A randomised trial to compare the pharmacokinetic,
pharmacodynamic,and antiviral e?ects of peginterferon alfa-2b
and peginterferon alfa-2a in patients with chronic hepatitis C (COMPARE)
Marcelo Silva 1,*,Jorge Poo 2,Frank Wagner 3,Mary Jackson 4,David Cutler 4,Michael Grace 4,Ronald Bordens 4,Connie Cullen 4,Joann Harvey 4,Mark Laughlin 4
1
Hospital Universitario Austral,Pilar,Argentina
2
CIF-BIOTEC/Hospital Medical Sur,Mexico City,Mexico
3
Clinical Research,Berlin,Germany
4
Schering-Plough Research Institute,Kenilworth,NJ,USA
See Editorial,pages 172–173
Background /Aims :To compare the pharmacokinetics,pharmacodynamics,and antiviral activity of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C virus genotype 1.
Methods :Thirty-six patients were randomised to peginterferon alfa-2b (1.5l g /kg/week)or peginterferon alfa-2a (180l g/week)for 4weeks,then in combination with ribavirin (13mg/kg/day)for a further 4weeks.The pharmacokinetic pro?le of both peginterferons,mRNA expression of a selected group of interferon-induced gene transcripts,and serum HCV-RNA levels were assessed.
Results :Patients receiving peginterferon alfa-2b had signi?cantly greater up-regulation of interferon-alfa response genes compared with those receiving peginterferon alfa-2a.Correspondingly,patients treated with peginterferon alfa-2b also had a signi?cantly greater log 10maximum and log 10time-weighted average decrease in serum HCV-RNA.A greater propor-tion of peginterferon alfa-2b patients achieved a P 2.0log 10reduction in serum HCV-RNA levels by week 8(72%vs 44%of peginterferon alfa-2a patients,P =0.09).There was an approximately 16-fold greater exposure to peginterferon in the serum of patients treated with peginterferon alfa-2a.
Conclusions :These ?ndings suggest that the biological activity,measured by early interferon-induced gene transcripts and early antiviral responsiveness,may have been greater in patients treated with peginterferon alfa-2b despite their lower exposure to the drug compared with patients treated with peginterferon alfa-2a.
ó2006European Association for the Study of the Liver.Published by Elsevier B.V.All rights reserved.
Keywords :Chronic hepatitis C infection;Pegylated interferon;Peginterferon alfa-2b;Peginterferon alfa-2a;Ribavirin
1.Introduction
Hepatitis C virus (HCV)is the leading cause of liver transplantation in the US and Europe and is associated
with an increased risk of hepatocellular carcinoma [1,2].Owing to the chronic nature of the disease,estimates suggest that its healthcare burden will increase dramat-ically [3].The current standard of treatment is based on interferon alfa therapy and consists of the combina-tion of peginterferon alfa-2plus ribavirin [4].
Type I interferons do not interact directly with the virus but rather exert their e?ects through interaction with their speci?c receptor.The interaction initiates a
0168-8278/$32.00ó2006European Association for the Study of the Liver.Published by Elsevier B.V.All rights reserved.doi:10.1016/j.jhep.2006.03.008
Received 15August 2005;received in revised form 7March 2006;accepted 9March 2006;available online 18April 2006*
Corresponding author.Tel.:+542322482624.
E-mail address:msilva@https://www.doczj.com/doc/6516773010.html,.ar (M.Silva).
https://www.doczj.com/doc/6516773010.html,/locate/jhep
Journal of Hepatology 45(2006)
204–213
cascade of intracellular Janus-kinase-mediated events, leading to changes in gene-transcript expression.Some of these up-regulated genes[e.g.,RNA-dependent pro-tein kinase(PKR),2050oligoadenylate synthetase (OAS)]are believed to have an important role in the interruption of HCV replication within infected hepato-cytes[5–7].
Recent advances in pegylation chemistry have led to the development of interferon alfas with longer half-lives.The covalent attachment of a polyethylene glycol (PEG)molecule to the interferon alfa protein results in decreased renal clearance and a longer half-life in the plasma[8–10].The size and position of the PEG mole-cule used in the two currently licensed peginterferons: peginterferon alfa-2b(PegIntronò,Schering Corp., Kenilworth,NJ,USA)and peginterferon alfa-2a(Pega-sysò,Ho?mann-La Roche,Basel,Switzerland)di?er signi?cantly in their respective physical-chemical charac-teristics[11–14].Although pegylation improves the pharmacokinetic properties of the core protein,it also results in loss of in vitro biological activity[8,15].The antiviral activity of peginterferon alfa-2b is approxi-mately28%of the interferon alfa-2b core protein[12]. The antiviral activity of peginterferon alfa-2a ranges between1%and7%of the antiviral activity of the inter-feron alfa-2a core protein[16].Recent work has demon-strated that the size and site of attachment of the PEG moiety on the interferon alfa molecule markedly a?ects its speci?c activity[12,17].
The purpose of this trial was to determine if these in vitro di?erences between peginterferon alfa-2b and peginterferon alfa-2a would translate to observable dif-ferences in their in vivo biological activity.This was done by assessing the e?ect of treatment on early viro-logic response as well as on expression of interferon response genes as markers of their mechanism of action [12,17].
2.Materials and methods
2.1.Study design
This was an8-week,double-blind,randomised,multicentre,paral-lel-group study comparing the pharmacokinetics,pharmacodynamics, and antiviral activity of peginterferon alfa-2b and peginterferon alfa-2a in patients infected with HCV genotype1.Study drug was prepared by a site pharmacist and administered by a quali?ed,independent third party who was blinded to protocol assignments.Neither the pharma-cist nor the individual administering the injection had further involve-ment in the study.
Patients eligible for the study were randomised to receive once-weekly subcutaneous injections of either peginterferon alfa-2b1.5 l g/kg or peginterferon alfa-2a180l g for8weeks.After the fourth week of treatment,oral ribavirin therapy was added to the regimen at a dose of13mg/kg,in a divided BID dose.At the end of the study period,patients were o?ered a full course of weight-based peginterfer-on alfa-2b and ribavirin.The study protocol and patient-informed con-sent were approved by independent Ethics Committees of the participating institutions and regulatory agencies of their respective countries,and the study was conducted according to the Declaration of Helsinki and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use(ICH)Guidance for Good Clinical Practice.Written informed consent was obtained from all patients prior to conducting study-related procedures.
2.2.Patients
Thirty-six treatment-na?¨ve patients between the ages of18and65 years who were infected with HCV genotype1a or1b[with a minimum of6.0·105HCV-RNA IU/mL,determined by quantitative polymer-ase chain reaction(PCR)]were eligible for enrollment into the study. Additional inclusion criteria were alanine aminotransferase(ALT)/as-partate aminotransferase(AST)levels610times the upper limit of normal(ULN),normal haemoglobin,white-blood-cell count P4000cells/l L,neutrophil count P1500cells/l L,and platelet count P100,000/l L.Subjects were excluded from participation if they had evidence of liver disease due to causes other than chronic HCV infec-tion,HIV positivity,haemoglobinopathy,haemophilia,severe pre-ex-isting psychiatric disease,poorly controlled diabetes mellitus, signi?cant ischaemic heart disease,chronic obstructive lung disease, or active autoimmune disease.
2.3.Study endpoints
The primary outcome was to assess the di?erential impact on inter-feron response genes and early viral kinetics of the two peginterferon treatments.Secondary outcome measures included the proportion of virologic responders(i.e.,patients with a P2.0log10decrease in HCV-RNA by8weeks of peginterferon treatment)as well as the safety and tolerability of treatment.
2.4.Study procedures
When subjects met inclusion/exclusion criteria and quali?ed to enter the study,the investigator requested randomisation by faxing the central randomisation service.Only the site pharmacist responsible for medication preparation received con?rmation of both the assigned treatment and the subject number.The investigator received the sub-ject number only.
Screening evaluations were performed at three independent,research out-patient clinics.Patients were con?ned to pharmacology in-patient units on day1of week1(day1)and day1of week4(day22)for approximately72h while pharmacokinetic,pharmacodynamic,and antiviral samples were https://www.doczj.com/doc/6516773010.html,boratory safety tests were performed at the sites,but viral kinetics,interferon pharmacokinetics,and pharmacodynamics were centrally analysed in a blinded fashion.
2.5.Interferon serum concentrations
Serum interferon samples were drawn at days1and22immediately before peginterferon administration and at6,10,12,24,48,72,and 120h after the dose.The peginterferon serum concentrations were determined in a blinded manner,using a validated immunological (electrochemiluminescent)assay[18,19]and standards for both alfa peg-interferons.Once the study was unblinded,the values from the appro-priate standard were reported in pg/mL as per the assigned treatment.
2.6.Interferon-alfa response-gene-transcript analysis
Blood samples for determination of interferon-stimulated gene reg-ulation were collected into PAX-Gene tubes(Becton–Dickinson, Franklin Lakes,NJ,USA)prior to the?rst dose and at6,24,48, and72h after the?rst dose of peginterferon.Samples were analysed for mRNA using quantitative real-time PCR(qRT-PCR)(TaqManò, Applied Biosystems,Foster City,CA,USA)[19,20].Interferon-modu-lated genes,including signal transducers and activators of transcrip-tion(STAT)-1,STAT-2,cyclin D,interferon-gamma,inducible
M.Silva et al./Journal of Hepatology45(2006)204–213205
protein10(IP10),interferon-stimulated gene(ISG)15,ISG54,perforin, PKR,and2050OAS,were tested.Data were expressed as fold increase in mRNA over baseline.In order to investigate the cumulative expres-sion or sustained activity of treatment on gene transcription,changes in mRNA observed over the sampling period were expressed as maxi-mal fold increase from baseline(C max)and area under the curve (AUC),derived from the time-weighted averages of the mRNA fold-increase data.
2.7.HCV-RNA serum determinations
HCV-RNA was determined prior to the?rst administration of study drug to establish the baseline and at0,24,48,72,120,and 168h after the?rst and fourth dose of peginterferon alfa.HCV-RNA was also assessed immediately prior to the weekly dose of pegin-terferon alfa at weeks2,3,5,6,7,and8.Data were expressed as log10 decrease in HCV-RNA from baseline.Maximal decrease and time-weighted average decrease over the sampling period were calculated from the data at weeks1and4.HCV-RNA was quanti?ed by qRT-PCR(TaqManò;Schering-Plough Research Institute,Kenilworth, NJ,USA),with a lower limit of detection of29IU/mL.HCV genotyp-ing was performed by direct sequencing of the50-noncoding region.
2.8.Adverse events and laboratory testing
Standard safety laboratories were collected weekly.Adverse events were recorded at each visit and throughout the con?nement.Patients were withdrawn from the study for a white-blood-cell count <1500cells/l L,neutrophil count<750cells/l L,platelet count <80,000/l L,creatinine clearance<50mL/min,ALT/AST levels >10·ULN,or indirect bilirubin>5mg/dL.No modi?cation of the peginterferon alfa or ribavirin dose was allowed.
2.9.Statistical analysis
The assessment of the viral concentration kinetics during weeks1 and4was made by determining the time-weighted mean decrease in viral concentration and the mean maximal decrease in viral concentra-tion over the week.For the weekly pre-dosing determinations,patients were de?ned as responders if a P2.0log10reduction in viral concentra-tion was achieved at the last determination.
The viral kinetic di?erences between treatment groups were tested using Wilcoxon rank-sum tests of the average and maximum decreases from weekly baseline.The di?erence between treatment groups with respect to the once-weekly measurements of viral load change from baseline was tested using a model that tested for equality of slopes via SAS PROC MIXED.The model included?xed e?ects terms for treatment,day,and treatment by day interaction(slope).Random e?ects included in the model were the patient and the addition of ribavirin.
Using the observed standard deviation in the sample size calcula-tion,a sample size of18in each group would have80%power to detect a di?erence in means of log viral change of1.65(the di?erence between a group1mean ofà3.65and a group2mean ofà2.00)at week8, assuming that the common standard deviation is1.700using a two-group t-test with a0.050two-sided signi?cance level.
The association between the mRNA changes and the attainment of a P2.0log10drop in viral load was tested using Wilcoxon rank-sum tests of AUC of the fold increase in mRNA over baseline.The change from baseline of a patient’s last virologic observation,carried forward to week8if necessary,was used to ascertain whether a patient had attained a P2.0log10decrease in viral load during the treatment period.
A post hoc multivariate correlation analysis using Spearman correlation values was performed in order to further explore the rela-tionship between treatment,gene expression,and viral response.To complement these?ndings,a secondary post hoc analysis using princi-pal components was conducted.Principal component analysis(PCA)is a variable reduction technique in which a number of[possibly]corre-lated variables are transformed into an equal number of uncorrelated variables called principal components[21].PCA was used to con?rm the ?ndings of the?rst post hoc analysis by determining whether the inter-feron-response genes identi?ed in the?rst analysis remained signi?-cantly correlated with treatment and viral response.
Table1
Baseline characteristics
Baseline parameter Peginterferon
alfa-2a(n=18)
Peginterferon
alfa-2b(n=18) Age(years)45.6(±11.8)a48.3(±9.7)a Males(n)910
Ethnicity(n)
Caucasian1614
Hispanic24
Weight(kg)71.0(±11.9)a69.6(±15.4)a Baseline viral load
(·106IU/mL)
1.8(±0.1)a 1.8(±0.2)a
Prothrombin time
(%of control)
109.5(±9.4)a111.4(±13.1)a Platelets(·103/l L)233(±75.8)a223(±80.7)a Neutrophils(·103/l L) 3.96(±1.26)a 3.34(±1.36)a ALT(IU/L)82.9(±59.8)a70.5(±51.5)a AST(IU/L)60.0(±42.8)a46.3(±25.5)a
a Data are reported as means
(±SD).
Fig. 1.Individual time–concentration pro?les following subcutaneous administration of(a)peginterferon alfa-2a180l g or(b)peginterferon alfa-2b1.5l g/kg.There was a$16-fold greater exposure in the serum of patients treated with peginterferon alfa-2a compared with peginterferon alfa-2b,but there was also a larger variability in patient exposure(38% vs20%,respectively).
206M.Silva et al./Journal of Hepatology45(2006)204–213
3.Results
The study was conducted in three centres,in Argenti-na,Mexico,and Germany,between November 2002and November 2003.
3.1.Baseline characteristics
The baseline characteristics in the two peginterferon treatment groups were comparable with respect to race,gender,weight,and viral load (Table 1).3.2.Pharmacokinetics results
The comparative exposure of patients to peginterfer-on alfa-2b and peginterferon alfa-2a during the ?rst week of dosing is shown in Fig.1.There was a $16-fold greater exposure in the serum of patients treated with
peginterferon alfa-2a;however,there was also a larger variability in their exposure,compared with peginterfer-on alfa-2b (38%vs 20%,respectively).The week 1AUC 0–168h for each treatment group plotted against bodyweight is shown in Fig.2.There was no e?ect of weight on exposure when peginterferon alfa-2b was dosed according to patient weight.In contrast,when peginterferon alfa-2a was administered as a ?xed dose,there was a decrease in exposure with increasing bodyweight.
3.3.Interferon-alfa response-gene transcript results Thirty-one patients had su?cient,recoverable mRNA at baseline (as acquired via sampling prior to and immediately after the ?rst treatment dose).Based on the results of a preliminary Wilcoxon rank-sum test that suggested a correlation with treat-ment response,transcripts were analysed for the fol-lowing interferon-response genes:IP10,ISG15,PKR,2050OAS,and ISG54[no statistically signi?cant di?er-ences in mRNA expression were observed for patients with or without a virologic response (P 2.0log 10decline in HCV-RNA after 8weeks of treatment)for the other genes tested].
Patients who achieved a virologic response by 8weeks of treatment had signi?cantly greater up-regula-tion of transcripts for the interferon-alfa response genes IP10,ISG15,PKR,2050OAS,and ISG54as assessed by mRNA C max and AUC levels (P <0.05;Table 2).
There was consistently greater up-regulation of tran-scripts in patients treated with peginterferon alfa-2b (n =14)compared with patients treated with peginter-feron alfa-2a (n =17)(Table 2),with the
di?erences
Fig.2.Week 1exposure to peginterferon by weight.Unlike peginterferon alfa-2b (b),in which there was no e?ect of weight on exposure when dosed by patient weight,peginterferon alfa-2a (a),administered as a ?xed dose,showed a trend towards decrease in exposure with increasing bodyweight.
Table 2
Mean AUC and C max of interferon-alfa response-gene transcripts analysed by virologic response and treatment group
Responders (n =17)Nonresponders (n =14)Peginterferon alfa-2a (n =17)Peginterferon alfa-2b
(n =14)
C max (fold increase)
IP10253.2*83.4126.4237.3ISG1591.0*39.741.999.3PKR 11.3* 6.57.511.1*2050OAS 21.0*13.313.322.6*ISG5441.1*17.018.044.9*Mean AUC (fold increase ?h)
IP104654.1*
1703.72427.04408.1*ISG153589.8*
1854.8
1886.73922.8*PKR 502.3*
314.9345.2505.72050OAS 1099.6*669.0
682.11176.1*ISG54
1368.7*
630.6
678.9
1468.1*
*
P <0.05by Wilcoxon rank-sum test for responders vs nonre-sponders and peginterferon alfa-2b vs peginterferon alfa-2a.(Respond-ers were de?ned as patients with a P 2.0log 10decrease in HCV-RNA
by week 8.)
M.Silva et al./Journal of Hepatology 45(2006)204–213207
reaching statistical signi?cance (P <0.05)for the majority of the interferon-response genes investigated,as illus-trated in Fig.3.Within each treatment group,respond-ers demonstrated greater up-regulation of transcripts (as measured by AUC)than did nonresponders,although statistical signi?cance was generally not demonstrated (Fig.4).The proportion of responders with available mRNA in the peginterferon alfa-2b group was 71%compared with 41%in the peginterferon alfa-2a group.3.4.Antiviral results
There was a signi?cantly greater decline in HCV-RNA in patients treated with peginterferon alfa-2b com-pared with patients treated with peginterferon alfa-2a during weeks 1and 4(P <0.05)(Table 3),as illustrated by the mean maximum log 10reductions from baseline (Fig.5).At week 4(day 29),the mean log 10decrease from baseline was à1.891(95%CI:à2.468,à1.313)for peginterferon alfa-2b (n =16)and à1.331(95%CI:à2.159,à0.502)for peginterferon alfa-2a (n =17).The mean reduction from baseline in HCV-RNA over the course of 8weeks,by treatment group,is shown in Fig.6.The viral concentration curves begin to diverge at week 2.The curve for patients treated with peginterferon alfa-2b showed a trend towards a greater mean decrease in HCV-RNA through the 4weeks of monotherapy,a trend that persisted throughout the study.The rate of decline (95%CI)in HCV-RNA during the 8weeks of treatment was signi?cantly greater in patients treated with peginter-feron alfa-2b compared with the rate for patients treated with peginterferon alfa-2a,à0.346(à0.396,
à0.296)log 10/week vs à0.233(à0.281,à0.185)log 10/week,respectively (P <0.002).At the end of the study,the mean reduction in HCV-RNA was 3.13log 10in patients treated with peginterferon alfa-2b and 2.44log 10in patients treated with peginterferon alfa-2a (Fig.6).
There was a larger number of virologic responders (de?ned as a P 2.0log 10reduction in HCV-RNA)to peginterferon alfa-2b than peginterferon alfa-2a at week 4(50%vs 28%,respectively;P =0.17)and week 8(72%vs 44%,respectively;P =0.09).Although sustained virologic response (SVR)was not measured as part of the study,such data were available for one of the centres (Argentina).Eleven patients were treated with peginterferon alfa-2b for 48weeks,of which 9patients achieved SVR,1patient was a non-responder,and 1patient
discontinued.
Fig. 3.Mean AUC of interferon-alfa response-gene transcripts by treatment group.There was consistently greater up-regulation of transcripts in patients treated with peginterferon alfa-2b compared with patients treated with peginterferon alfa-2a,with the di?erences reaching statistical signi?cance (P <0.05)for most of the interferon-response genes
investigated.
Fig.4.Mean AUC of interferon-alfa response-gene transcripts analysed by within-treatment responders vs nonresponders.In general,responders demonstrated more up-regulation of transcripts than nonresponders,although statistical signi?cance was only reached for one AUC group in each treatment arm.The proportion of responders with available mRNA in the peginterferon alfa-2b group (b)was 71%compared with 41%in the peginterferon alfa-2a group (a).(Responders were de?ned as patients with a P 2.0log 10decrease in HCV-RNA by week 8.)
208M.Silva et al./Journal of Hepatology 45(2006)204–213
3.5.Post hoc multivariate correlation analysis
Pairwise correlations(Spearman correlation values) between mRNA AUC values(gene expression),treat-ment response,and treatment arm(peginterferon alfa-2b or peginterferon alfa-2a)were determined to explore the relationship between these variables.IP10,ISG15, ISG54,PKR,and2050OAS were signi?cantly correlat-ed with treatment group and virologic response at week 8(Table4).A secondary correlation analysis using the combined set of mRNA AUC data for these?ve genes and their derived principal components showed that the?rst principal component,which accounts for 63%of the variability in each individual mRNA AUC value,was signi?cantly correlated with both treatment group and treatment response(Table5),thus providing further evidence of a link between these variables.
3.6.Adverse events
Adverse events were typical of those reported previ-ously with administration of pegylated interferons: fever,myalgia,headache,?u-like symptoms,fatigue, anaemia,and leucopenia.Treatment-emergent adverse events are shown in Table6(classi?ed by body system). Patients treated with peginterferon alfa-2a showed sta-tistically signi?cantly greater reductions in total white-blood-cell count over the8weeks of treatment compared with patients treated with peginterferon alfa-2b(P=0.04,Fig.7).This was due to statistically signi?cantly greater reductions in the absolute neutro-phil count(P=0.03),as shown in Fig.8.There were no di?erences in monocyte or lymphocyte counts between the two groups(data not shown).
Six patients discontinued treatment due to adverse events prior to completion of the8-week study,four receiving treatment with peginterferon alfa-2b and two with peginterferon alfa-2a.Three patients in the peginterferon alfa-2b group discontinued due to reduced platelet counts(<80,000/l L);however,all three began treatment with platelet counts close to the exclusion threshold,ranging from96,000to100,000/l L.The patient in the peginterferon alfa-2a group who discontinued due to thrombocytopenia had a baseline level of125,000/l L that dropped to71,000/l L.The remaining reasons for subject discontinuations were a case of anaemia in the peginterferon alfa-2b group and one of erythaema multiforme in the peginterferon alfa-2a group.
4.Discussion
In this study,we used changes in the mRNA abun-dance for genes known to be regulated by interferons as a marker of biological activity.The data presented are consistent with the in vitro data[12,17,20]and sug-gest that biological activity,as indicated by gene response,is greater with peginterferon alfa-2b than with peginterferon alfa-2a.Beginning as early as week2, when the viral concentration curves began to diverge, the rate of decline in HCV-RNA during the8weeks of treatment was signi?cantly greater in patients treated with peginterferon alfa-2b compared to patients treated with peginterferon alfa-2a.The kinetic studies,conduct-ed at weeks1and4during the monotherapy phase, revealed that treatment with peginterferon alfa-2b resulted in signi?cantly greater reduction in the maximal and time-weighted mean viral concentration during each week when compared with peginterfesron alfa-2a.Cor-respondingly,compared with peginterferon alfa-2a, peginterferon alfa-2b treatment also stimulated greater increases in many interferon-alfa response-gene tran-scripts for proteins believed to be associated with antiviral activity.The apparently greater biological
Table3
HCV viral load reductions during weeks1and4
Week1Week4
Peginterferon alfa-2a(n=18)Peginterferon alfa-2b(n=18)Peginterferon alfa-2a(n=18)Peginterferon alfa-2b(n=18) Log10time-weighted average decrease in HCV-RNA
Mean(±SD)0.58(0.76) 1.21(0.52)*0.04(0.29)0.73(0.48)***
Median0.43 1.240.040.64
Max 2.36 2.320.44 1.18
Minà0.290.20à0.45à0.01
Maximum log10decrease from baseline in HCV-RNA
Mean(±SD) 1.08(0.93) 2.11(0.79)**0.38(0.33) 1.46(0.83)***
Median0.64 2.080.29 1.44
Max 3.23 3.310.96 2.92
Min0.000.590.000.33
*P<0.05by Wilcoxon rank-sum test for peginterferon alfa-2b vs peginterferon alfa-2a.
**P<0.01by Wilcoxon rank-sum test for peginterferon alfa-2b vs peginterferon alfa-2a.
***P<0.001by Wilcoxon rank-sum test for peginterferon alfa-2b vs peginterferon alfa-2a.
M.Silva et al./Journal of Hepatology45(2006)204–213209
activity associated with peginterferon alfa-2b treatment was observed despite an approximately16-fold greater exposure in the serum of patients treated with peginter-feron alfa-2a.
The?ndings of the post hoc analysis(Tables4and5) and the data shown in Fig.4both demonstrated that treatment response was correlated with a signi?cantly greater increase in mRNA expression.They suggest that the higher antiviral activity of peginterferon alfa-2b is directly related to its higher associated interferon-mediated gene expression.However, because of small patient numbers,these analyses, and their implications for other therapies,require con-?rmation in larger trials.
Adverse events and impact on haematological param-eters were not unexpected for peginterferon alfa treat-ment.However,there was a signi?cantly greater reduction in white-blood-cell and neutrophil counts associated with peginterferon alfa-2a treatment,even though the biological activity in these patients was low-er,a?nding recently reported elsewhere[22].Peginter-feron alfa-2b treatment was associated with a greater incidence of fever compared with peginterferon alfa-2a (10patients vs1,respectively).Because?u-like symp-toms and fever are associated with the natural response induced by endogenous interferon,this may re?ect the greater biological activity of peginterferon alfa-2b. These observations,however,need to be con?rmed in a larger study before making any conclusions regarding their clinical implications.
This study provides a better understanding of the in vivo impact that the size and site of an attached PEG molecule can have on interferon-alfa-dependent biological activity and subsequent anti-viral activity. Because peginterferon alfa-2b appears to induce inter-feron-response genes more e?ectively than peginterferon alfa-2a,despite a lower drug exposure,this implies that peginterferon alfa-2b has a better interaction with the interferon-alfa receptor.However,due to
di?erential Fig.6.Mean HCV viral load reduction at the end of each weekly dosing interval.Baseline viral loads were equivalent in both treatment groups, 1.8·106IU/mL;however,the rate of decline(95%CI)in HCV-RNA during the8weeks of treatment was signi?cantly greater in patients treated with peginterferon alfa-2b than in patients treated with pegin-terferon alfa-2a,à0.346(à0.396,à0.296)log10/week vsà0.233 (à0.281,à0.185)log10/week,respectively(P<0.002).[The estimated slopes(i.e.,HCV-RNA reduction rates,95%CIs,and subsequent P-value)were derived from the mixed-model analysis.]Each data point is the mean HCV concentration determined at the pre-dosing weekly sampling
interval.
Fig.5.Mean maximum HCV viral load reductions from baseline during
weeks1and4.The mean maximum log10decrease from baseline(day22
for week4)in HCV-RNA was signi?cantly greater in patients treated
with peginterferon alfa-2b than in patients treated with peginterferon
alfa-2a during both weeks1(a)and4(b)(P<0.01).
210M.Silva et al./Journal of Hepatology45(2006)204–213
dropout in the peginterferon alfa-2b treatment arm and the subsequent gene analysis of only 14patients in this arm,the meaning of these ?ndings must be interpreted with caution until they are reproduced in a large-scale study without such limitations.
As di?erences in PEG modi?cation between pegin-terferon alfa-2a and peginterferon alfa-2b may explain the di?erences in early biological activity,care must be taken when modifying proteins that function through a cognate–receptor interaction.The bene?cial aspects of pegylation (i.e.,increased serum exposure to the pro-tein)must be weighed against the protein’s potential loss of activity at the receptor itself.Whether the bio-logical di?erences observed in this exploratory study have an impact on SVR remains to be demonstrated.A large-scale,randomised clinical trial is underway to compare the rate of sustained virologic response in patients with HCV genotype 1treated with peginterfer-on alfa-2a or peginterferon alfa-2b in combination with ribavirin.
5.Disclosures
Marcelo Silva has received honoraria from Schering-Plough for participating in investigator meetings.Jorge
Table 6
Number of subjects (%)with treatment-emergent adverse events occur-ring in P 20%of subjects in either treatment group (classi?ed by body system)
Adverse event,n (%)a
Peginterferon alfa-2a (n =18)
Peginterferon alfa-2b (n =18)Body as a whole –general disorders Anorexia 2(11)6(33)Asthenia 6(33)5(28)Fatigue 4(22)6(33)Fever 1(6)10(56)Headache 16(89)16(89)In?uenza-like symptoms 3(17)5(28)Disorders of blood and lymphatic system Anaemia 9(50)10(56)Haematocrit decreased 9(50)5(28)Haemoglobin decreased 12(67)6(33)Leucopenia 14(78)9(50)Neutropenia 12(67)10(56)
Disorders of reproductive system and breast b Dysmenorrhoea 2(22)0(0)Gastrointestinal system disorders Abdominal pain 4(22)5(28)Diarrhoea 2(11)5(28)Nausea 6(33)7(39)Liver and biliary system disorders Bilirubinaemia 6(33)2(11)Musculo-skeletal system disorders Back pain 6(33)3(17)Musculo-skeletal pain 9(50)7(39)Myalgia 7(39)11(61)Platelet,bleeding,and clotting disorders Platelet count decreased 5(28)5(28)Thrombocytopenia 5(28)
3(17)
a A subject may have reported more than one adverse event.b
Percentages are based on the number of males or females.
Table 5
Correlations between the principal components derived from the set of mRNA AUC values of ?ve interferon-mediated genes (IP10,ISG15,ISG54,PKR,and 2050OAS),treatment (peginterferon alfa-2a or peginterferon alfa-2b),and treatment response at week 8
Spearman correlation coe?cient Prob >|r|under H0:Rho =0Number of observations (pairs)Prin1
Prin2Prin3Prin4Prin5Peg-2a vs Peg-2b
0.492810.04348à0.123200.115950.217410.00490.81630.50910.53450.24003131313131W8cfresp
0.514550.275390.137700.028990.000000.00310.13380.46010.8770 1.000031
31
31
31
31
Peg-2a,peginterferon alfa-2a;Peg-2b,peginterferon alfa-2b;W8cfresp,week 8carry forward response (de?ned as a P 2.0log 10decrease in HCV-RNA);Prin,principal component.
Table 4
Correlations between mRNA AUC values,treatment (peginterferon alfa-2a or peginterferon alfa-2b),and treatment response at week 8
Spearman correlation coe?cient Prob >|r|under H0:Rho =0Number of observations (pairs)Peg-2a vs Peg-2b
W8cfresp Cyclin D IFN-gamma IP10ISG15ISG54Perforin PKR STAT-1STAT-22050OAS Peg-2a vs Peg-2b
1.000000.281720.270150.140130.362360.362360.369600.086970.355110.210170.115950.45657–0.09600.23630.49480.04510.04510.04070.64180.05000.25650.53450.009836
3621263131313131313131W8cfresp
0.28172 1.000000.206580.257170.565280.369600.492810.173930.478310.289890.253650.420330.0960–0.36890.20470.00090.04070.00490.34940.00650.11370.16860.018636
36
21
26
31
31
31
31
31
31
31
31
Peg-2a,peginterferon alfa-2a;Peg-2b,peginterferon alfa-2b;W8cfresp,week 8carry forward response (de?ned as a P 2.0log 10decrease in HCV-RNA).
M.Silva et al./Journal of Hepatology 45(2006)204–213
211
Poo and Frank Wagner have no ?nancial relationships to disclose.Mary Jackson,Michael Grace and Mark Laughlin are former employees of Schering-Plough,and Mark Laughlin owns company stock.David Cutler,Ronald Bordens,Connie Cullen and Joann Harvey are employees of Schering-Plough Research Institute and own company stock.
Acknowledgements
The authors would like to acknowledge Dr.Hartmut Schmidt for his clinical support,Dr.Musaddeq Hussain for his expertise and analytical support of HCV-RNA analysis,Dr.Diana Brassard for her development of the interferon-alfa response-gene-transcript assays,Dr.Amrik Shah for his statistical analyses,and Dr.Samir Gupta for his pharmacokinetic analyses.Editorial assis-tance was provided by Thomson Gardiner-Caldwell,London.References
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Compare 用法小议 最近，我在上B1U5时，涉及到有关Compare的用法。教参上把该词列为可做插入语一类词，本人认为不妥。我们知道，分词作插入语用时，是不与主语谈主谓关系或动宾关系的，就是一些习惯用法而已。例如： Generally speaking, girls develop earlier than boys. 一般讲来，女孩子比男孩子发育得要早一些。 Talking about the matter, he became excited. 谈到那件事，他变得激动起来。 Considering his age, he was excused from being punished. 考虑到他的年龄，他被免除了受到惩罚。 Judging from his clothes, he came from the countryside. 根据他的衣着来看，他来自乡下。 以上句子的现在分词speaking、Talking、Considering、Judging都是作插入语用的，不考虑和主语是什么关系。但compare一词在用法上与以上几个词有很大的不同。请看例句：Comparing the two novels, you will find the former closer to life. 比较一下这两本小说，你会发现前一本更贴近生活。 Compared with other students, Tom is deligent. 与其他学生相比较，汤姆是勤奋的。 第一句话之所以用comparing现在分词形式，是因为与主语形成主谓关系；第二句话之所以用compared过去分词形式，是因为与主语形成动宾关系；compare在这两句中的用法都是与主语谈过关系之后而分别采用的形式。这种用法符合分词作状语时的特征,即：分词作状语时是要与主语谈主谓关系或动宾关系的。所以，compare一词不能归类为作插入语之类的词，而是作状语。
Beyond Compare这款软件是专门为常常要对文件及文件夹操作的朋友设计的。如平常我们要对文件进行对比，文件夹的同步等操作。适用人群：编程人员、网站管理人员、网吧管理及公司多文档管理。当然普通人员用处虽然比较小，但是也可以去试用和熟悉一下。 Beyond Compare界面： 图1
图2 >Beyond Compare文件夹的对比操作，平常我们常常要对两个相似的文件夹进行对比操作来查看这两个文件夹那些文件有所改动（如网管查看服务器上的文件是否被改动），如果通过肉眼来查看字节数的话，那是很麻烦的，用Beyond Compare就可以很方便判断两个文件夹的不同。具体操作方法如下： 1.启动Beyond Compare，点击Beyond Compare界面（图1）中的“文件夹比较”按钮，即可进入文件夹比较界面。 2.在“文件夹比较”界面分别添加我们要比较的两个文件夹。这里我们还可以添加网络上的FTP文件夹，这个功能就适用网站制作对网页文件的对比。
图3 3.添加两个对比文件夹之后，我们点击Beyond Compare工具栏上的 按钮，就可以显示这两个文件夹对比的不同之处出来。 Beyond Compare将文件夹比较更进一步细分（点击右边的向下箭头即可显示分类）： 1.显示差异：所有的不同都显示出来，只要是有不同的都列 出来。 2.显示不孤立部分：就是文件名相同的文件。 3.显示有差异但不孤立部分：在文件名相同的情况下，显示 内容有差别的。 4.显示孤立：即显示出两个文件夹只有单独的一个多余的文 件。 5.其它的几个选项可以根据字面意思很容易理解，我这里就 不重复介绍。 >Beyond Compare对文件内容的对比，一般文件内容对比前提是很进行文件夹对比来发现两个文件的差别，然后再对这两个文件进行内容对比。而使用Beyond Compare的具体操作步骤如下：
compare用法与搭配 1. 表示“把……与……比较”，通常用compare…with…，但在现代英语中，也可用compare… to…，或者用compare…and…。如： If you compare his work with [and] hers, you’ll find hers is much better. 要是把他俩的工作比较一下，就会发现她的好得多。 Having compared the new dictionary with [to, an d] the old one, he found the new one more helpful. 将新旧词典比较之后，他发现新词典更有用。 2. 表示“把……比作……”，通常用compare…to…， 一般不用compare…with…。如： Shakespeare compared the world to a stage. 莎士 比亚把世界比作舞台。 The poet compares the woman he loves to a rose. 诗人把他所爱的女人比作玫瑰。 3. 在compared to [with]（与……相比）这一习语中，用to或with已没什么区别。如： Compared with [to] him, I’m just a beginner. 和他相比，我只是一个初学者。 Compared to [with] many women, she was very for tunate. 和许多女人相比，她算是很幸运的了。 4. 用作不及物动词时，其后习惯上接with(也有时接t o)，多与情态动词can连用，表示“比得上”“能与……比美”，但一般用于否定句或疑问句中。如： Nothing can compare with wool for warmth. 没有 比羊毛更暖和的东西了。 Life in a town can’t compare with life in the c ountry. 乡村的生活比城镇的生活好得多。
第3章Word2000的使用 3.1 Word2000概述 Word2000是Microsoft公司套装办公软件office2000中的文字处理软件。主要特征是所见即所得、易学易用，它具有丰富的文字处理功能，可以将图、文、表格混排。通过使用Word2000，用户可以很方便地处理日常工作中的各类文档。 3.1.1 Word2000环境 1．Word2000视图方式 “视图”是指显示文档的方式，有普通视图、页面视图、Web版式和大纲视图四种，对于不同的操作需求采用不同的视图。视图之间的切换可以使用【视图】菜单中的命令，或者是使用水平滚动条左端的视图切换按钮。 2．帮助功能的使用 3.1.2 基本术语 1．Word2000窗口组成 2．工作区 3．插入点 工作区有一个闪烁着的黑色竖条“I”（或称光标），称为插入点。Word2000启动后自动创建一个名为“文档1”的空文档。在编辑文档时，可以移动“I”状的鼠标指针到插入点位置并单击，也可使用光标键移动插入点到所希望的位置。 3.2 Word2000基本操作 3.2.1 Word的启动与退出 1．Word2000的启动 Word2000的启动有如下几种方法。
（1）依次单击任务栏上的“开始”按纽→【程序】菜单→【MicrosoftWord】命令，启动文字处理软件。 （2）双击Windows桌面上的Word2000快捷方式图标，是启动Word2000的快捷方法。 （3）双击Word2000文档文件可直接关联打开文字处理软件。 2．Word2000的退出 Word2000的退出有如下几种方法： （1）单击【文件】菜单→【退出】命令。 （2）单击标题栏右端的Word2000窗口“关闭”按钮。 （3）双击标题栏左端Word2000窗口的“控制菜单”图标。 （4）按快捷键【Alt+F4】。 3.2.2 创建新文档 创建Word2000文档的方法很简单，当Word2000启动后会自动打开一个新的空文档并命名为“文档1”。除了自动创建新文档的办法以外，在编辑文档的过程中还需另外创建一个或多个新文档时，可以用如下几种方法创建。 （1）单击常用工具栏中的“新建空白文档”按钮（基于默认模板）。 （2）单击【文件】菜单→【新建】命令。 （3）单击【文件】菜单→直接按【N】键，单击“确定”按钮。 （4）快捷键【Ctrl+N】。 3.2.2 文档打开方法 1．打开文档 常用下列三种常用的方法打开一个或多个已存在的Word文档： （1）依次单击【文件】菜单→【打开】命令。 （2）单击常用工具栏中的“打开”按钮。 （3）直接按快捷键【Ctrl+O】。 （4）依次单击【文件】菜单→【打开】命令，弹出“打开”对话框。选择对话框“查找范围”列表框中要打开的文档名，单击“确定”按纽。 Word2000可同时打开多个文档，最后打开的一个文档成为当前活动文档。 2．打开wps格式文档 3．最近使用过的文档 3.2.3 文本输入 1．即点即输 使用Word2000新增的功能“即点即输”在文档的空白区域中快速插入文
文本加工工具 教学目的： 1．知识与技能 （1）了解常见的应用文档。 （2）体验不同的文字处理软件。 (3)了解文字处理软件的基本特征,学会根据需要选择合适的软件。 2．过程与方法 (1) 鉴赏生活中常见的应用文档，体验其创作思想，感悟其中所蕴含的意义。 (2)在教师引导下，让学生自主体验和探究不同文字处理软件的特点。 3．情感态度与价值观 （1）通过生活实例，激发学生学习与应用文字处理软件的浓厚兴趣，培养学生选择合适软件解决问题的能力。 （2）通过小组协作，培养学生积极、合作、进取的品质。 4.教学重点与难点： （1）、教学重点：不同文字处理软件。 （2）、教学难点：无 5.教学方法：任务探究、体验学习、实验学习。 教学过程： 1．创设情境,导入新课 （1）、教师演示日常生活中，漂亮的信函、广告、海报、明信片、贺卡、电子小报等作品。提问：这些作品漂不漂亮？我们想不想做？ （2）、导入新课（文本加工工具）。 设计意图：培养学生的审美意识，激发学生的学习乐情。 学生分组讨论并完成教材第49页的讨论学习，体验计算机加工文本信息的特点。
2．布置实践活动 课堂调研，完成教材第50页讨论学习，了解学生对常用文字处理软件的使用情况。 你曾用过的文本处理软件：□Word □WPS □写字板□记事本□其他 你曾用它来处理的作品：□信函□贺卡□调查报告□通知□卡片□海报□文章□其他你对它掌握的程度：□熟练□一般□不熟练□较差 通过调研，了解学生掌握文字处理软件的水平，通过学生的实践体验，师生共同探讨文字处理软件的基本特征。 3．实践操作，探究学习 将学生分成若干个小组，小组成员进行分工协作，充分发挥学生的主体作用，体验不同的应用文档格式。 尝试用“记事本”、“写字板”、Word、WPS等软件分别打开素材库中的文件“天安门.txt”、“天安门.doc”、“天安门.wps”文件，观察实践结果，在下表中选择各种软件所能打开的文件格式。（√：打开，×：不能打开，○：能打开但显示乱码） 学生讨论：不同的软件有不同的特点，如何根据需要选择合适的字处理软件？ 4．总结 老师总结本课的知识点。 5．课外延伸 利用文字处理软件来解决生活中的实际问题，比如利用Word写一个通知或一篇作文等。 教学反思：学生上本节课之前，已经对文字处理软件有了一定的认识，这节课的内容对学 生无丝毫难度。这节课主要是为第2节打好基础，同时培养学生发现生活中处处有美，缺少的只是我们的发现。培养学生的审美情趣，审美意识。
1中文文本预处理 1.1分词软件调用（中科院分词系统） 1.1.1软件下载：https://www.doczj.com/doc/6516773010.html,/ 1.1.2软件包目录&介绍 | Readme.txt-------------------------->介绍 | +---bin | +---DocExtractor----------->文档篇章语义抽取系统 | | DocExtractor.bat-->批处理，可以针对指定的文件夹进行语义抽取 | | DocExtractor.dll-->支撑的动态链接库，基于分词基础上 | | DocExtractorSample.exe-->应用程序 | | | \---ICTCLAS2015----------->分词系统 | ICTCLAS-tools.exe-->分词的支撑工具，可用于测试，本处主要用来做用户词典导入 | importuserdict.bat-->可将用户词典自动导入到系统内 | NLPIR.dll-->Win32下的支撑动态链接库，其他环境的库，可以访问lib对应环境的库文件 | NLPIR.lib | NLPIR_WinDemo.exe-->Win32下的演示程序，在Win8 32位下编译而成，部分环境可能不支持，或者显示异常 | userdic.txt-->用户词典，用户可以自行编辑 | +---Data-->系统核心词库 | \---English-->英文处理的支持知识库，如果不需要英文处理的功能，可以不加载本库。 | +---doc-->相关文档支持 | ICTPOS3.0.doc-->我们的词性标注集说明 | NLPIR-ICTCLAS2015分词系统开发手册.pdf-->开发使用手册 | +---include-->系统头文件 | NLPIR.h | +---lib-->不同环境下的支撑库，每一种库，同时支持C/C++/C#/Java库。其他小众化的环境支持，请联系我们 | +---linux32-->Linux 32bit操作系统下的支持库 | | libNLPIR.so | | | +---linux64-->Linux 64bit操作系统下的支持库 | | libNLPIR.so | | Readme.txt | |
单选题： 1、在Word中，控制屏幕显示文本内容的主要工具是______。 A.标尺 B.控制按钮 C.滚动条 D.最大化按钮 答案：C 2、在Word 2010中，如果用户错误地删除了文本并想恢复，可以使用快速访问工具栏中的按钮是______。 A.剪切 B.恢复 C.粘贴 D.撤消 答案：D 3、在Word中，执行“粘贴”命令后，______。 A.文档中被选择的内容复制到当前插入点处 B.文档中被选择的内容移到剪贴板 C.剪贴板中的内容复制到当前插入点处 D.剪贴板中的内容移到当前插入点处 答案：C 4、在Word中，要将当前编辑的文档复制到指定文件夹，应当使用______。 A.“开始”选项卡中的“粘贴”命令 B.“文件”选项卡中的“保存”命令 C.“文件”选项卡中的“新建”命令 D.“文件”选项卡中的“另存为”命令 答案：D 5、在Word编辑状态下，要想删除光标前面的字符，可以使用键______。 A.Ctrl+P B.Del C.Backspace D.空格 答案：C 6、在Word中，创建表格不建议使用的方法是______。 A.使用“快速表格”命令 B.使用表格拖曳方式 C.使用“插入表格”命令 D.使用“自选绘图”工具画一个
答案：D 7、Word具有的功能是______。 A.表格绘制功能 B.文字校对功能 C.图文处理功能 D.以上三项都是 答案：D 8、在word 2010中，“标尺”命令，位于______。 A.“视图”选项卡中 B.“插入”选项卡中 C.“编辑”功能区中 D.垂直滚动条顶端 答案：D 9、在Word 2010中，如果打开了两个以上的文档窗口，则切换窗口操作可以在______完成。 A.视图选项卡 B.状态栏 C.开始选项卡 D.页面布局选项卡 答案：A 10、在默认鼠标打开方式时，启动Word并打开该文档时应______。 A.右键单击 B.右键双击 C.左键单击 D.左键双击 答案：D 11、运行在Windows环境下的文字处理软件是______。 A.Excel B.Word C.Outlook D.foxmail 答案：B 12、在Word中，选择某段文本，双击格式刷进行格式应用时，格式刷可以使用的次数是______。 A.1 B.2 C.有限次 D.无限次 答案：D
Beyond Compare使用教程 Beyond Compare是一套非常实用的文件及文件夹比较软件，其功能非常强大，但对于软件初学者，往往会感觉对这么软件很陌生，不知道从何学起，从而快速掌握这款软件的使用技巧。下面小编就简单给大家介绍下Beyond Compare软件使用方法。 步骤一下载Beyond Compare软件 我们可以到Beyond Compare中文官网进行下载，目前的版本已经更新到了4.1.3，大家可以根据自己的操作系统选择Windows、Linux或Mac系统下的Beyond Compare 4简体中文版。 步骤二安装Beyond Compare软件。 安装过程比较简单。安装完成后我们打开软件，发现此软件的可以对比的不止是文件，还有文件夹，MP3，图片等，可见Beyond Compare功能还是比较强大的，下面我们就来应用下吧。 Beyond Compare软件主界面示例 步骤三首先我们来看下文件夹的对比。 为了测试，我们新建了两个文件夹，里面的文件有的相同，有的不同。用软件打开两个文件夹后我们可以看到黑色，红色和蓝色三种颜色的文件。其中黑色代表两侧文件相同，蓝色代表其中一侧没有另一侧文件，红色代表两边都有这个文件，但是不完全相同。
文件夹对比界面示例 步骤四 细心的朋友会发现，同名的文件左侧可能是黑色，右侧就变为了红色，根据上述黑色和红色的定义不是自相矛盾吗？其实也并不矛盾，黑色的文件一般是创建或者是修改时间较早的，而红色的文件是创建或者是修改时间较晚的，这样有利于标识那个是最后修改的文件，方便我们进行文件的替换操作。 文件颜色显示不同示例 步骤五 对于黑色和红色大家应该有了个初步的了解，下面我们就来看下蓝色的文件，上面也介绍了，蓝色的文件代表另一侧的文件夹中没有这个文件，我们可以根据需求看是否复制这个文件到另一个文件夹中，复制的方法就很简单了，右击文件，然后点击复制到另一侧即可。
工具软件文本编辑软件 文本编辑软件是在日常工作和生活中使用相当频繁的应用软件之一。其主要包括两大类，即文本编辑器和文字处理器。 1．文本编辑器 几乎所有的操作系统和软件开发包都会提供文本编辑器，用于修改配置文件和代码。狭义的文本编辑器只提供一些基本的文本编辑功能，例如查找、替换、剪切、复制、粘贴等，例如，Windows系统自带的记事本软件等。 广义的文本编辑器，主要包括一些功能强大的文本编辑器，则会更多的功能。例如，多行折叠、自动行首缩进、行号排版、注释排版等，甚至针对某些编程语言或标记语言的语法校对，例如，UltraEdit等。 早期的文本编辑器在撤销更改和恢复更改方面的功能并不强大，大多只支持一级的编辑历史，只能撤销或恢复上一步的更改操作。随着软件技术的发展，现在新的文本编辑器往往可以支持多级的编辑历史，甚至可以恢复到任意一步操作。 2．文字处理器 文字处理器的作用是为桌面出版提供排版支持。多数文字处理器并非作用于各种普通文字，而是按照特定的格式处理文档，帮助无程序编制经验的人员完成文稿的创建、修改、印发工作。文字处理器通常会具备以下几种功能。 ●定义字体类型和大小 文字处理器往往可以指定文档中各种文本所使用的字体类型，例如宋体、微软雅黑等；也可以指定字体的大小。 ●定义字体颜色、斜体、粗体和下划线等样式 大多数文字处理器都允许用户为字体设置前景色（字体本身的颜色）和背景色，同时可以对字体进行加粗、倾斜、上标、下标并添加下划线和删除线。甚至还可以对英文中的字母进行处理，切换字母的大小写。 ●定义对齐方式、缩进和文字方向 在日常书写中，经常需要将根据纸张和文字的段落类型，以左、右和居中等方式和横排、竖排等方式书写。同时在段落的首行还需要缩进两个字的距离。多数文字处理器也都会提供这些功能。 ●定义列表和表格 早期的文字处理器往往只提供文字处理功能。随着技术的发展，越来越多的文字处理器允许在文字中插入各种列表和表格，并支持多种列表的项目符号。 ●插入图像和简单图像编辑 一些功能强大的文字处理器往往还会提供在文档中插入图像的功能，以及图文混排方式的选择和简单的图像编辑功能。 ●页面设置 为了面向打印输出，多数文字处理器都会提供设置各种纸张、页边距的功能，以帮助用户预览打印的效果。 3．文本编辑器与文字处理器的区别 由于文本编辑器和文字处理器等两类文本编辑软件在用途上的不同，其功能上也有较大的区别。 文本编辑器编辑的各种文档往往是未编译的文本文档或16进制文档，因此不支持各种文本样式的设置，只支持换行、制表符等简单的排版方式。使用文本编辑器打开文档，将显
插入语用法归纳 插入语用法很多,在句子中的位置比较灵活,在学习中应当认真去体会。大体而言,插入语可以分为以下几类: 1. 用简短的句子结构作插入语。这类短语有:I think, I hope, I guess, I believe, I suppose, I wonder, I tell you, I say, I'm afraid, I'm sure, you see, you know, as you know, that is, that is to say, what's more等等,它们可以置于句中或句尾。如: I suggest you choose someone who you think is kind and friendly. This diet, I think, will do good to your health. It won't be raining long, I hope. You will have to work harder, you know, if you want to succeed. 2. 副词或副词短语用作插入语,这类插入语一般放在句首或句尾。如: Happily for him, his father's second wife was kind to him too. You'll be able to pass the coming exam, surely. Luckily for him, he didn't hurt in the accident. Honestly, I don't need it at the moment. 3. 介词或介词短语作插入语,这类插入语一般放在句首,有时也可放在句中。如: Like most of my schoolmates, I have neither brothers nor sisters-in other words, I'm an only child. By the way, Bob sends his best wishes. On the other hand, I didn't know you were there. In short, things have begun to improve since schools were called on to reduce learning load. 4. 分词短语作插入语。如: Judging from your accent, you must be from England. Generally speaking, he is the best student in our class. Compared with China, the USA is smaller. 5. 不定式短语作插入语。如: To put it mildly, he was not up to the mark. To tell you the truth, I don't want to see her. To be sure, Jim is a faster skater, but he is not good at doing figures. To conclude, it was a great success. 在日常交际用语和书面表达中，插入语频频出现。英语中的插入语（Parenthesis）是插在句子中的一个词，短语或从句，通常被逗号、破折号或句子的其他部分隔开，它与句子的其他部分之间没有语法上的关系，因此，有的语法学家将其归为独立成分。 插入语在句中通常是对一句话的一些附加解释，说明或总结；有时表示说话者的态度和看法；有时起强调的作用；有时是为了引起对方的注意；还可以起转移话题或说明事由的作用；也可以承上启下，使句子与前面的语句衔接的更紧密一些。 插入语大致可分为以下10种类型： 1. 形容词或形容词短语作插入语
《文本信息加工—字处理软件》教案 一、教学目标： 1. 要求学生了解文字处理技术的发展变化及其意义，特别是从中文信息处理技术发展过程中领悟传播民族文化的必要性和紧迫性 ; 2. 了解文字在计算机中的编码方式 ; 3. 根据需要选择适当的文字处理工具，围绕主题加工文本信息； 4. 在模仿的基础上尝试合乎规范地使用结构化和形象化的方式加工信息。 二、教学内容： 1. 体验文字处理技术的发展变化及其意义 2. 了解文字在计算机中的编码方式 3. 根据需要，围绕主题加工文本信息 4. 使用结构化和形象化的方式加工和表达信息 三、教学重点： 1. 体验文字处理技术 2. 文本信息的结构化表达和形象化表达 四、教学难点： 1. 根据需要选择合适的字处理软件 2. 结构化表达信息的适用范围 3. 形象化表达信息的适用范围 五、教学主要内容： ①如何适应迅速变化的字处理软件的发展 ②如何根据需要选择合适的字处理软件 一、字处理软件的基本特征 文字处理——进行文字类稿件的输入、编辑、排版和发布。（如： Wps 、 Word 、永中 Office ） 1 ．GUI （图形用户）界面：简单易学 ①功能菜单置于程序窗口的顶部，用户可以方便从菜单中选择菜单。 ②使用滚动条可方便用户在文本窗口中浏览。 ③在选定一个对象之前，必须操作“选择对象——操作对象”这个方式 ④软件将操作的结果直接显示出来 特点：直观、简洁、交互性强的友好界面，易于学习和掌握 2 ．功能丰富：个性选择 使用 word 软件频率最低和最高的五个功能 从上面的表格可以得出结论： （ 1 ）即使像“录制新宏”等很少被用到的功能，软件中也要加入它们，因为只要有人需要，就可以随时使用这些功能。这给软件带来适应性。 （ 2 ）对于用户来说，只要能满足自己工作中的需要，并不需要熟练掌握某个软件的所有功能。
comparison的用法解析大全 comparison的意思是比较，比喻，下面我把它的相关知识点整理给大家，希望你们会喜欢！ 释义 comparison n. 比较;对照;比喻;比较关系 [ 复数 comparisons ] 词组短语 comparison with 与…相比 in comparison adj. 相比之下;与……比较 in comparison with 与…比较，同…比较起来 by comparison 相比之下，比较起来 comparison method 比较法 make a comparison 进行比较 comparison test 比较检验 comparison theorem 比较定理 beyond comparison adv. 无以伦比 comparison table 对照表 comparison shopping 比较购物;采购条件的比较调查 paired comp arison 成对比较 同根词 词根： comparing adj. comparative 比较的;相当的 comparable 可比较的;比得上的 adv. comparatively 比较地;相当地 comparably 同等地;可比较地 n.
comparative 比较级;对手 comparing 比较 comparability 相似性;可比较性 v. comparing 比较;对照(compare的ing形式) 双语例句 He liked the comparison. 他喜欢这个比喻。 There is no comparison between the two. 二者不能相比。 Your conclusion is wrong in comparison with their conclusion. 你们的结论与他们的相比是错误的。 comparison的用法解析大全相关文章： 1.by的用法总结大全
【e800编译】此示例演示如何比较两个Microsoft Word 2010文档的各项特点。 此代码段是Office 2010的101项VBA代码示例中的一部分。与其它示例一样，这些将可以直接写入您的代码中。 每块示例代码包含约5至50行的代码，分别演示了一个独特的功能或功能集，在VBA 或VB以及C＃中（在Visual Studio 2010中创建）。每个示例之中都会包含代码以及相应注释，这样您就可以直接运行获取预期的结果，或者是根据代码注释提示来调整环境，运行示例代码。 Microsoft Office 2010提供了你所需要的工具来创建功能强大的应用程序。Microsoft Visual Basic Application（VBA）代码示例可以帮助你创建自己的应用程序，以执行特定功能或者以此为出发点实现更为复杂的功能。 实例代码 在一个新文档键入以下文本，然后按Enter键： =rand（5，5） 这会在当前文档中插入各包含5个句子的5个段落。然后在VBA编辑器中，复制这段代码到ThisDocument类中。将光标放在DemoCompare内，然后按F8单步执行代码。将VBA 和Word窗口并排排列在屏幕上，这样你就可以查看单步代码的动作。 Sub DemoCompareDocuments() ' Save the current document, including this code. Const path1As String="C:\Temp\Doc1.docm" Const path2As String="C:\Temp\Doc2.docm" Const path3As String="C:\Temp\Doc3.docm" Dim doc1As Document Dim doc2As Document Dim doc3As Document ' Save with macros enabled, because this code exists within ' the document you're saving. If the document didn't contain ' code, you would not need to specify the file format. Set doc1=ActiveDocument doc1.SaveAspath1,wdFormatXMLDocumentMacroEnabled ' Make some changes to the current document:
compare的用法和短语例句 compare有比较;对比;比喻等意思，那么你知道compare的用法吗?下面跟着一起来学习一下，希望对大家的学习有所帮助! compare的用法： compare的用法1：confirm的基本意思是“证实”“确定”,指以不可辩驳的事实或不容置疑的陈述证实某事的真实性、准确性、正确性以及有效程度，引申可表示为“认可”“坚定”。 compare的用法2：confirm是及物动词,其主语多为人,宾语可以是名词、代词或that从句,也可接以as短语充当补足语的复合宾语。 compare的常用短语： 用作动词(v.) compare to (v.+prep.) compare with (v.+prep.) compare的用法例句： 1. He programmed his computer to compare all the possible combinations. 他给他的计算机编制了一套程序，以比较所有可能的组合。 2. How do the two techniques compare in terms of application?
这两种手法实际运用起来哪个好一些? 3. The more recent conifer plantations cannot yet compare with the old woodlands. 年代较近的针叶树林场还比不上年代久远的林场。 4. Childcare facilities in Britain compare unfavourably with other European countries. 英国的保育设施与欧洲其他国家比起来相形见绌。 5. It's instructive to compare his technique with Alan Bennett's. 把他的手法与艾伦;贝内特进行比较很富启发意义。 6. Was it fair to compare independent schools with state schools? 拿私立学校与州立学校相比，这样公平吗? 7. It is often very hard to compare all-male and all-female jobs. 纯男性工作和纯女性工作之间常常很难作比较。 8. Compare the following passages. 比较下列片段。 9. Compare the two illustrations in Fig 60. 比较图60中的两幅插图。 10. She was a storyteller beyond compare. 她是个无与伦比的讲故事高手。
第二讲文本素材的采集与处理 本讲目标： 1．明确文本素材的五种获取方法。 2．掌握扫描仪的使用方法，会用扫描仪获取大量文本，并能利用文字识别软件对获取的文本进行修改编辑。 重点：获取文本素材的方法。 难点：大量文本的采集—扫描仪扫描文字识别法。 一、五种文本素材的获取方法 文本素材的获取有直接获取与间接获取两种方式，直接获取是指通过多媒体教学制作工具软件的文字工具或在文字编辑处理软件中用键盘直接输入或复制，一般在文本内容不多的场合下使用该方式。间接获取是指用扫描仪或其他输入设备输入文本素材，常用于大量文本的获取。 文本素材的获取方法如下： （1）键盘输入方法 键盘输入方法是文本输入的主要方法，使用计算机输入汉字，需要对汉字进行编码，根据汉字的某种规律将汉字用数字或英文字符编码，然后由计算机键盘输入。汉字有音、形、义三个要素，根据汉字读音的编码叫音码，根据汉字字形的编码叫形码，兼顾汉字读音和字形的编码叫音形码或形音码。在常用的多媒体教学制作软件中，都带有文字工具，在文本内容不多的情况下，可以直接输入文字，对输入的文字可进行直接编辑处理。 （2）手写输入方法 使用“输入笔”设备，在写字板上书写文字，来完成文本输入。利用手写输入法获取文本的方式，类似于平时我们在纸上写字，但对在写字板上书写的文字要经选择。手写输入方法使用的输入笔有两种：一种是与写字板相连的有线笔，另一种是无线笔。无线笔携带和使用均很方便，是手写输入笔的发展方向。写字板也有两种，一种是电阻式，另一种是感应式。 （3）语音输入方法 将要输入的文字内容用规范的语音朗读出来，通过麦克风等输入设备送到计算机中，计算机的语音识别系统对语音进行识别，将语音转换为相应的文字，完成文字的输入。 语音输入方法目前开始使用，但识别率还不是很高，对发音的准确性要求比较高。 （4）扫描仪输入法 将印刷品中的文字以图像的方式扫描到计算机中，再用光学识别器（OCR）软件将图像中的文字识别出来，并转换为文本格式的文件。目前，OCR的英文识别率可达90%以上，中文识别率可达85%以上。 （5）从互联网上获取文本 从互联网上可以搜索到许多有用的文本素材，在不侵犯版权的情况下，可以从互联网上获取有用的文字。从互联网的html页面上获取部分文本的方法是：首先拖动鼠标选取有用的文本，或单击鼠标右键，在弹出的快捷菜单中，选择“全选”命令，将整个页面上文字全部选中，然后选择“复制”命令，打开文字处理软件（如Word），选择“编辑”/“粘贴”命令，就可以将复制的文字在文字处理软件中进行编辑处理了。如果将互联网上其他格式的文本文件（如：.pdf，.caj）格式的文件进行保存，然后使用部分有用文本，常用的方法是：选择“文件”菜单中的“另存为”命令，将文本文件进行保存，
一、beyond作介词用时，使用最广，常用于下列几种情况： 1.表示位置，意思是“在……的那一边；在……之外；在更远处”。例如： Beyond the river stood a power station. 过了这条河就是一个发电站。 The sea is beyond that hill. 大海在山的那边。 2.表示时间，其意为“迟于；超过” 例如： Some shops keep open beyond midnight 有些商店营业到半夜以后。 He never sees beyond the present.他从未看到将来。 3.表示范围、水平、限度、能力等，意思是“超出；多于；为……所不能及”。在句中常作表语、定语或状语。 作表语 Your work is beyond all praise. 你的作品叫人赞扬不尽。 ②作定语 These were matters beyond his understanding as yet. 这些事情他那时候还不了解。 ③作状语 We succeeded beyond our hopes. 我们获得如此之成功，是我们始料所不及的。 She was really touched beyond words. 她确实感动得无法形容。 4.用在否定和疑问句中，意思是“除……之外”。例如： I know nothing beyond what he told me. 除了他告诉我的以外，别的我都不知道。 Is there anything more you can say beyond that？ 除了那点之外，你还能说些什么吗？ 5.beyond有时还可表示年龄或数量，意思是“超过”。例如： He didn't believe in people living beyond 100. 他不相信人能活到100岁以上。 At the meeting there were not beyond 20 people. 到会的人不超过二十。 二、beyond也常作副词用，主要有下面两种用法： 1.指时空或正在进行中的活动，意思是“在远处；向远处；更远处”。例如： If we cross the mountains we may find people living in the valley beyond.如果我们翻过这些大山，我们就可以发现在远处山谷中生活的人们。 I'll go with you to the bridge，but not a step beyond.我愿意同你一道走到桥头，但再远的地方一步也不愿意去。 2.表示外加，意思是“此外；以外”。例如： He told me nothing beyond.此外他没告诉我什么。 三、beyond也可作名词用，常有下面三种情况： 1.指“远处的东西”。例如： That is a river for small boats expending 30miles back into the beyond. 那是一条小船能上行30英里的河流。 2.表示超出普通经验范围的某种事物。例如： What can we poor human beings know of the great beyond？ 我们可怜的人类能知道来世的什么情况呢？
word文字处理技巧大全 去除页眉的横线方法两则 在页眉插入信息的时候经常会在下面出现一条横线，如果这条横线影响你的视觉，这时你可以采用下述的两种方法去掉： 用第一种的朋友比较多，即选中页眉的内容后，选取“格式”选项，选取“边框和底纹”，边框设置选项设为“无”，“应用于”处选择“段落”，确定即可。 第二种方法更为简单，当设定好页眉的文字后，鼠标移向“样式”框，在“字体选择”框左边，把样式改为“页脚”、“正文样式”或“清除格式”，便可轻松搞定。 在Word中快速选择字体 为了能够快速地选择字体，可以将常用的字体以按钮的形式放到工具栏上。首先在Word 的工具栏上单击鼠标右键，在右键菜单中选择最后一项“ 自定义” 。然后在出现的自定义编辑界面中选中“ 命令” 选项卡，再选择“ 类别” 中的“ 字体” 项。最后从右边列出的Windows 已安装的字体中， 选择常用的字体并用鼠标直接将它拖曳到工具栏上，这样在以后的使用中就可以快速选择字体了。 用Word实现快速隔行删除 先将全文复制Word 中，按Ctrl+A 键全选，再选择“ 表格” 下拉菜单中的“ 转换/ 文字转换成表格” ，在弹出的对话框中，将“ 列数栏” 定为“2列” ，将“文字分隔位置” 选为“ 段落标记”，确定后便出现一个 2 列n 行的表格，再全选表格，右击鼠标“合并单元格” 。
清除Word文档中多余的空行 如果Word 文档中有很多空行，用手工逐个删除又太累人，直接打印吧，又太浪费墨水和打印纸。有没有较便捷的方式呢?我们可以得用Word 自带的替换功能来进行处理。在Word 中打开编辑菜单，单击“ 替换” ，在弹出的“ 查找和替换” 窗口中，单击“ 高级” 按钮，将光标移动到“ 查找内容” 文本框，然后单击“ 特殊字符” 按钮，选取“ 段落标记” ，我们会看到“^p” 出现在文本框内，然后再同样输入一个“^p” ，在“ 替换为” 文本框中输入“^p” ，即用“^p” 替换“^p^p” ，然后选择“ 全部替换” ，怎么样，多余的空行不见了吧。 同时保存所有打开的Word文档 有时在同时编辑多个Word文档时，每个文件要逐一保存，既费时又费力，有没有简单的方法呢?在按下Shift键的同时，单击“文件”菜单，大家看，已经多出了“同时保存”和“同时关闭”命令，这可就方便多了。 巧妙设置文档保护 在用Word2000打印一份文件时，要暂时离开一下，关闭文件吧，既费事又没必要，但又不想辛辛苦苦写的文件被别人破坏了。怎么办呢?执行“工具”菜单中的“保护文档”命令，在弹出的窗口中选择“保护窗体”，然后设上密码。怎么样，光标跑到了文件头，任你怎么移动鼠标、敲击键盘就是无法编辑了，不错吧。等回来时，执行“工具”菜单中的“解除文档保护”命令，一切又正常了。