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Targeting Vascular Endothelial Growth Factor and Angiogenesis for the Treatment of Colorectal Cancer

Timothy S.Collins and Herbert I.Hurwitz

Angiogenesis,the development and proliferation of new blood vessels,is critical for the growth of tumors.The process of new blood vessel formation is under complex control from a variety of pro-and anti-angiogenesis factors.By identifying and understanding these factors,new therapies have been developed to inhibit tumor growth and survival by blocking tumor-related angiogenesis.Recent success with the monoclonal antibody against vascular endothelial growth factor (VEGF;bevacizumab)in a large,randomized,phase III study has provided a critical proof of principle for this therapeutic area.This review will outline the biology of angiogenesis in colorectal cancer and discuss the current status of angiogenesis inhibition in its treatment.

olorectal cancer is the second leading cause of cancer-re-lated death in the United States.In 2004,there were an estimated 146,940patients diagnosed with colorectal cancer and an estimated 56,730disease-related deaths.1For several decades,5-?uorouracil (FU)-based chemotherapy regimens have been the mainstay of treatment for advanced colorectal cancer.Over the past decade,new chemotherapeutic agents,such as irinotecan and oxaliplatin,have been introduced and have improved outcomes in patients with advanced colorectal cancer.2-4Despite this,the median survival of patients with met-astatic colorectal cancer remains less than 2years.New strategies are clearly needed for this disease.

Angiogenesis,the process of new blood vessel formation,is considered critical for the growth of tumors.In 1971,Judah Folkman ?rst proposed that tumor angiogenesis could serve as a potential target for anticancer therapy.5This idea led him and others to search for and ?nd speci?c tumor angiogenesis factors.5-10Numerous studies have established that angiogen-esis is a necessary component for solid tumor growth,and may contribute to hematologic malignancies as well.11,12The extensive work done to better understand the underlying mechanisms regulating tumor angiogenesis has been well re-viewed.13In turn,this has led to the development and clinical testing of numerous novel anti-angiogenesis agents with po-tentially broad applicability for cancer,as well as a number of other angiogenesis-dependent diseases.

Angiogenesis inhibition represents a new paradigm in the treatment of cancer.Unlike traditional chemotherapy,angio-genesis inhibitors speci?cally target the formation of new blood vessels.By not interfering with dividing hematopoeitic stem cells or dividing gastrointestinal cells,there is a poten-tial for reduced toxicities.In addition,angiogenesis inhibi-tors have the potential to treat a wide variety of tumors since the requirement for neovascularization is nearly universal across different tumor types.Nevertheless,potential limita-tions exist.Most of these agents are likely to have limited single-agent activity and may lead primarily to tumor growth inhibition rather than regression.Dose-limiting toxicities may not be seen.However,many of these agents have indeed shown signi?cant,even dose-limiting toxicities.14-17These factors have complicated dose selection in early-stage clinical trials.Nevertheless,while dose selection is still primarily guided by pharmacokinetics and safety considerations,sev-eral early-phase clinical trials of angiogenesis inhibitors have tried to incorporate biomarkers to help de?ne optimal dos-ing.It should be remembered that all biomarkers for this ?eld have limitations and none has been validated thus far.

Several lines of evidence suggest that advanced colorectal cancer may be an excellent tumor type to target via angiogen-esis inhibition.Although there are limitations in interpreting modest-sized studies using different assay methods,in gen-eral,for colorectal cancer,angiogenesis as measured by mi-crovessel count has been shown to correlate with a worse prognosis.18In addition,the expression of pro-angiogenesis factors,such as vascular endothelial growth factor (VEGF),has been reported to correlate with increased vascularity,advanced disease,and a worse prognosis.19,20Finally,colo-Department of Medical Oncology,Duke University Medical Center,Durham,NC.

Address reprint requests to Herbert I.Hurtwitz,MD,Duke University Med-ical Center,Department of Medical Oncology,Durham,NC 27710.E-mail:

hurwi004@https://www.sodocs.net/doc/3011816742.html,

rectal cancer was the?rst solid tumor type in which anti-angiogenesis therapy was de?nitively demonstrated to im-prove patient survival.This important proof of principle was reached last year when the results of a large,randomized, phase III trial were announced.21This report will review the biology of angiogenesis and the current status of angiogenesis inhibition for the treatment of advanced colorectal cancer. Biology of VEGF

in Tumor Angiogenesis

The development of an angiogenic phenotype is a key step in the progression of tumor growth.22The process by which tumors develop an angiogenic phenotype has been termed the“angio-genic switch.”This switch is a proposed conceptual framework to understand the complex interplay between pro-and anti-angiogenesis factors.23Several of these factors have been identi-?ed and are listed in Table1.Among these factors,VEGF has received considerable attention from basic science,pharmaceu-tical,clinical,and translational researchers.

The complex biology within the VEGF axis has been ex-tensively reviewed.13,24VEGF,also known as vascular perme-ability factor(VPF),was?rst cloned in1989by Ferrara and colleagues and Connolly and colleagues.7,9The VEGF family consists of six glycoproteins,including VEGF-A,-B,-C,-D, -E,and placental growth factor.25-29VEGF-A,commonly re-ferred to as VEGF,was the?rst factor identi?ed and is con-sidered to be a key regulator of blood vessel growth.13As a result of alternative exon splicing,VEGF-A exists in four different isoforms of varying amino acid length(VEGF121, VEGF165,VEGF189,and VEGF206).30Important biologic dif-ferences exist among the isoforms.30VEGF121is acidic,does not bind heparin,and is freely diffusible.VEGF189and VEGF206are highly basic and as a result are tightly bound to the heparan-sulfate rich extracellular matrix.VEGF165has intermediate properties.VEGF expression is regulated by nu-merous factors,including other angiogenic factors and cyto-kines,hypoxia,and many tumor oncogenes.31-36Impor-tantly,VEGF is partially regulated by hypoxia inducible factor(Hif),which is constitutively activated in the setting of mutations of the Von Hippel-Lindau gene(VHL).These gene mutations are commonly found in familial and sporadic clear cell carcinomas of the kidney,leading to the notably high levels of VEGF expression in this tumor type.

In general,VEGF family members mediate their effects by binding to one or more of the VEGF receptors and/or core-ceptors,leading to dimerization,with resultant phosphory-lation and activation of the receptor’s intracellular tyrosine kinase domain.There are three members of the VEGF recep-tor family,including VEGFR-1(Flt-1),VEGFR-2(KDR or Flk-1),and VEGFR-3(Flt-4).24In addition,there are two coreceptors,neuropilin-1(NP1)and neuropilin-2(NP2).37,38 VEGF binds to VEGFR-1,VEGFR-2,and both NPs,but not to VEGFR-3.In contrast,VEGF-C and VEGF-D bind VEGFR-2 and VEGFR-3,but not VEGFR-1.13Interestingly,VEGFR-1 and VEGFR-2are located not only on the cell surface of vascular endothelial cells,but also on the surface of certain tumor types,particularly on hematologic malignancies, where these receptors may be functional.39-41VEGF’s down-stream signaling is also complex,with activation of the Ras-Raf-ERK,Src-FAK,AKT-mTOR(molecular target of rapamy-cin),and small G-protein-eNOS(epithelial nitric oxide synthase)pathways.24

VEGF and VEGFR-2are generally thought to be the most critical endothelial cell ligand and receptor,respectively,in solid tumor angiogenesis.Indeed,VEGFR-2is capable of mediating all key endothelial cell functions needed to estab-lish a tumor’s neovasculature,including endothelial cell pro-liferation,survival,migration,tube formation,and perme-ability.42-46While VEGF is a key regulator of tumor angiogenesis,it should be remembered that there are numer-ous other factors that regulate and/or are regulated by VEGF, including but not limited to?broblast growth factor,inter-leukin-8,platelet-derived growth factor(PDGF),platelet-de-rived endothelial growth factor,epidermal growth factor, transforming growth factor?,insulin-like growth factor-1, hepatocyte growth factor,matrix metalloproteinases,compo-nents of the plasminogen system,and various integrins. Anti-VEGF Inhibitors

in Colorectal Cancer

Tumor angiogenesis can be blocked by a number of ap-proaches.Anti-VEGF therapies are furthest along and serve as a good model for broader issues shared by all anti-angio-genesis agents.Bevacizumab,for example,binds to and neu-tralizes the ligand VEGF,preventing its binding and activa-tion of VEGF receptors.A similar ligand depleting approach, using a soluble VEGFR-1receptor linked to an IgG1back-bone,is used by the VEGF-Trap system.47The VEGF recep-tors can also be blocked directly by antibodies to the extra-

Table1Endogenous Pro-and Anti-angiogenesis Factors

Pro-angiogenesis Anti-angiogenesis

Angiogenin Angiostatin

Angiopoietin-1Endostatin

Ephrins Interferon(?and?)

Epidermal growth factor Interferon-inducible protein

Estrogen Interleukin-12

Fibroblast growth factor

(acid-and basic-)

Maspin

Hepatocyte growth factor Platelet factor4

Interleukin-8Thrombospondin

Placental growth factor Tissue inhibitors of

metalloproteinases

Platelet-derived growth

factor

Tumstatin

Pleiotropin Vascular endothelial growth

factor inhibitor

Proliferin

Prostaglandin E1and E2Vasostatin

Transforming growth factor

(?and?)

Vasostatin

Tumor necrosis factor-?

Vascular endothelial growth

factor

62T.S.Collins and H.I.Hurwitz

cellular domain of the receptor,by ribozymes which deplete the receptor,and by small molecules that bind the catalytic kinase domain of the receptor,preventing activation of downstream effector signaling molecules.Additional anti-angiogenesis targets include the numerous other angiogenic growth factors and regulators,such as integrins,matrix met-alloproteinases,and endogenous angiogenesis inhibitors, such as endostatin,angiostatin,tumstatin,and the throm-bospondin mimetic ABT-510.Each approach has distinct advantages and disadvantages with respect to pharmacology, target speci?city,and receptor signaling biology.Each agent may also have additional unique properties that may also be highly relevant.

We will focus our review on the agents that have been tested to date in patients with colorectal cancer.Table2pre-sents a summary of studies either completed or ongoing us-ing angiogenesis inhibitors to treat colorectal cancer. Bevacizumab

Bevacizumab(Avastin;Genentech,South San Francisco,CA) is a recombinant,humanized,monoclonal antibody directed against VEGF.48The antibody blocks binding of the ligand VEGF with its receptor.Several preclinical models have dem-onstrated that monoclonal antibodies directed against VEGF inhibit tumor growth in mice.49-51Warren et al studied the use of a recombinant monoclonal antibody directed against VEGF in a subcutaneous xenograft model.50Mice received twice weekly intraperitoneal injections of VEGF antibody beginning the day after a subcutaneous inoculation of HM7 and LS LiM6tumor lines.Treatment with anti-VEGF therapy resulted in a reduction of tumor weight by76%and88%in the two models,respectively.In an experimental liver metas-tasis model,mice received splenic injections of HM7cells followed by twice weekly intraperitoneal antibody injections. The number of liver metastases and tumor volumes were markedly and signi?cantly reduced with anti-VEGF treat-ment.

Initial phase I studies demonstrated a convenient17-to 21-day half-life and no signi?cant toxicities at doses that reduced free plasma VEGF to undetectable levels.52Subse-quently,a randomized phase II trial was performed compar-ing bevacizumab plus FU/leucovorin(LV)with FU/LV alone in patients with metastatic colorectal cancer.53One hundred four patients were randomized to one of three arms:FU/LV alone,FU/LV plus low-dose bevacizumab(5mg/kg every2 weeks),and FU/LV plus high-dose bevacizumab(10mg/kg every2weeks).FU/LV was given according to Roswell Park regimen with weekly administration of FU/LV for?rst6 weeks of an8-week cycle.54Con?rmed response rates were higher in both bevacizumab arms:17%for FU/LV alone, 40%for FU/LV/low-dose bevacizumab,and24%for FU/LV/ high-dose bevacizumab.Furthermore,time to disease pro-gression was longer in both bevacizumab arms:5.2months for FU/LV alone,9.0months for FU/LV/low-dose bevaci-zumab,and7.2months with FU/LV/high-dose bevacizumab. Following these encouraging results,a large,randomized, placebo-controlled phase III trial combining bevacizumab with?rst-line chemotherapy was performed in patients with metastatic colorectal cancer.21The initial study design out-lined three arms including irinotecan/FU/LV(IFL)plus pla-cebo,IFL plus bevacizumab(5mg/kg every2weeks),and FU/LV plus bevacizumab.Given the robust activity and lim-ited toxicity of5FU/LV/bevacizumab in the phase II study, the third arm was included as a potential comparator arm to IFL in case the combination of IFL/bevacizumab had unex-pected toxicities.Since IFL had just become the standard of care at the time this study started,there were no safety data on the combination.Once it was con?rmed that there was no signi?cant excess toxicity in the IFL/bevacizumab arm,the 5FU/LV/bevacizumab arm was discontinued,as prespeci?ed in the protocol.The study then completed enrollment of813 patients into the two primary arms:IFL/placebo and IFL/ bevacizumab.Table3presents the results for the primary and secondary end points.The addition of bevacizumab to IFL resulted in a reduction in the daily hazard of death by34% (P?.00004)as compared to IFL chemotherapy alone.55In

Table2Completed or Current Trials of Angiogenesis inhibitors in Colorectal Cancer

Study Phase

No.of

Patients Protocol Population

Giantonio et al79II92Bevacizumab?IFL Previously untreated Kabbinavar et al53II104Bevacizumab?FU/LV Previously untreated Hurwitz et al20III925Bevacizumab v placebo?IFL Previously untreated Benson et al62III880*Bevacizumab v placebo?FOLFOX-4Previously treated

SWOG-030380III2,200*Bevacizumab v placebo?FOLFOX v CAPOX Previously untreated Trarbach et al81I/II51?PTK787?FOLFOX or PTK787?FOLFIRI Previously untreated CONFIRM-180III1,090*PTK787v placebo?FOLFOX Previously untreated CONFIRM-280III830*PTK787v placebo?FOLFOX Previously treated

Blanke et al72II23Celecoxib?IFL Previously untreated

Pan et al73II41Celecoxib?glutamine?IFL Previously untreated Koehne et al74III692*Celecoxib v placebo?IFL v

irinotecan/capecitabine

Previously untreated

Libutti et al80II94*Thalidomide Resected metastatic disease Venook et al78II83Angiozyme?IFL Previously untreated

*Expected enrollment.

?Reported to date.

Targeting VEGF and angiogenesis63

addition,patients receiving the combination of bevacizumab plus IFL had an improvement in median survival by4.7 months(15.6months for IFL/placebo v20.3months for IFL/bevacizumab,hazard ratio of death0.66favoring IFL/ bevacizumab,P?.00003).A consistent survival bene?t was seen for all prespeci?ed subgroups,including age,sex,race, Eastern Cooperative Oncology Group(ECOG)performance status,location of primary tumor,prior adjuvant therapy, duration of metastatic disease,number of organ sites with metastases,years since colorectal cancer diagnosis,prior ra-diotherapy,and baseline tumor burden.The use of second-line therapies,which can confound survival data,was also equal in both arms.In addition,progression-free survival (6.2months for IFL/placebo v10.6months for IFL/bevaci-zumab,hazard ratio of progression0.54for IFL/bevaci-zumab,P?.00001)and overall response rates(35%for IFL/placebo v45%for IFL/bevacizumab,P?.003)were improved in the bevacizumab-containing arm.Importantly, based on the arm3results of this pivotal study,FU/LV plus bevacizumab(without irinotecan)also seems to be an active platform regimen,with a response rate of40%,median pro-gression-free survival of8.8months,and a median overall survival of18.3months.56These results are consistent with those seen in the previously mentioned phase II study,as well as the results of another large randomized phase II compar-ison of FU/LV?bevacizumab in patients who were not candidates for irinotecan,where the FU/LV/bevacizumab group demonstrated a29%increase in median survival and a 67%increase in median progression-free survival compared to the FU/LV-alone group.57A detailed molecular analysis of archived para?n-embedded tumor samples from patients in this trial evaluated VEGF expression by immunohistochem-istry and in situ hybridization,as well as mutations in genes known to regulate VEGF,such as k-ras,b-raf,and p53.Bev-acizumab treatment was associated with a survival bene?t in all molecular subgroups,ie,VEGF expression did not predict for response(or for nonresponse)to bevacizumab.The ex-planation for the lack of association in this trial between target level and clinical bene?t for this targeted therapy is likely multifactorial,and probably relates at least in part to the technical dif?culty of measuring activated VEGF recep-tors,which was not possible in this study.58

In the large phase III study,the monoclonal antibody was remarkably well tolerated.IFL-related toxicities were not in-creased.Only grade3hypertension was signi?cantly in-creased(11.0%in the bevacizumab arm v2.3%in the pla-cebo arm)and this was easily managed with addition of oral antihypertensives.This study may have also uncovered a rare but important side effect of bevacizumab treatment,a risk of gastrointestinal perforation.This event occurred in six pa-tients(1.5%)in the IFL/bevacizumab arm compared to none in the IFL arm.Although there were no cases in the chemo-therapy-alone group,bowel perforation has previously been reported in patients receiving systemic chemotherapy.59,60 Importantly,three of the six patients with gastrointestinal perforation recovered and were able to restart treatment without any further complications,although two patients discontinued treatment permanently and one patient died as a complication of this event.What causes this rare side effect is unclear but may relate to the known role of VEGF in wound healing biology.The events were clinically varied in their presentation,and,aside from a possible association with tumor response,it is unclear if any predisposing factors could have predicted this rare complication.

In addition to this phase III study,bevacizumab has been combined with IFL in an Eastern Cooperative Oncology Group(ECOG)phase II study(E2200).Updated results on this study were presented at the American Society of Clinical Oncology(ASCO)Gastrointestinal Cancers Symposium ear-lier this year.61In this study,92previously untreated patients with advanced colorectal cancer were treated with combined IFL and bevacizumab.The?rst20patients received irinote-can(125mg/m2),FU(500mg/m2),and LV(20mg/m2) weekly for4of6weeks and bevacizumab(10mg/kg)every other week.Based on toxicity seen with IFL reported in other trials,the next72patients received reduced starting doses of irinotecan(100mg/m2)and FU(400mg/m2)in addition to LV and bevacizumab.Similar to the phase III study men-tioned above,there was substantial activity of this combina-tion with an overall response rate of49%(6%complete re-sponses and43%partial responses).In addition,the mean progression-free survival was10months and the1-year sur-vival was85%?4%.

In addition to the combination of bevacizumab and IFL, investigators are studying the role of bevacizumab with ox-aliplatin-containing regimens.An ECOG trial in the second-line setting,E3200,is a randomized phase III trial with three arms:FOLFOX-4(bolus plus infusional FU,LV,and oxali-platin)plus bevacizumab(10mg/kg biweekly),FOLFOX-4 alone,or bevacizumab alone(10mg/kg biweekly).This study has completed enrollment.An interim toxicity analysis from this study was presented at ASCO2003,and showed no signi?cant change in the overall safety pro?le of FOLFOX-4.62In this study,the median overall survival for the FOLFOX-4/bevacizumab group was12.5months com-pared with10.7months for FOLFOX/placebo,which was

Table3Primary and Secondary End Points:A Phase III Trial of Bevacizumab Versus Placebo in Combination With IFL Chemotherapy in First-Line Treatment of Metastatic Colorectal Cancer

End Point IFL/Placebo IFL/Bevacizumab P Value Randomized410403

Median survival(mo)15.620.3.00003 PFS(mo) 6.210.6<.00001 Overall response rate(CR?PR)3545.003 Duration of response(mo)7.110.4.001 Abbreviations:PFS,progression-free survival;CR,complete response;PR,partial response.

64T.S.Collins and H.I.Hurwitz

associated with a reduced hazard ratio for death of0.76.63In

addition,a large,randomized phase III trial in the?rst-line

setting with the Southwest Oncology Group(S0303)will

compare in a two-by-two design,FOLFOX-6versus XELOX

(capecitabine/oxaliplatin).Each of these two chemotherapy

arms will undergo further randomization to bevacizumab

versus placebo.

Vatalanib

Vatalanib(PTK787/ZK222584;Novartis/Schering,East

Hanover,NJ)is a small molecule belonging to the phthala-

zine family of compounds.Initial testing determined that

it is a potent and selective tyrosine kinase inhibitor.Its

predominant inhibitory effects are on VEGFR-1and

VEGFR-2(IC500.077?mol/L and0.037?mol/L,respec-tively)but it also has inhibitory effects on VEGFR-3,c-KIT

and PDGFR-?(IC500.66?mol/L,0.73?mol/L,and0.58?mol/L,respectively).62By inhibiting VEGF at the level of the receptor’s tyrosine kinase,vatalanib disrupts down-

stream VEGF signal activation pathways.This disruption

may overcome some theoretical mechanisms of resistance

related to promiscuous ligand-receptor interactions.Im-

portantly,early preclinical models also demonstrated that

vatalanib has potent anti-angiogenic and antitumor ef-

fects.64

Several disease-speci?c phase I trials have been reported

using vatalanib as a single agent in patients with advanced

cancer with liver metastases,glioblastoma multiforme,and

advanced genitourinary cancers.65A phase I dose-escalation

and pharmacokinetic study was performed in patients with

liver metastasis from advanced cancer.66In this study,14of

15patients had metastatic colorectal cancer and no dose-

limiting toxicities were observed at doses up to1,200mg

daily.

In addition to these monotherapy trials,vatalanib has been

combined with chemotherapy in patients with untreated,

metastatic colorectal cancer,including the FOLFIRI(infu-

sional FU/LV plus irinotecan)and FOLFOX regimens.67,68

These studies have paved the way for two large phase III

trials,which are currently enrolling patients.CONFIRM-1

(Colorectal Oral Novel Therapy for the Inhibition of Angio-

genesis and Retarding of Metastases)is a multinational trial

comparing vatalanib in combination with FOLFOX-4to

FOLFOX-4with placebo in previously untreated patients

with metastatic colorectal cancer.Primary end points are pro-

gression-free and overall survival.CONFIRM-2will study

once-daily vatalanib in combination with FOLFOX-4com-

pared to FOLFOX-4with placebo in patients with metastatic

colorectal cancer who have progressed after irinotecan-based

?rst-line chemotherapy.Both studies are currently under-

way,and results are anticipated in the near future.

An interesting aspect of the development of vatalanib has

been the attempt to incorporate radiologic correlates with

clinical response.Morgan et al reported their work studying

the ability of vatalanib to alter blood perfusion and perme-

ability,as measured by a complex magnetic resonance imag-

ing(MRI)parameter known as Ki,or the bidirectional trans-

fer constant.69These data demonstrated a reduction in this MRI parameter that was dose-dependent.Furthermore,a de-crease in contrast enhancement correlated with higher re-sponse rates in this small study.However,since effects on permeability may not necessarily correlate with effects on endothelial cell survival and/or proliferation,these?ndings will need additional validation before they can be used for dose selection or for prognostic purposes.

Celecoxib

Celecoxib(Celebrex;P?zer,New York,NY)is a selective cyclooxygenase-2inhibitor?rst developed for the use in pa-tients with rheumatoid arthritis and osteoarthritis.70Re-cently,celecoxib was found to both inhibit angiogenesis and block tumor cell growth.71These?ndings led to two phase II trials combining celecoxib with standard chemotherapy to treat advanced colorectal cancer.72,73Currently,a large,ran-domized,placebo-controlled,phase III trial is studying the use of celecoxib in combination with?rst-line chemotherapy in metastatic colorectal cancer.74Mature results are not yet available.

Thalidomide

Thalidomide,an agent previously removed from the market for its teratogenic properties,is generating interest since its immu-nomodulatory and anti-angiogenesis properties were recog-nized.75,76Thalidomide is a Food and Drug Adminstration–rec-ognized therapy for the treatment of multiple myeloma.77 Further trials with thalidomide are ongoing or planned to treat a wide variety of other malignancies.A randomized,placebo-con-trolled phase II trial is currently enrolling patients with recurrent or metastatic colorectal cancer who have undergone curative resection.Following surgery,patients without evidence of resid-ual disease are randomized to receive either thalidomide or pla-cebo.A total of94patients are to be enrolled. Angiozyme

Angiozyme is an agent belonging to the family of ribozymes that exerts their effects through a unique mechanism of ac-tion.Ribozymes catalyze the degredation of speci?c mRNAs, thus preventing the translation of speci?c proteins.An-giozyme speci?cally cleaves the mRNA encoding the VEGFR-1and VEGFR-2receptors.An open-label phase II trial combining angiozyme with IFL chemotherapy has been performed in83previously untreated patents with metastatic colorectal cancer.78As a potential biomarker,serum levels of soluble VEGFR-1were measured before and after treatment to assess their correlation with clinical response.A full report has not been published yet and future trials with this agent in colorectal cancer have not been announced.

Other Agents

In addition to these agents,numerous other anti-VEGF and anti-angiogenic agents have also entered clinical testing;Table4 summarizes the angiogenesis inhibitors currently in clinical de-velopment.While many have reported phase I results or prelim-inary phase II data,none of these other agents has yet initiated phase III studies in colorectal cancer.

Targeting VEGF and angiogenesis65

Conclusions

After decades of progress in the?eld of tumor angiogenesis, the positive phase III results of bevacizumab in colorectal cancer have validated the potential of anti-angiogenesis ther-apies for the treatment of human cancers.The role of bevaci-zumab in other settings is under active investigation.In ad-dition,many other anti-VEGF and anti-angiogenic agents are in clinical testing,each with the potential to make a unique contribution to the therapy of colorectal and other cancers. As the number of active agents to treat colorectal cancer increases,new empiric and mechanism based combination regimens will need to be evaluated.Since many anti-angio-genic agents,like other anticancer agents,have failed to show clinical bene?t thus far,this process of clinical validation still needs to be deliberate and focused.Recent improvement in imaging,molecular diagnostics,and drug design should speed this process.With the positive results of bevacizumab in colorectal cancer,the question is no longer whether the approach of targeting tumor vasculature is worthwhile,but how we can make further progress most quickly. References

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Table4Angiogenesis Inhibitors in Clinical Development

Agent Manufacturer Description

VEGF antagonists

Bevacizumab*Genentech Monoclonal antibody directed against VEGF48

VEGF-Trap Regeneron Binds and inactivates VEGF47

VEGF receptor antagonists

Angiozyme*Sirna Ribozyme targeting VEGFR82

GW786034GlaxoSmithKline Oral VEGFR tyrosine kinase inhibitor

IMC-IC11Imclone Monoclonal antibody against VEGFR-283

SU11248P?zer Oral VEGFR/PDGFR/cKIT tyrosine kinase inhibitor84 Vatalanib*Novartis,Schering Oral VEGFR tyrosine kinase inhibitor64

ZD-6474Astra Zeneca Oral VEGFR/EGFR tyrosine kinase inhibitor85,86

Naturally occurring inhibitors

of angiogenesis

ABT-510Abbott Thrombospondin-1mimetic87

Angiostatin Entremed Inhibits endothelial cell proliferation and migration88,89 Endostatin Entremed Inhibits endothelial cell proliferation90

Vascular targeting agents

AVE8062Aventis Combretastatin derivative91

Combretastatin Oxigene Selectively disrupts cytoskeleton within endothelial cells92 ZD6126Astra Zeneca Selectively disrupts cytoskeleton within endothelial cells93 Other agents

Celecoxib*P?zer Cyclooxygenase-2inhibitor with anti-angiogenic properties71 NM-3Ilex Iscocoumarin inhibitor of endothelial cell growth94,95 Thalidomide*Celgene Unde?ned anti-angiogenesis properties75

TNP-470TAP Fumagillin analog,which inhibits endothelial cell growth96

*Reviewed earlier.

66T.S.Collins and H.I.Hurwitz

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68T.S.Collins and H.I.Hurwitz

图表与口诀记忆when、as、while的区别

图表与口诀记忆when、as、while的区别 1.图表与口诀前知识关键是比较主从句子的动词，看其动词的持续性。瞬间的理解成点，持续的理解成线。主从关系有：点（点点、点线），线线，线点。点：为瞬间动词，准确地称为“终止性动词”，指动词具有某种内在界限的含义，一旦达到这个界限，该动作就完成了。如come（来），一旦“到来”，该动作就不再继续下去了。瞬间动词：arrive, begin, borrow, become, buy, catch, come, die, find, go，give, graduate, join, kill, lose, leave, marry, realize… 线：为非瞬间动词，准确地称为叫“延续性动词”。包括动态动词静态动词。动态动词：live, sit, stand, study, talk, work, write… 静态动词（状态动词）：情感、看法、愿望等。Be, belong, consist, exist, feel, hate, have, hope, love, want… 兼有瞬时和非瞬时的动词：feel，look，move，run，work，write…，需要根据不同的语境判断。 2. when、as、while的区别一览表【表格说明】：第一个点或者线表示从句谓语动词的持续性特征，黑点表示从句所表示的动作持续短，为瞬间动词，线表示持续长，为非瞬间动词。1~7为主句与从句所表示的动作时间有重合，第8为主句与从句所表示的动作不是同时发生，而是有先后顺序。线线重相并发生，长线” 【主句谓语为非瞬间动词中的动态动词】【记忆：等线动，相并发生，但：【主句谓语为非瞬间动词中的静态动词】【记忆：等线动，

新版质量管理体系样本

西咸新区沣河综合治理高压迁改工程质量管理体系编制人: 审核人: 审批人: 编制单位: 陕西秦电机电设备工程集团有限责任公司( 联合体) 编制日期: 月日目录一、工程概况 (1)

二、质量目标 (1) 三、质量管理组织机构、指挥系统 (1) 四、质量保证措施 (1) 五、质量监控系统、联络协调系统 (3) 六、项目部质量管理组织机构 (5) 七、质量管理生产目标 (5) 八、质量保证体系说明 (13) 九、质量管理制度 (13) 十、分项工程施工过程控制框图 (15) 十一、质量管理检查制度 (19) 十二、质量管理例会制度 (19) 十三、质量事故报告制度 (26)

工程概况 1、工程名称: 西咸新区沣河综合治理高压迁改工程设计施工总承包 2、建设地点: 丝路经济带能源金融贸易区内 3、工程计划工期 3.1设计工期: 37个日历天 3.2施工工期: 150日历天 4、( 1) 蓝马专线110KV电力迁改; ( 2) 仁陈小王庄支线10KV电力迁改; ( 3) 咸阳南污水厂10KV专线电力迁改。二、质量目标单位工程达到合格工程, 分项工程合格率100%, 优良率90%, 观感评定得分率90%以上, 力争95%以上, 消灭质量事故。三、质量管理组织机构、指挥系统严格执行国家和各级有关部门颁布的技术质量法规, 建立以项目经理为中心, 项目质量检验员全面负责的质量体系, 全面推行ISO9002《质量管理和质量保证体系》标准, 对工程进行质量目标管理和质量控制。四、质量保证措施 3.1建立技术交底制度, 实行图纸交底, 施工阶段设计交底, 设计变更交底, 分部分项工程技术交底, 做到抓方案, 抓措施, 抓交底, 抓落实。 3.2抓住质量通病的防治, 对质量通病有防治措施, 并落实。 3.3质量”三工三检”制度, ”三工”即开工前交底, 工中检查, 工后验收评定; ”三检”及自检、互检、交接检。把质量管理做到”点、线、

when,while,as的区别

一、根据从句动作的持续性来区分 1.“主短从长”型：即主句是一个短暂性的动作，而从句是一个持续性动作，此时三者都可用。如： Jim hurt his arm while [when, as] he was playing tennis. 吉姆打网球时把手臂扭了。 As [When, While] she was waiting for the train, she became very impatient. 她在等火车时，变得很不耐烦。注意：as用于引出一个持续性动词表示“在……期间”时，其谓语通常只能是那些含有动作和发展意味的动词，一般不能是那些不用于进行时态的动词(如be, seem, love, want, agree, see, know, have 等)，所以下面一句中的while不能换为as： A：I’m going to the post office. 我要去邮局。 B：While you are there, can you get me some stamps? 当你在邮局时，能帮我买几张邮票吗? 若主句与从句表示的是两个几乎同时发生的动作，含有类似汉语“刚要……就”“正要……却”的意思，英语一般要用as(也可用when)，且此时通常连用副词just。且此时，从句一般用进行时，主句用短暂性动词的一般时态。【注意与六区别】 I caught him just when [as] he was leaving the building. 他正要离开大楼的时候，我把他截住了。 Just as [when] the two men were leaving, a message arrived. 就在这两个人要离开的时候，突然有了消息。 2.“主长从长”型：即主句和从句为两个同时进行的动作或存在的状态，且强调主句动作或状态延续到从句所指的整个时间，此时通常要用while。如： I always listen to the radio while I’m driving. 我总是一边开车一边听收音机。 He didn’t ask me in; he kept me standing at the door while he read the me ssage. 他没有让我进去，他只顾看那张条子，让我站在门口等着。但是，若主句和从句所表示的两个同时进行的动作含有“一边……一边”之意时，则习惯上要用as。如： He swung his arms as he walked. 他走路时摆动着手臂。 I couldn’t remember a story to tell the children, so I made one up as I went along. 我想不出有什么故事可给孩子讲了，只好现编现讲。 3.“主长从短”型：即主句是一个持续性动作，而从句是一个短暂性动作，此时可以用a s或when，但不能用while。如：

质量管理手册范本

重庆公司质量手册200 年月日

目录 0企业概况 1．质量管理职责 1.1组织领导 1.1.1组织结构图 1.1.2任命书 1.1.3管理手册发布令 1.1.4 关于设立质管科的决定质管科职责和权限 1.1.5相关记录 1.2质量目标 1.3管理职责 1.3.1质量管理制度 1.3.2部门职责、权限及考核办法 1.3.3岗位职责 1.3.4不合格品的控制管理办法 1.3.5 相关记录 a《不合格报告》 b《纠正措施处理单》 2.生产资源提供 2.1生产场所 2.1.1 企业区位图 2.1.2生产布局平面示意图

2.1.3 防尘、防鼠、防蝇控制管理办法2.1.4生产车间卫生管理制度 2.1.5相关记录《卫生检查表》 2.2生产设备 2.2.1设施、设备卫生管理制度 2.2.2管道、设备清洗消毒管理制度2.2.3设备和容器清洁控制程序 2.2.4相关记录 a《设施设备清单》 b《保养、检修、维护计划》 c《保养、检修、维护记录》 2.3人员要求 2.3.1岗位人员任职要求 2.3.2人员健康卫生控制管理制度 2.3.3 相关记录 a《员工登记表》 b《人员培训记录》 3.技术文件管理 3.1技术标准 3.1.1相关记录 a《标准清单》 3.2工艺文件 3.2.1工艺流程图

3.2.2工艺作业指导书 3.3文件管理 3.3.1技术性文件管理制度 3.3.2相关记录 a《文件清单》 b《文件借阅、发放、回收记录》 c《记录清单》 4.采购质量控制 4.1采购制度 4.1.1采购管理制度 4.2采购文件 4.2.1采购原材料的管理办法 4.2.2采购合同 4.2.3食品添加剂的使用规定 4.2.4相关记录 a《合格供方名录》 b《采购计划》 c《采购清单》 4.3采购验证 4.3.1相关记录 a《原辅材料进货验证记录汇总表》b《原辅材料验证记录》 c《原辅材料不合格处理单》 d《包装物进货验证记录汇总表》

while、when和as的用法区别

as when while 的区别和用法 as when while的用法一、as的意思是“正当……时候”,它既可表示一个具体的时间点，也可以表示一段时间。as可表示主句和从句的动作同时发生或同时持续，即“点点重合”“线线重合”；又可表示一个动作发生在另一个动作的持续过程中，即“点线重合”，但不能表示两个动作一前一后发生。如果主句和从句的谓语动词都表示持续性的动作，二者均可用进行时，也可以一个用进行时，一个用一般时或者都用一般时。 1、As I got on the bus，he got off. 我上车，他下车。（点点重合）两个动作都是非延续性的 2、He was writing as I was reading. 我看书时，他在写字。（线线重合）两个动作都是延续性的 3、The students were talking as the teacher came in. 老师进来时，学生们正在讲话。（点线重合）前一个动作是延续性的，而后一个动作时非延续性的二、while的意思是“在……同时（at the same time that )”“在……期间(for as long as, during the time that）”。从while的本身词义来看，它只能表示一段时间，不能表示具体的时间点。在时间上可以是“线线重合”或“点线重合”，但不能表示“点点重合”。例如： 1、He was watching TV while she was cooking. 她做饭时，他在看电视。（线线重合） 2、He was waiting for me while I was working. 我工作的时候，他正等着我。（线线重合） 3、He asked me a question while I was speaking. 我在讲话时，他问了我一个问题。（点线重合）

2015版质量管理体系手册(范本)

XXXX包装材料有限公司质量管理体系手册 (符合GB/T19001-2015 idt ISO9001:2015标准) 文件编号：编制：XX 审核：XX 批准：XX

2016年6月1日发布2016年6月1日实施发布令为提升公司质量管理水平，更好地为顾客提供优质产品和服务，提高顾客满意度，学习并应用国际先进的管理标准，本公司建立了系统化、文件化的质量管理体系。本手册参照GB/T19001-2015 idt ISO9001：2015标准的要求起草，规定了公司质量管理体系的要求。对内是公司最高的强制性工作要求；对外是关于公司质量管理体系的说明。要求全体员工必须严格贯彻执行。特此发布。董事长: XX 2016年6月1日任命书为了贯彻执行GB/T19001-2015 idt ISO9001：2015标准的要求，加强对质量管理体系的领导和日常管理，特任命XXX 同志兼任公司管理者代表，任命陈燕兼任质量管理体系专员。管理者代表的主要职责是代表董事长全面建设、领导和管理公司的质量管理体系并承担与质量管理体系相关的外联工作，具体包括： a）确保公司的质量管理体系持续符合国际标准的要求； b）确保质量管理体系各项工作获得预期的绩效； c）在公司内部通报质量管理体系的绩效及改进机会，特别是向董事长报告； d）确保在整个公司推动以顾客为关注焦点； e）确保在策划和实施质量管理体系变更时保持其完整性。质量管理体系专员的主要职责是承担质量管理体系日常运行的策划、指挥、执行、监督、改进等具体工作，辅助管理者代表履行好职责。公司各职能、部门可推荐骨干成员参与质量管理体系的建设和改进工作，成立质量管理体系推进小组，小组成员由管理者代表任命并由体系专员领导日常工作。董事长：XX

第七--when-while-as-区别及练习.

When while as区别一、根据从句动作的持续性来区分 1、“主短从长”型：即主句是一个短暂性动作，而从句是一个持续性动作，此时三者都可用。如： Jim hurt his arm while［when， as］ he was playing tennis. 吉姆打网球时把手臂扭伤了。 2、“主长从长”型：即主句和从句为两个同时进行的动作或存在的状态，且强调主句动作或状态延续到从句所指的整个时间，此时通常要用while。 I always listen to the radio while I’m driving. 我总是一边开车一边听收音机。 He didn’t ask me in; he kept me standing at the door while he read the message. 他没有让我进去，他只顾看那张条子，让我站在门口等着。但是，若主句和从句所表示的两个同时进行的动作含有“一边……一边”之意时，则习惯上要用as。如： He swung his arms as he walked. 他走路时摆动着手臂。 3、“主长从短”型：即主句是一个持续性动作，而从句是一个短暂性动作，此时可以用as 或when，但不能用while。如： It was raining hard when [as] we arrived. 我们到达时正下着大雨。二、根据主句与从句动作是否同时发生来区分 1、若主句与从句表示的是两个同时发生的短暂性动作，含有类似汉语“一……就”的意思，英语一般要用as (也可用when)。如： The ice cracked as [when] I stepped onto it. 我一踩冰就裂了。 2、若主句与从句表示的是两个几乎同时发生的短暂性动作，含有类似汉语“刚要……就”“正要……却”的意思，英语一般要用as(也可用when)，且此时通常连用副词just。如： I caught him just when [as] he was leaving the building. 他正要离开大楼的时候，我把他截住了。三、根据是否具有伴随变化来区分若要表示主句动作伴随从句动作同时发展变化，有类似汉语“随着”的意思，英语习惯上要用as，而不用when或while。如： The room grew colder as the fire burnt down. 随着炉火逐渐减弱，房间越来越冷。注：若不是引导从句，而是引出一个短语，则用with，不用as。如： With winter coming on, it’s time to buy warm clothes. 随着冬天到来，该买暖和衣裳了。四、根据从句动作的规律性来区分若暗示一种规律性，表示“每当……的时候”，英语一般要用when。如： It’s cold when it snows. 下雪时天冷。五、根据主从句动作的先后顺序来区分若主句与从句所表示的动作不是同时发生，而是有先后顺序时，一般要用when。

质量管理体系总结模板

质量管理体系总结模板任何单位和个人在开展工作时都有自己一套不同于别人的方法，写总结时要认真分析、比较，写出自己的特色。有些单位或个人的总结“几年一贯制”，内容差不多，只是换了某些数字，这样的总结就缺乏价值。篇一：质量管理体系总结模板1、什么是ISO9000? ISO是国际标准化组织的简称．是国际标准化领域中一个十分重要的组织．ISO9000标准是一个系统性的标准，涉及的范围、内容广泛．可以针对不同的组织，实施质量管理。在组织系统内部．明确各部门的职责权限．强调计划和协调．使企业能行之有效地、有秩序地开展各项活动．保证生产经营活动的顺利进行。ISO9001质量管理体系标准．是对从设计开发到生产、安装及服务等全过程提出的要求，适用于出版社的管理、经营活动。对稳定和提高产品及服务质量、改善内部管理、降低管理成本、增强市场竞争力具有重要作用。我们应将ISO9001质量管理体系引入出版流程．制定出符合出版社特点的流程管理体系．以及保证企业持续改进、不断满足顾客需求的纲领。出版社生产经营的终极目标．就是要通过不断满足读者的需求．得到企业效益的最大化。ISO9000族正是基于企业行为管理的理念．满足企业需要． 2、质量管理的理论与实践发展的产物随着质量管理的理论与实践的发展，许多国家和企业为

了保证产品质量，选择和控制供应商，纷纷制定国家或公司标准，对公司内部和供方的质量活动制定质量体系要求，产生了质量保证标准。 3、国际贸易的迅速发展的产物随着国际贸易的迅速发展，为了适应产品和资本流动的国际化趋势，寻求消除国际贸易中技术壁垒的措施，ISO/TC176组织各国专家在总结各国质量管理经验的基础上，制定了ISO 9000系列国际标准。 4、四个核心标准： ISO9000《质量管理体系基础和术语》； ISO9001《质量管理体系要求》； ISO9004《质量管理体系业绩改进指南》； ISO19011《质量和环境管理体系审核指南》。通过对质量管理体系的的学习，我认识到质量是成功的伙伴，贯标是质量的保障。如今，贯彻标准已被众多企业所看重，成为企业证明自己产品质量、工作质量的一种护照。有专家认为，贯标为广大企业完善管理、提高产品和服务质量提供了科学指南，同时为企业走向市场找到了共同语言。随着市场化进程的不断深入，各行各业将加快推进国际标准化进程，贯标变得更加迫切。毋庸置疑，贯标不是万金油，不能包治百病，但通过贯标，增强了企业全体员工的质量意识与管理意识，明确了各项管理的职责和工作的程序，促使企业的管理工作由人治转向法治，真正做到了凡事有人负责、

When while as的区别和用法(综合整理)

When while as的区别和用法 when的用法当主句使用持续性动词时. Dave was eating,when the doorbell rang.门铃响时,大卫在吃饭. 2.一个动作紧接着另一个动作发生. When the lights went out, I lit some candles.灯灭了,我赶紧点上一些蜡烛. 3.谈论生命中的某一阶段,或过去的某段时间. His mother called him Robbie when he was a baby. 在他很小时,他妈妈叫他Robbin. 4.指"每一次" When I turn on the TV, smoke comes out the back. 每当我打开电视,就有烟从后面冒出. while/as 的用法从句多为进行时,而且为持续性动词. I'll look after the children while you are making dinner. 你做饭,我来照顾孩子. 注意事项: (1) “主短从长”型：主句表示的是一个短暂性动作，从句表示的是一个持续性动作，三者都可用： He fell asleep when [while, as] he was reading. 他看书时睡着了。 Jim hurt his arm while［when，as］he was playing tennis. 吉姆打网球时把手臂扭伤了。 As［When，While］she was waiting for the train，she became very impatient. 她在等火车时，变得很不耐烦。 (2) “主长从长”型：若主、从句表示两个同时进行的持续性动作，且强调主句表示的动作延续到从句所指的整个时间，通常要用while： Don’t talk while you’re eating. 吃饭时不要说话。 I kept silent while he was writing. 在他写的时候，我默不做声。但是，若主从句表示的两个同时进行的动作含有“一边…一边”之意思，通常用as：

质量管理体系范本(DOC 53页)

浙江省台州市X X X X X X X有限公司质量管理体系（依据ISO9001:2015）文件编号：QM-01 版本：A/0 编制：审核：批准：分发号：持有部门：控制状态：

0 目录 1 范围 2 规范性引用文件 3 术语和定义 4 组织的背景 4.1 理解组织及其背景 4.2 理解相关方的需求和期望 4.3 质量管理体系范围的确定 4.4 质量管理体系 5 领导作用 5.1 领导作用和承诺 5.2 质量方针 5.3 组织的作用、职责和权限 6 策划 6.1 风险和机遇的应对措施 6.2 质量目标及其实施的策划 6.3 变更的策划 7 支持 7.1 资源 7.2 能力 7.3 意识 7.4 沟通 7.5 形成文件的信息 8 运行 8.1 运行的策划和控制 8.2 市场需求的确定和顾客沟通 8.3 运行策划过程 8.4 外部供应产品和服务的控制 8.5 产品和服务开发 8.6 产品生产和服务提供 8.7 产品和服务放行

8.8 不合格产品和服务 9 绩效评价 9.1 监视、测量、分析和评价 9.2 内部审核 9.3 管理评审 10 持续改进 10.1 不符合和纠正措施 10.2 改进 1范围企业依据ISO9001：2015标准要求建立并保持质量管理体系，制定质量方针和目标，运用过程方法及各过程的输入、输出、管理职责、工作要求、绩效考核，并使其文件化。通过对质量管理体系全过程的管理，遵守法律法规和其他相关要求，以证实本公司具有不断提高顾客满意度和持续改进质量管理体系及产品质量水平的能力。 2 规范性引用文件 ISO9000：2015 质量管理体系基础和术语 3 术语和定义本标准采用ISO9000：2015 中所确立的术语和定义。 4 组织的背景环境 4.1 理解组织及其背景环境理解组织及其背景环境—过程分析乌龟图企业外部宗旨：为汽车相关顾客提供优质低廉的塑件、高精耐用的模具；企业内部宗旨：为员工提供家庭一样的安稳舒适的工作条件；企业战略方向：丰富自我，发展企业，贡献社会。公司简介公司位于中国塑料模具之乡——台州市黄岩，公司所在地北依宁波，南靠温州，是中国沿海最有经济活力城市之一，海、陆、空

when,while,as引导时间状语从句的区别

when，while，as引导时间状语从句的区别 when，while，as显然都可以引导时间状语从句，但用法区别非常大。一、when可以和延续性动词连用，也可以和短暂性动词连用；而while和as只能和延续性动词连用。 ①Why do you want a new job when youve got such a good one already？（get 为短暂性动词）你已经找到如此好的工作，为何还想再找新的？ ②Sorry，I was out when you called me．（call为短暂性动词）对不起，你打电话时我刚好外出了。 ③Strike while the iron is hot．（is为延续性动词，表示一种持续的状态）趁热打铁。 ④The students took notes as they listened．（listen为延续性动词）学生们边听课边做笔记。二、when从句的谓语动词可以在主句谓语动作之前、之后或同时发生；while 和as从句的谓语动作必须是和主句谓语动作同时发生。 1．从句动作在主句动作前发生，只用when。 ①When he had finished his homework，he took a short rest．（finished先发生）当他完成作业后，他休息了一会儿。 ②When I got to the airport，the guests had left．（got to后发生）当我赶到飞机场时，客人们已经离开了。 2．从句动作和主句动作同时发生，且从句动作为延续性动词时，when，while，as都可使用。 ①When ／While ／As we were dancing，a stranger came in．（dance为延续性动词）当我们跳舞时，一位陌生人走了进来。 ②When ／While ／As she was making a phonecall，I was writing a letter．（make为延续性动词）当她在打电话时，我正在写信。 3．当主句、从句动作同时进行，从句动作的时间概念淡化，而主要表示主句动作发生的背景或条件时，只能用as。这时，as常表示“随着……”；“一边……，一边……”之意。 ①As the time went on，the weather got worse．（as表示“随着……”之意） ②The atmosphere gets thinner and thinner as the height increases．随着高度的增加，大气越来越稀薄。 ③As years go by，China is getting stronger and richer．随着时间一年一年过去，中国变得越来越富强了。 ④The little girls sang as they went．小姑娘们一边走，一边唱。 ⑤The sad mother sat on the roadside，shouting as she was crying．伤心的妈妈坐在路边，边哭边叫。 4．在将来时从句中，常用when，且从句须用一般时代替将来时。 ①You shall borrow the book when I have finished reading it．在我读完这本书后，你可以借阅。 ②When the manager comes here for a visit next week，Ill talk with him about this．下周，经理来这参观时，我会和他谈谈此事。三、when用于表示“一……就……”的句型中（指过去的事情）。 sb．had hardly（＝scarcely）done sth．when．．．＝Hardly ／Scarcely had sb．done sth．when．．．

质量管理制度体系文件范本精编版

质量管理制度体系文件范本精编版 MQS system office room 【MQS16H-TTMS2A-MQSS8Q8-MQSH16898】

目录质量管理体系制度文件第一章概述我公司严格按“ISO9001-2001质量管理体系”施工，以“IS09001—2001”要求为蓝本建立了质量管理体系并编写了《质量手册》，它是工程施工的质量保证。我们的运作程序包括：客户需求分析、系统方案设计、系统工程设备施工安装与调试、客户培训、系统交付运行、跟踪服务等，给客户提供全方位优良的全过程服务。根据工程的实际情况，依照《质量手册》，和ISO9001-2001质量体系文件进行编写工程施工质量大纲。工程项目的质量大纲是实施质量管理和质量保证的纲领性和行动准则，适用于工程设计、施工、安装、调试交付使用、维修保养全过程的质量管理和质量控制。编制依据《中华人民共和国建筑法》；《建设工程项目管理规范》GB/T50326-2001；《建设工程质量管理办法》；建设单位和相关部门提供的主要设计依据和要求； IS09001质量管理文件；文件和资料控制程序等第二章质量管理的标准

按ISO9001-2001质量管理体系要求为蓝本建立了质量管理体系，确保工程安装质量符合设计规定要求；并针对设计、开发、生产、安装、服务过程制定质量措施，确保工程项目、产品质量满足合同规定要求。该质量体系将适用于工程实施的全过程。质量方针：精心负责认真，保证方案质量；引进先进系统，保证产品质量；科学安全严谨，保证施工质量；积极快速完善，保证服务质量。质量目标：方案一次通过率100%；验货一次合格率100%；工程一次验收率100%；售后服务满意率100%。第三章质量管理的环节严格执行ISO9001系统工程质量体系，并在整个施工过程中，切实抓好以下环节： 1、施工图的规范化和制图的质量标准 2、管线施工的质量检查和监督 3、配线规格的审查和质量要求 4、配线施工的质量检查和监督 5、现场设备或前端设备的质量检查和监督 6、主控设备的质量检查和监督 7、调试大纲的审核和实施及质量监督 8、系统运行时的参数统计和质量分析 9、系统验收的步骤和方法 10、系统验收的质量标准 11、系统操作于运行管理的规范要求 12、系统的保养和维修的规范与要求 13、年检的记录和系统运行总结等第四章组织结构/质量安全岗位责任制组织结构第一把手负责，项目经理主管，质量安全员执行，各专业配合，各班组自检、自查，供应部密切配合，做到全员行动，全面管理。实行每周质量安全例会，天天小检查，周周大检查，奖罚分明，责任到人。项目管理部质量岗位职责负责现场的协调管理工作，还包括与单位内部各专业间、部门间的协作，保证施工用物料的及时供应、技术支持、质量安全监督等的顺利开展，保证对工程质量、安全进度的有效控制。项目经理质量岗位职责负责现场具体事务，包括与现场项目各方的协调，作为工程质量的直接负责人，合理安排调配人力、物力，组织各项工作的计划与实施，对进度、工艺、安全等全面控制，定期向总经理汇报，解决施工过程中的各种问题，保证工程按计划进行。项目副经理质量岗位职责协助项目经理开展各项安全质量工作。质量安全检查员岗位职责在项目经理领导下，负责检查监督施工组织设计的质量保证措施的实施，组织建立各级质量监督体系。严格按图施工、以标准规定检验工程质量，判断工程产品的正确性，做出合格的结论，对因错、漏检造成的质量问题负责。对不合格品按类别和程度进行分类，做出标识，及时填写不合格品通知单、返工通知单、废品通知单，做好废品隔离工作。监督施工过程中的质量控制情况，严格执行“三检制”，并做好被检查品和部位的检验标识，发现质量问题及时反映：正确填写工序质量表，做好各种原始记录和数据处理工作，对所填写的各种数据、文字问题负责。

When,While,As引导时间状语从句的区别

When，While，As引导时间状语从句的区别 when，while，as显然都可以引导时间状语从句，但用法区别非常大。一、when可以和延续性动词连用，也可以和短暂性动词连用；而while和as 只能和延续性动词连用。 ① Why do you want a new job when you’ve got such a good one already？（get为短暂性动词）你已经找到如此好的工作，为何还想再找新的？ ②Sorry，I was out when you called me．（call为短暂性动词）对不起，你打电话时我刚好外出了。 ③Strike while the iron is hot．（is为延续性动词，表示一种持续的状态）趁热打铁。 ④ The students took notes as they listened．（listen为延续性动词）学生们边听课边做笔记。二、when从句的谓语动词可以在主句谓语动作之前、之后或同时发生；while 和as从句的谓语动作必须是和主句谓语动作同时发生。 1．从句动作在主句动作前发生，只用 when。 ①When he had finished his homework，he took a short rest．（finished 先发生）当他完成作业后，他休息了一会儿。 ②When I got to the airport，the guests had left．（got to后发生）当我赶到飞机场时，客人们已经离开了。 2．从句动作和主句动作同时发生，且从句动作为延续性动词时，when，while，as都可使用。 ①When ／While ／As we were dancing，a stranger came in．（dance为延续性动词）当我们跳舞时，一位陌生人走了进来。 ②When ／While ／As she was making a phone call，I was writing a letter．（make为延续性动词）当她在打电话时，我正在写信。 3．当主句、从句动作同时进行，从句动作的时间概念淡化，而主要表示主句动作发生的背景或条件时，只能用 as。这时，as常表示“随着……”；“一边……，一边……”之意。 ① As the time went on，the weather got worse．（as表示“随着……”之意） ② The atmosphere gets thinner and thinner as the height increases．随着高度的增加，大气越来越稀薄。 ③As years go by，China is getting stronger and richer．随着时间一年一年过去，中国变得越来越富强了。 ④The little girls sang as they went．小姑娘们一边走，一边唱。 ⑤The sad mother sat on the roadside，shouting as she was crying．伤心的妈妈坐在路边，边哭边叫。 4．在将来时从句中，常用when，且从句须用一般时代替将来时。 ①You shall borrow the book when I have finished reading it．在我读完这本书后，你可以借阅。 ②When the manager comes here for a visit next week，Ill talk with him about this．下周，经理来这参观时，我会和他谈谈此事。三、when用于表示“一……就……”的句型中（指过去的事情）。

ISO 485：质量管理体系认证咨询合同(标准范本)专业版

ISO 485：质量管理体系认证咨询合同专业版 In accordance with the relevant provisions and clear responsibilities and obligations of both parties, the following terms are reached on the principle of voluntariness, equality and mutual benefit. 甲方：__________________ 乙方：__________________ 签订日期：__________________ 本合同书下载后可随意修改

合同编号：YH-FS-652890 ISO 485：质量管理体系认证咨询合同专业版说明：本服务合同书根据有关规定，及明确双方责任与义务，同时对当事人进行法律约束，本着自愿及平等互利的原则达成以下条款。文档格式为docx可任意编辑使用时请仔细阅读。项目名称：iso13485：XX质量管理体系认证咨询委托方（甲方）：_________ 咨询方（乙方）：_________ 签订地点：_________ 签订日期：_________年_________月_________日一、咨询的目的和范围 1．甲方为提高质量管理水平，建立健全质量管理体系，获得质量管理体系认证证书，特邀请乙方为其进行质量管理体系认证咨询（以下简称为咨询）服务。 2．甲方质量管理体系覆盖的产品／服务范围：_________。 3．甲方质量管理体系覆盖的人数：_________人。二、建立质量管理体系选用的质量保证模式标准为iso13485：XX标准。

质量管理制度体系文件范本

目录质量管理体系制度文件第一章概述

我公司严格按“ISO9001-2001质量管理体系”施工，以“IS09001—2001”要求为蓝本建立了质量管理体系并编写了《质量手册》，它是工程施工的质量保证。我们的运作程序包括：客户需求分析、系统方案设计、系统工程设备施工安装与调试、客户培训、系统交付运行、跟踪服务等，给客户提供全方位优良的全过程服务。根据工程的实际情况，依照《质量手册》，和ISO9001-2001质量体系文件进行编写工程施工质量大纲。工程项目的质量大纲是实施质量管理和质量保证的纲领性和行动准则，适用于工程设计、施工、安装、调试交付使用、维修保养全过程的质量管理和质量控制。编制依据《中华人民共和国建筑法》；《建设工程项目管理规范》GB/T50326-2001；《建设工程质量管理办法》；建设单位和相关部门提供的主要设计依据和要求； IS09001质量管理文件；文件和资料控制程序等第二章质量管理的标准按ISO9001-2001质量管理体系要求为蓝本建立了质量管理体系，确保工程安装质量符合设计规定要求；并针对设计、开发、生产、安装、服务过程制定质量措施，确保工程项目、产品质量满足合同规定要求。该质量体系将适用于工程实施的全过程。质量方针：精心负责认真，保证方案质量；引进先进系统，保证产品质量；科学安全严谨，保证施工质量；积极快速完善，保证服务质量。质量目标：方案一次通过率100%；验货一次合格率100%；工程一次验收率100%；售后服务满意率100%。第三章质量管理的环节严格执行ISO9001系统工程质量体系，并在整个施工过程中，切实抓好以下环节： 1、施工图的规范化和制图的质量标准 2、管线施工的质量检查和监督 3、配线规格的审查和质量要求 4、配线施工的质量检查和监督 5、现场设备或前端设备的质量检查和监督

When, while, as的区别和用法

When, while, as的区别和用法版本一 (1) 若主句表示的是一个短暂性动作，从句表示的是一个持续性动作，三者都可用： He fell asleep when [while, as] he was reading. 他看书时睡着了。【注】as 用于引出一个持续性动词表示“在……期间”时，其谓语通常只能是那些含有动作(action)和发展(development) 意味的动词，一般不能是那些不用于进行时态的动词(如be, seem, love, want, agree, see, know, have 等)，所以下面一句中的while 不能换为as： A：I’m going to the post office. 我要去邮局。 B：While you’re there, can you get me some stamps? 当你在邮局时，能帮我买几张邮票吗? (2) 若主、从句表示两个同时进行的持续性动作，且强调主句表示的动作延续到从句所指的整个时间，通常要用while： Don’t talk while you’re eating. 吃饭时不要说话。 I kept silent while he was writing. 在他写的时候，我默不做声。但是，若主从句表示的两个同时进行的动作含有“一边…一边”之意思，通常用as： She sang as she went along. 她边走边唱。 (3) 若从句是一个短暂性动作，主句是一个持续性动作，可用as / when 但不用while： It was raining hard when [as] we arrived. 我们到达时正下着大雨。 (4) 若主从句表示的是两个同时(或几乎同时)发生的短暂性动作，用as / when： I thought of it just when [as] you opened your mouth. 就在你要说的时候，我也想到了。 (5) 若要表示两个正在发展变化的情况，相当于汉语的“随着”，一般用as： Things are getting better and better as time goes on. 随着时间的推移，情况越来越好。 As it grew darker, it became colder. 天色越晚，天气越冷。 (6) 表示“每当…的时候”(暗示一种规律性)，一般要用when： It’s cold when it snows. 下雪时天冷。 He smiles when you praise him. 你夸奖他时他总是笑笑。 (7) 若主从句所表示的动作不是同时发生，而是有先后顺序时，一般要用when： I will go home when he comes back. 他回来时，我就回家去。 (8) when 可用作并列连词，表示“这时(突然)”；while 也可以用作并列连词，表示“而”、“却”(表示对比)；但as 则没有类似用法： We were about to start when it began to rain. 我们正要出发，这时天开始下雨了。 He likes coffee, while she likes tea. 他喜欢咖啡，而她却喜欢茶。 (9) as 和when 后均可直接跟一个名词，构成省略句，但while 一般不这样用： As [When] a boy, he lived in Japan. 他小时候在日本。

质量管理体系要求样本模板

质量管理体系要求样本质量管理体系－要求 Quality management systems — Requirements GB/T 19001:

目录 ISO前言 0.1 总则 0.2 过程方法 0.3 与GB/T19004的关系 0.4 与其它管理体系的相容性 1 范围 1.1 总则 1.2 应用 2. 引用标准 3 术语与定义 4 质量管理体系 4.1总要求 4.2文件要求4.2.1总则 4.2.2质量手册 4.2.3文件控制 4.2.4质量记录的控制 5 管理职责 5.1 管理承诺 5.2 以顾客为中心 5.3 质量方针

5.4 策划 5.4.1质量目标 5.4.2质量管理体系策划 5.5职责、权限和沟通 5.5.1 职责和权限 5.5.2管理者代表 5.5.3内部沟通 5.6 管理评审 5.6.1总则 5.6.2评审输入 5.6.3评审输出 6 资源管理 6.1 资源的提供 6.2 人力资源 6.2.1总则 6.2.2能力、培训和意识 6.3 基础设施 6.4 工作环境 7 产品实现 7.1 产品实现的策划 7.2 与顾客有关的过程 7.2.1与产品有关的要求的确定

7.2.2与产品有关的要求的评审7.2.3顾客沟通 7.3 设计和开发 7.3.1设计和开发策划 7.3.2设计和开发输入 7.3.3设计和开发输出 7.3.4设计和开发评审 7.3.5设计和开发验证 7.3.6设计和开发确认 7.3.7设计和开发更改的控制 7.4 采购 7.4.1采购过程 7.4.2采购信息 7.4.3采购产品的验证 7.5 生产和服务提供 7.5.1生产和服务提供的控制 7.5.2生产和服务提供过程的确认7.5.3表示和可追溯性 7.5.4顾客财产 7.5.5产品防护 7.6 监视和测量装置的控制 8 测量、分析和改进