok et al.2010).Therefore,the RIND-EDSB repair process of hypomethylated genomes is faster and more error-prone.Because the LINE-1methyla-tion levels of each locus are distinct,the mutation rate caused by RIND-EDSB repair errors is dependent on the methyla-tion status of the genome near the EDSBs.Currently,there are only two reports focused on RIND-EDSBs (Pornthanakasem et al.2008;Kongruttanachok et al.2010).Further studies are needed to explore the causes and roles of RIND-EDSBs and to determine how genomic hypomethylation promotes instability.A third possible mechanism is that LINE-1hypomethy-lation down-regulates DNA repair genes.One of these genes is PPP2R2B ,which contains intragenic LINE-1s.In cancer,these LINE-1s are frequently hypomethylated and PPP2R2B is frequently down-regulated (Aporntewan et al.2011).One of the functions of PPP2R2B is to increase nuclear ATM protein (Suyarnsestakorn et al.2010).ATM is a serine/threonine protein kinase that is important in the activation of the DNA damage checkpoint,leading to cell cycle arrest,DNA repair,or apoptosis (Mavrou et al.2008).A lack of ATM promotes genomic instability (Kim et al.2002).Therefore,LINE-1hypomethylation may indirectly promote genomic instability by interfering with ATM

function.

Fig.3Intragenic hypomethy-lated LINE-1s repress host gene expression via AGO2.The schematic demonstrates that the same gene from three different cells has different levels of intragenic LINE-1methylation.a Hypermethylated LINE-1.b Partially methylated LINE-1.c Hypomethylated LINE-1.LINE-1RNA is produced when the methylation of the LINE-15′UTR is reduced.The LINE-1RNA –pre-mRNA complex is bound by AGO2,and mRNA production is prevented

LINE-1methylation patterns in normal and cancer cells It is commonly assumed that LINE-1elements in normal cells are completely https://www.wendangku.net/doc/ca134952.html,bined bisulfite restric-tion analysis or COBRA,deep sequencing,and microarray analysis demonstrated that the genomic distribution of the methylation of LINE-1s and other IRS loci is not homogenous (Phokaew et al.2008;Xie et al.2009,2011;Szpakowski et al.2009).The methylation levels of LINE-1loci can be divided into three groups:hypermethylated,partially methylated,and hypomethylated (Pobsook et al.2011).Classification is based on the number of methylated and unmethylated CpG dinucleotides (Fig.1).In normal cells,the majorities of LINE-1loci are hypermethylated or partially methylated.Few LINE-1loci are https://www.wendangku.net/doc/ca134952.html,parisons between normal white blood cells and normal oral epithelium showed that even though LINE-1methyl-ation levels are different,the number of hypomethylated loci was not distinguishable between the two normal tissues (Fig.4).Therefore,the differences in methylation levels between normal cell types are primarily influenced by the number of hypermethylated and partially methylated loci.In cancer cells,the methylation of a majority of LINE-1loci is decreased,with some loci remaining unchanged and a few being increased when compared with normal cells.Thus,the number of hypomethylated loci is increased in cancer cells (Fig.4).

A recent report showed distinctive characteristics of LINE-1partial methylation that was dependent on malig-nant transformation (Pobsook et al.2011).In normal cells,the number of partially methylated LINE-1loci in each sample was directly correlated with the number of hypomethylated loci,but was inversely associated with the number of hypermethylated loci.This result suggested that a dynamic form of LINE-1epigenetic modification,between partial methylation and hypermethylation,is present in normal cells.Because hypomethylated LINE-1s were not distinguishable between different types of normal cells,the dynamic between the partially methylated and hypermethylated forms may be the cause of the variation in LINE-1methylation levels between normal cell types.Moreover,the more partially methylated loci may represent the lower LINE-1methylation level.In contrast,in the cancer genome,the number of partially methylated LINE-1s was directly correlated with the number of hyper-methylated LINE-1s.Therefore,in striking contrast to the normal genome,partially methylated LINE-1loci represent a subset of methylated LINE-1s in cancer cells (Pobsook et al.2011).Current PCR-based techniques,by real-time quantitative PCR,COBRA,and pyrosequencing,determine LINE-1hypomethylation levels by combining all unmethy-lated CpG nucleotides from both partially methylated or hypomethylated loci (Xiong and Laird 1997;Laird 2010;Weisenberger et al.2005;Yang et al.2004).Therefore,the sensitivity in distinguishing cancer DNA is low.Pobsook et al.(2011)also showed that excluding partial methylation loci from the count of hypomethylated LINE-1loci improved the sensitivity and specificity of cancer DNA detection.

From biology to clinical application and future direction of LINE-1hypomethylation in cancer

Understanding how LINE-1methylation levels change during multistep carcinogenesis has implications for diagnostic applications.Several LINE-1and other IRS methylation studies have shown that global hypomethy-lation is a common epigenetic change in cancer (Table 1).Moreover,this process is directly correlated with cancer progression.Therefore,lower LINE-1meth-ylation levels have been shown to be associated with higher cancer stages and may also be a promising marker for the prognostic prediction of many cancers (Table 2and ESM Table 1).Global methylation changes initiate early,and the genome becomes progressively hypo-methylated during the process of multistep carcinogene-sis.Therefore,LINE-1and other IRS hypomethylation levels are candidate tumor markers for cancer (Table 2and ESM Table 1

).

Fig.4Examples of LINE-1methylation patterns in three cells.The number of LINE-1loci and the methylation levels were approximated from the average levels of a previous report (Pobsook et al.2011).Type I normal cells (a ),type II normal cells (b ),and cancer cells (c )possess LINE-1methylation levels of 60.87%,56.52%,and 44.44%,respectively.Even though different normal cell types contain different methylation levels,the numbers of partially methylated,hypermethy-lated,and hypomethylated loci were not different.Cancer cells showed lower methylation levels and a lower number of partially methylated loci,but a higher number of hypomethylated LINE-1loci

There is a technical advantage to using PCR-based assays to measure IRS methylation levels.Multiple copies of IRSs are present in the genome;therefore,this detection method is highly sensitive even in poor-quality clinical DNA samples.These clinical samples include paraffin-embedded sections,plasma,and other fluid or washes,such as oral rinses(Chalitchagorn et al.2004;Tangkijvanich et al.2007;Aparicio et al.2009;Subbalekha et al.2009) (Vaissiere et al.2009).LINE-1hypomethylation was also detected in the white blood cells of cancer patients (Hsiung et al.2007;Wilhelm et al.2010).The source of the hypomethylated cells in cancer patients still needs to be identified to determine whether these cells are from cancer cells or from normal cells with systemic hypo-methylated LINE-1s.Nevertheless,this evidence suggests that LINE-1methylation is a promising marker in cancer risk prediction.

Cells must have a correct amount of LINE-1methylation to maintain their physiological functions(Aporntewan et al. 2011).Consequently,there is a wide range of LINE-1 methylation levels found in normal cells,depending on cell type(Chalitchagorn et al.2004).This methylation range leads to low specificity when using LINE-1hypomethyla-tion as a cancer screening marker.The ability to distinguish between normal and tumor DNA is low,particularly because clinical samples,including plasma,mouth washes, or Papanicolaou smears,are routinely contaminated with DNA from several normal cell types.LINE-1methylation pattern analysis demonstrated unprecedented characteristics of LINE-1partial methylation in normal cells and in the cancer global hypomethylation process(Pobsook et al. 2011).The interchangeable pattern between LINE-1hyper-methylation and partial methylation is a mechanism that may result in different LINE-1methylation levels in normal cells(Pobsook et al.2011).In cancer,global hypomethy-lation is observed because of the loss of methylation of previously hypermethylated and partial methylated loci. Most PCR-based LINE-1methylation measurement tech-niques cannot differentiate unmethylated CpG dinucleo-tides of partially methylated LINE-1s from unmethylated LINE-1s.There was a recent report using COBRA to classify LINE-1s into the three classes.This report showed that the number of unmethylated LINE-1loci was a more sensitive and specific marker than LINE-1 methylation level to detect cancer DNA in mouthwash samples(Pobsook et al.2011).It may be interesting to compare the number of unmethylated LINE-1loci with LINE-1methylation levels in other clinical samples. Moreover,it may be worth exploring whether changes in partially methylated LINE-1loci can be observed in,and are able to predict,malignant transformation in pathological lesions in the very early stages of carcinogenesis or tissues in patients at risk of developing cancer.

Although the methylation of a majority of LINE-1loci is reduced in cancer,some loci are unchanged.Currently, there are several advanced genomic techniques,including deep sequencing(Xie et al.2009;Xie et al.2011)and custom-made microarrays(Szpakowski et al.2009),that are capable of measuring the methylation level of each LINE-1 or IRS locus.These approaches identified certain classes of LINE-1s and IRSs that more frequently show loss of methylation in cancer.Improved deep sequencing techni-ques will be able to determine the proportions of the three LINE-1methylation classes at each LINE-1locus.It is important to reevaluate the clinical significance of LINE-1 methylation by these advanced techniques.These methods should help define the relevant LINE-1locations,sequen-ces,and methylation patterns that are specific to carcino-genesis.Moreover,some intragenic LINE-1loci are methylated cis-regulatory elements of their host genes (Aporntewan et al.2011).Altered expression of these genes may lead to certain cellular phenotypes and clinical presentations.Genome-wide arrays or deep sequencing may be used to design promising new sets of methylated LINE-1PCR-based techniques specifically aimed for the classification of the epigenome of the tumor phenotype.

Interestingly,some pathological lesions with increased potential for malignant transformation,such as myelodys-plastic syndrome lesions,liver cirrhosis,and partial hydatidiform moles,possess LINE-1hypermethylation (Takai et al.2000;Romermann et al.2007;Perrin et al. 2007).Further descriptive studies of other lesions,genomic distributions,and methylation patterns will clarify in detail whether this epigenetic process occurs during the early steps of LINE-1hypomethylation in cancer.It is important to note that genome-wide hypomethylation in cancer can result in hypermethylated LINE-1s at some loci(Fig.4; Phokaew et al.2008).If LINE-1hypermethylation and hypomethylation are present at the same loci in premalig-nant tissues and cancer,this finding would be a break-through by showing that epigenomic changes precede genetic changes during carcinogenesis.Detailed molecular biological approaches to explain how LINE-1methylation fluctuates from hypermethylation to hypomethylation will be important to understand the development of global hypomethylation in cancer.

Finally,global hypomethylation mechanisms may be crucial for future cancer prevention and treatment.Genome-wide hypomethylation is common,occurs at an earlier stage of carcinogenesis,and is still an active process in most cancers(Tables1and2and ESM Table1).Global hypomethylation is an epigenomic process that leads to cellular phenotypic changes.LINE-1hypomethylation in cancer alters the expression of a large number of genes. Therefore,this epigenomic alteration should be an impor-tant target for future cancer prevention strategies.More-

over,unlike mutation,hypomethylation is reversible. Therefore,global hypomethylation in cancer is a candidate for new cancer treatments in the future. Acknowledgments References in Thailand have been supported by the Thailand Research Fund,the National Center for Biotechnology and Genetic Engineering(Thailand),Four Seasons Hotel Bangkok and the Thai Red Cross Society4th Cancer Care Charity,a RF-MRG Scientific Researcher grant,and Chulalongkorn University.

Conflict of interest The authors have no conflict of interest to report.

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Y oshida T,Y amashita S,Takamura-Enya T,Niwa T,Ando T,Enomoto S, Maekita T,Nakazawa K,Tatematsu M,Ichinose M,Ushijima T(2011) Alu and Satalpha hypomethylation in Helicobacter pylori-infected gastric mucosae.Int J Cancer128(1):33–39.doi:10.1002/ijc.25534

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全国高考历年各省录取分数线比较与分析 (2012-01-12 18:02:09) 转载▼ 分类:杂谈 标签: 全国高考 各省 分数 比较 分析 山东 河北 北京 上海 湖北 江苏 浙江 甘肃 陕西 主要以时间序列来考察中央部属大学分省招生的公平性问题,本节主要考察恢复高考以来各省分数线的整体演变趋势,这也是被社会各界广泛关注的焦点问题。具体来说,依据分省招生的数量、基础教育的水平和高等教育资源的丰富程度三个因素来揭示其演变的动因。首先,高考分数线的变化与招生名额的投放有很大关系,即在相同的条件下,招生数量越多,录取分数线就越低;其次,基础教育水平的高低决定了该省生源的优劣程度,在同等条件下,基础教育水平越高,分数线也相应越高;最后,高等教育资源的丰富程度决定了招生数量的多寡,也会影响到分数线的变化,其中,高校的数量,特别是“211工程”院校和“985”工程院校的数量在很大程度上决定了本科一批分数线的高低。本节主要选取这三个因素来反映各省高考录取分数线的变化情况。 一、恢复高考以来各省分数线的变化趋势 高考建制之初,由于招生数在整体上多于高中毕业生数,所以录取分数线也较低,并且实行以大行政区为主的招生体制,所以当时的分数线没有太多实质的意义。1958 年高考制度暂时中断,次年旋即恢复,并从此确立了分省录取制度,至此才出现了分省的高考录取分数线。但因 20 世纪 60 年代强烈的**因素的干扰,高考制度经历了较大的反复,科目改革频

仍,且相关数据散佚难以获取。 故此,只研究恢复高考以来各省分数线的变化情况。笔者选取 1980 年、1991 年和 1999 年的三个时间点的分省高考录取分数线来研究其基本的走势,之所以选取这三个时间点,出于以下考虑: 其一,1977 年到 1979 年考生众多、竞争激烈,属于特殊时期,从 1980 年开始,各项教育事业和高考制度逐步趋于正常; 其二,1999 年除广东实行“3+X”改革和上海单独命题之外,其他省区均采用全国卷,分数易于比较,之后因“3+X”改革方案在全国推广,试卷纷繁多样而难以比较;其三,1991 年大致处于两者之间,且大多数省区采用全国卷,分数易于比较。故此,选取以上三个年份的数据。大体而言,三个时段的分数线基本能够反应各省分数线变化的趋势。 将 1977年至 1999 年的各省录取分数线整理如下

2012美国商学院排名

商学院Rank排名University大学名称 1 Stanford University斯坦福大学 2 Harvard University哈佛大学 3 Massachusetts Institute of Technology麻省理工学院(Sloan) 3 University of Pennsylvania宾夕法尼亚大学(Wharton) 5 Northwestern University西北大学(Kellogg) 5 The University of Chicago芝加哥大学(Booth) 7 Dartmouth College达特茅斯学院(Tuck) 7 University of California Berkeley加州大学伯克利分校(Haas) 9 Columbia University哥伦比亚大学 10 New York University纽约大学(Stern) 10 Yale University耶鲁大学 12 Duke University杜克大学(Fuqua) 13 University of Virginia弗吉尼亚大学(Darden) 14 University of California Los Angeles加州大学洛杉机分校(Anderson) 1 4 University of Michigan Ann Arbor密西根大学-安娜堡分校(Ross) 16 Cornell University康乃尔大学(Johnson) 17 The University of Texas at Austin德克萨斯大学奥斯汀分校(McCombs) 18 Carnegie Mellon University卡内基美隆大学(Tepper) 1 9 The University of North Carolina at Chapel Hill北卡罗来纳大学教堂山分校(Kenan-Flagler) 20 Washington University in St Louis圣路易斯华盛顿大学(Olin) 21 University of Minnesota Twin Cities明尼苏达大学Twin Cities分校(Carlson) 21 University of Southern California南加州大学(Marshall) 23 Emory University埃默里大学(Goizueta) 23 Indiana University,Bloomington印地安那大学伯明顿分校(Kelley) 25 Georgetown University乔治城大学(McDonough) 25 Ohio State University (Fisher) 27 Arizona State University亚利桑那州立大学(Carey) 28 Georgia Institute of Technology佐治亚理工学院 28 University of California Davis加州大学戴维斯分校 28 University of Wisconsin Madison威斯康星大学麦迪逊分校 28 Vanderbilt University范德堡大学(Owen) 32 Brigham Young University杨百翰大学(Marriott) 32 Texas A&M University--College Station (Mays) 34 Boston College波士顿学院(Carroll) 34 BOSTON University波士顿大学 34 Rice University莱斯大学(Jones) 37 University of Illinois Urbana Champaign伊利诺伊大学厄本那―香槟分校 37 University of Notre Dame圣母大学(Mendoza) 37 University of Washington华盛顿大学(Foster) 40 Penn State University Park宾州州立大学-University Park Campus (Smeal) 40 Tulane University杜兰大学(Freeman) 40 University of California Irvine加州大学欧文分校(Merage) 40 The University of Iowa爱荷华大学(Tippie) 40 University of Texas--Dallas 45 University of Maryland College Park马里兰大学帕克分校(Smith) 45 University of Rochester罗切斯特大学(Simon) 47 University of Florida佛罗里达大学(Hough) 47 Wake Forest University维克森林大学(Babcock) 49 Michigan State University密歇根州立大学(Broad) 49 Purdue University,West Lafayette普渡大学西拉法叶校区(Krannert) 51 University of Arkansas阿肯色大学--Fayetteville (Walton) 52 Babson College (Olin) 52 The George Washington University乔治华盛顿大学 54 University of Missouri Columbia密苏里大学哥伦比亚分校--Columbia (Trulaske) 54

优课评分表

三岔小学优课评选参考标准 科目执教教师年级课题总分 指标参考评分细则分 值 评 分 教学设计 能从知识与能力,过程与方法,情感态度价值观三个维度确定教学目标。目标明确、具体、 可行,体现学科、年段及学生认知特点。 15 分紧紧围绕教学目标和学情精选教学内容,正确理解和科学处理教材。内容安排合理,容量适当,重难点清晰。 教学步骤清晰明了,循序渐进。教学结构完整,方法多样,具有鲜明的创新性,有利于促进 学生主动参与和个性发展。 板书设计简明、扼要,有利于学生把握重点,突破难点。 作业设计体现差异性,学生有自主选择的空间。作业形式活泼,能与生活实践有机结合。 教学过程 面向全体学生,充分体现学生的主体性,切实做好组织者、引导者、促进者的工作,将教师 的引导与学生的自主学习有机结合。 40 分创设情境,营造民主、和谐、宽松的学习生态,师生互动多元,有效激发学习动机提高学习 效率。 能针对不同层次与个性的学生,采用个别化的策略进行积极地干预。尤其关注学习困难或遭 遇问题的学生,有切实可行的方法帮助他们获得提升,走出困境。 教学深入浅出,点拨得当,反馈及时。教学评价富有激励性和针对性。能根据课堂生成灵活 调整教学流程与方法,帮助学生自主建构,全面发展。 注重能力和习惯的培养,渗透学习方法,精讲多练,举一反三,注重知识的迁移和生活中的 运用,目标达成度高。 课堂提问富有启发性,开放性和针对性。善于运用问题链引发学生深度思考,持续学习。为 学生独立思考和自主学习提供有效支撑和导引。 有独到的学科思想和教学策略,基本形成个人特有的教学风格。 教学手段 能够运用多媒体、电子白板或网络平台,以及直观教具等进行交互式教学模式的创新,有效 辅助教学目标的达成。15 分准确选择信息技术与教学内容的结合点,资源组织恰当、丰富、有实效,真正体现信息技术 与教学的深度融合。 资源内容丰富,链接便捷,操作简单,使用熟练。媒体运行稳定,响应及时,播放流畅,学 生关注度高。 学生活动 学习积极主动,活动参与度高,学习情绪高昂,提升明显。 20 分善于倾听,独立思考,问题解决与创新表达的欲望强烈。 有多边、多样的信息联系,能与教师和同伴展开协作学习,学习共同体相互依赖度高。 能从教师推荐的资源(网络图文资源、资料袋等)中自主选择、重组信息、发现规律,形成 自己的见解并高质量表达。 专业素养运用普通话教学,教学语言清晰、准确、简练、生动、逻辑严密,富有启发性和感染力。 10 分教态亲切、自然、大方,非言语行为呈现合理。 富有教学机智,课堂调控能力强,做到因势利导,顺学而教。 知识储备和文化积淀丰厚,专业功底扎实,无知识性错误。书写规范,工整,美观。

2012年全球商学院排名

2012年全球商学院排名 斯坦福首次折桂英国《金融时报》商学院排名的编纂涉及20个不同类别的数据,包括学校的国际前景、研究和思想成果、排名前100的全日制MBA项目毕业生的成就。在毕业三年后的平均工资这个类别上,斯坦福大学商学院的优势越来越明显,且据校友报道,该院MBA毕业生平均薪资过去6年来都是最高的。 在前十名的商学院中,除了头三名被美国所占据外,还有排名第5的哥伦比亚大学商学院,排名第7的麻省理工大学MIT商学院来自美国。其余分别由排名第4的英国伦敦商学院,两所西班牙的商学院,欧洲工商管理学院及中国的香港科技大学所占领。 香港科技大学稳居“亚洲一哥”在百强榜单中,共有5所中国的商学院入选,其中香港科技大学管理学院名列第十,其毕业生平均年薪为12.76万美元。这也是中国地区排名最高的商学院。而在全球范围内看,毕业于美国商学院的学生较亚洲欧洲其他商学院,薪水更高。 相关排名具体如下: 排名学校毕业生平均年薪(美元)1 斯坦福商学院 19.22万 2 哈佛商学院 17.83万 3 沃顿商学院 17.24万 4 伦敦商学院 15.30万 5 哥伦比亚大学商学院 16.65万

6 欧洲工商管理学院 14.44万 7 麻省理工大学商学院 15.73万 8 西班牙IE商学院 15.67万 9 西班牙Iese 商学院 13.39万 10 香港科技大学 12.76万 12 芝加哥大学商学院 15.26万14 加州伯克利商学院 14.68万17 纽约大学商学院 13.41万20 耶鲁大学商学院 14.25万20 牛津大学商学院 13.48万20 印度商学院 12.95万 24 康奈尔大学商学院 14.17万24 上海中欧管理学院 12.30万26 剑桥大学商学院 13.27万

温岭市2013年中考录取分数线公布

温岭市2013年高中录取分数线 提前批: 温中文科实验班:665.2/388(科学按80%计,数学成绩不低于全市平均分上25分,即144分) 新河中学文科实验班:652.4/386(科学按80%计,数学成绩不低于全市平均分上20分,即139分) 二中文科实验班:645/388(科学按80%计,数学成绩不低于全市平均分上20分,即139分) 第一批:温岭中学、新河中学、市二中正取分数线: 毕业学校温岭中学正取分数线新河中学正取分数线市二中正取分数线市三中学715/394 684.0/ 378.0/ 263.0 691.0/ 384 市四中714.0/ 392.0/ 276.0 685.0/ 373.0/ 260.0/ 127.0 689.0/ 373.0/ 260.0/ 131.0 温中实验学校712.0/ 393.0/ 275.0/ 135.0 691.0/ 379.0/ 261.0/ 124.0 689.0/ 383.0/ 269.0/ 132.0 实验学校714.0/ 392 689.0/ 371.0/ 257.0/ 133.0 687.0/ 386.0/ 272.0/ 134.0 少体校/ / / 653.0/ 365.0/ 258.0/ 120.0 642.0/ 359.0/ 257.0/ 129.0 敬业中学/ / / 675.0/ 383.0/ 266.0/ 125.0 673.0/ 367.0/ 252.0/ 123.0 温中双语学校699.0/ 381.0/ 267.0/ 127.0 686.0/ 372.0/ 255.0/ 125.0 681.0/ 375.0/ 257.0/ 120.0 第五中学698.0/ 387.0/ 271.0/ 133.0 686.0/ 371.0/ 254.0/ 115.0 681.0/ 374.0/ 256.0/ 125.0 第八中学697.0/ 386.0/ 269.0/ 128.0 685.0/ 382.0/ 270.0/ 135.0 674.0/ 371.0/ 254.0/ 129.0

“一师一优课、一课一名师”活动--“优课”评选参考标准及课例视频标准

“一师一优课、一课一名师”活动--“优课”评选参考标准及课例视频标准

“优课”评选参考标准 一、教学设计 (一)能从知识与能力,过程与方法,情感态度价值观三个维度确定教学目标。目标明确、具体、可行,体现学科、年段及学生认知特点。 (二)紧紧围绕教学目标和学情精选教学内容,正确理解和科学处理教材。内容安排合理,容量适当,重难点清晰。 (三)教学步骤清晰明了,循序渐进。教学结构完整,方法多样,具有鲜明的创新性,有利于促进学生主动参与和个性发展。 (四)板书设计简明、扼要,有利于学生把握重点,突破难点。 (五)作业设计体现差异性,学生有自主选择的空间。作业形式活泼,能与生活实践有机结合。 二、教学实施 (一)面向全体学生,充分体现学生的主体性,切实做好组织者、引导者、促进者的工作,将教师的引导与学生的自主学习有机结合。 (二)创设情境,营造民主、和谐、宽松的学习生态,师生互动多元,有效激发学习动机,提高学习效率。 (三)能针对不同层次与个性的学生,采用个别化的策略进行积极地干预。尤其关注学习困难或遭遇问题的学生,有切实可行的方法帮助他们获得提升,走出困境。

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