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hERG Review _TBI_2007(1)

hERG Review _TBI_2007(1)
hERG Review _TBI_2007(1)

Cardiac Drug Safety and hERG channel

naibo yang

Cardiac safety and QT prolongation

In recent years, multiple blockbuster drugs such as terfendadine (Sel -dane), cisapride (Propulsid) have been pulled out of the market due to a lethal side effect of drug on human heart. These drugs had caused cardiac arrhythmia called torsade de pointes. In the past decade, the single most common cause of the drug withdrawal (or additional restriction of the usage) is the side effect of prolongation of the QT interval associated with polymorphic ventricular arrhythmia or torsade de pointes. In almost all the cases, the potentially lethal side effect was induced by the drug interacting with a cardiac potassium channel, named hERG.

In order to protect clinical trial participants and patients, International Conference of Harmonization (ICH) published a guideline (S7B) in 2002 to suggest all new drugs being tested preclinically for cardiac safety and hERG sensitivity before submitting for regulatory reviews. This review will discuss long-QT syndrome, drug effect on the cardiac function and cardiac ion channels as well as assays for screening lead -ing compounds for cardiac toxicity.

What is long-QT syndrome (LQTS)

In electrocardiograms (ECGs), the QT interval refers to the time from the beginning of the QRS complex to the end of the T wave. In order to correct for different heart rates, long QT (LQT) abnormality is defined as a QTc (QT interval corrected for the heart rates) greater than 460 ms (figure 1).

where RR is the time between two heart beats (R-R interval), measured in seconds.

QT interval prolongation can be congenital (long QT syndrome) or acquired (drug-induced long QT). Long QT syndrome is a cardiac disorder that causes synope, seizures and even sudden death. The root causes of these clinical manifests are ventricular tachyarrhythmias, spe -cifically torsade de pointes, which frequently degenerate into ventricu -lar fibrillation. There are a number of genetic mutations that induce LQT. To date, the congenital LQT has been recognized in two forms: autosomal dominant LQT mutations cause Romano-Ward syndrome and autosomal-recessive LQT mutations cause Jervell and Lange-Nielsen syndrome 12. At least five LQT genes have been identified for autosomal-dominant LQT. Two genes so far have been identified to cause autosomal-recessive disorder. Table 1 summarizes these genes and their coded proteins.

RR

QT QTc / About the author: naibo yang, Ph.d. is a sr . manager of Product applications at molecular devices corporation. he is responsible for application development, r&d and sales support for two revolu-tionary high-throughput electrophysiol-ogy systems – IonWorks Quattro and PatchXpress 7000a. dr yang received his Ph.d. in Physiology from Thomas Jefferson university. he completed his postdoctoral training at stanford univer-sity. he has worked at affymax Inc as Program leader for ion channel drug dis-covery, where he led a cross-functional discovery team on immune-suppression projects. Prior to that, he was at exelixis Inc as the company’s sole electrophysi-ologist working on cardiac safety assays, ion channels target research on neuronal

drug discovery and insecticide research.

Figure 1 Schematic ECG waveforms and QTc calcula-tion. QT interval and RR interval are labeled red. Table 1 Genes causing congenital LQTS

LQT classification Gene Chromosome

location Ion channel protein

LQT1KCNQ111p15.5KVLQT1 (Kv7.1) Iks LQT2KCNH27q35-q36hERG (Kv11.1) Ikr LQT3SCN5A 3p24-p21Na(v) 1.5

LQT4ANK24q25-q27Ankyrin-B, accessory

protein

LQT5KCNE121q22Min K, Iks subunit LQT6KCNE221q22MiRP1

LQT7KCNJ217q23Kir2.1

LQT8CACNA1C12p13.3Ca(v) 1.2

Mutations in the KCNE1, KCNE2, KCNH2, KCNQ1, and SCN5A ion channel genes cause Romano-Ward syndrome. The ANK2 non-ion channel gene is also associated with Ro-mano-Ward syndrome. Mutations in the KCNE1 and KCNQ1 genes cause Jervell and Lange-Nielsen syndrome.

KVLQT1, Min K, HERG, MiRP1 and Kir2.1 are potassium channels or its subunits expressed in the heart. SCN5A en-codes cardiac sodium channel Na(v)1.5. CACNA1C encodes L type calcium channel Ca(v)1.2. And ANK2 encodes a protein called neuronal type ankyrin, which helps ion channel protein’s insertion into the membrane. So most, if not all of the genetic mutations, alter the function of cardiac ion channels. This is not surprising because the LQT disorder is manifested first as an ECG abnormality. And the underlining molecular mechanisms of ECG are cardiac ion channel activities (see

figure 2 clinical whole heart ECG and single myocyte ECG).Figure 2 Action potential (AP) of a cardiac myocyte (top) and whole heart ECG (bottom). The depolarization of myocytes correlates to the starting of QRS complex of ECG. And the repolarization of myocytes forms the T wave on ECG. Corresponding ionic currents underlining myocyte action potential was noted.

Although there have been just eight LQT genes discovered, a large number of mutations of these genes have been found in patient populations. A registry of LQTS mutations can be found at the following website: http://www.fsm.it/cardmoc/ New entries are constantly being added to the list.

Torsade de pointes

With a prolonged QT interval, there is an increased risk of ventricular tachyarrhythmia, including a specific form, called Torsade de pointes (TdP). Torsade de pointes (from the French, means “twisting of the points”) is a polymorphic ven-tricular tachycardia seen at the onset of QT prolongation. The ECG pattern of Torsade de pointes is distinctive, sometimes being described as a sine wave within a sine wave. It is called “twisting” because when the peaks are at their smallest in one ECG lead, they are at their largest in another, as if the several ECG leads were different views of a vibrating string whose plane of vibration was being slowly rotated around the axis of the string.

Triggers in LQTS

LQTS happens rarely, and usually being a consequence of some triggering events. But it is a serious threat to patients’ health and life. Some of its triggering factors are listed below: Sports: such as swimming, running

Startle: an alarm clock, a loud horn, a ringing phone

Emotions: anger, crying, test taking or other stressful situa-tions

Other: sudden death may also occur during sleep Medication: some medications can also trigger LQTS.

Drug-induced LQTS

Besides the genetically coded, inherent LQT abnormalities, there are also so called “acquired LQTS”, which refers to drug-induced LQTS in patients with healthy genetic back-ground. This drug-induced LQTS can lead to serious drug side effect, sometime even as severe as patient sudden death. Thus, drug-induced LQT has become a serious concern for pharmaceutical research.

Some marketed antiarrhythmic drugs, such as dofetilide (Tiko-syn), quinidine (Cardioquin), and sotalol (Betapace), induce TdP in a small number of patients who receive them. This

is not surprising since those drugs were meant to interfere with the cardiac electrophysiology. Those drugs, in general, are more beneficial to patients than the potential side effect caused by them.

However, there are drugs, which were designed for targets having no connection with cardiac function at all that induce TdP. The total incidence of drug induced TdP is largely un-known. But the absolute total number of reports is relatively low. Between 1983 and 1999, 761 cases of TdP, of which 34 were fatal cases, were reported to the World Health Organiza-tion Drug Monitoring Center by member states13. Although the occurrence of such side effect is rare, a few lethal cases are serious enough to cause withdrawal of those drugs from the market. Since 1999, a number of these drugs have been withdrawn, including terfenadine (Seldane, antihistamine for allergies) astermizole (Hismanal, antihistamine for allergies), cisapride (Propusid for GI stimulation) etc. Some other drugs such as ziprasidone (Geodon for antipsychotics), though not withdrawn from the market, have undergone severe labeling restrictions 1.

The number of drugs inducing LQTS or TdP has been grow-ing. Close monitoring of these drugs are needed for patient medication. A list of these drugs labeled with various risk levels can be found at the following website:

https://www.wendangku.net/doc/c116963539.html,/medical-pros/drug-lists/drug-lists. htm

Since ECG is composed by a family of ionic currents, in prin-ciple, drugs can induce LQTS through a variety of means. In practice, however, virtually every case of drug-induced LQTS and torsades de pointes can be traced back to one specific mechanism: blockade of a specific cardiac potassium channel called hERG. Therefore, the interaction between hERG chan-nel and drug candidate represents an important safety concern for the pharmaceutical industry. Because of this, screening of drug candidate on hERG is quickly becoming an industrial standard practice.

hERG channel, a molecular brake

What is hERG?

The h uman E ther-a-go-go Related Gene (hERG) encodes a voltage-gated potassium channel expressing in cardiac myo-cyte. It functions as an inward rectifier channel (preferably allow potassium ions to flow into the cell under balanced ionic concentration)11. But under physiological ionic concentra-tions, most of the potassium currents are flow outward. The channel name derived from a drosophila potassium channel gene, called ether-a-go-go. A mutation of this fly gene causes drosophila to dance like a go-go dancer when being exposed to ether.

hERG gene encodes a cardiac potassium channel that func-tions as a molecular brake for cardiac action potential. hERG expresses predominantly in the heart. It plays a critical role

of regulating the heart beat. Physiologically, its expression underlines the rapid delayed rectifier current, IKr (figure 2), while IKr is the major driving force of the repolarization of cardiac myocytes.

The hERG ion channel belongs to the voltage-gated ion chan-nel superfamily of membrane proteins. There are around 400 pore forming ion channel genes in human genome. Based on current estimations for the total number of genes in human genome, ion channels correspond to about 1.3% of the total genes. Ion channels are the third largest class of genes for drug discovery research, trailing in number only kinases and G-protein-coupled receptors (GPCRs). hERG channel, not being considered as a drug development target, is becoming an important toxicology target.

Structure and biophysical properties of hERG hERG channel belongs to the voltage-gated potassium chan-nel family of genes. The gene translates into a protein consists of six transmembrane domains, called a subunit. The fourth transmembrane segment forms the voltage sensing machin-ery. The loop between segment five and six lines the interior of the channel. Like other voltage-gated potassium channels, hERG channels are tetramers. Four subunits form a functional ion channel pore. Figure 3A shows a schematic transmem-brane topology of a single hERG subunit.

One unique property of hERG channel under physiologi-

cal conditions is that it conducts large inward current upon

membrane repolarization. Like most of the voltage-gated ion channels, hERG channels activate (open) upon depolariza-tion. But the channel quickly goes to the inactivated state under continued depolarization (figure 3B). So at the plateau phase of a cardiac action potential, there will not be signifi-cant amount of current following through the channel. When myocytes repolarize, the channel protein dwells in the open state before closing, hence a large outward current at the end of cardiac action potential, which helps to repolarize the cell quickly (figure 2 top). Any blockade of hERG currents will cause a prolonged plateau phase of action potential and cause QT prolongation. Figure 3C shows a typical hERG current recorded under voltage-clamp. The large outward tail current elucidated by membrane repolarization is characteristic of hERG channel.

Figure 3 A. Structure of hERG channel subunit (model).

B. The biophysical property hERG and

C. A typical current profile under patch-clamp recording. Although hERG is classified as an inward rectifier, it does conduct outward current too, as shown in this figure.

hERG channel is infamous for its promiscuousness of drug interaction. There are a large collection of drugs and com-pounds known to interact and block channel activity. The majority of aforementioned LQT-inducing drugs are in fact hERG blockers. A three dimensional structure model of hERG reveals a hydrophobic pocket near the mouth of the internal opening of the channel. This pocket is very unique compared to other similarly structured potassium channels. It is believed that this pocket plays a critical role in drug-channel interaction. 9.

Assaying compound safety on LQT

To avoid the fatal side effect of drug induced LQT, Interna-tional Conference of Harmonisation (ICH) has set up two guide lines for drug development in different stages. Section S7B was set for cardiac safety assessment during preclinical drug development. Section E14 was set for cardiac safety as-sessment during early clinical trials. Although the guide lines are not mandatory, all major pharmaceutical and biotech com-panies have adopted them and started testing drug-induced LQT and/or drug blockade of hERG channels prior to the starting of human clinical trials. As a matter of fact, due to the high costs of failing a lead compound in the late stage of drug discovery and development, more and more companies are moving the hERG assay to early stages of drug development.

In vivo assays for LQT

Drug-induced LQT can be assayed in vivo, employing either the whole animal or isolated perfused heart. Alternatively, drug-induced LQT can also be estimated by testing the drug in vitro, assaying the drug on recombinant hERG channels.

In vivo studies can employ either whole animal or whole heart. Intact animal models allow investigation of ventricular repo-larization or associated arrhythmias where integrated effects on the full complement of ion channels and all other physi-ological inputs are assessed. Whole animal studies are usually performed on dog or rabbit 14. Sometimes Zebra fish can also be utilized to assess drug’s cardiac effect 8.

In vitro assays for LQT

Isolated perfused heart can be used directly to assay the QT prologation. Since ECG and QT intervals can be measured from isolated spontaneously beating hearts, data so generated can be used to access the drug effect on heart-rate corrected QTc. Comparing with whole animal approach, an isolated heart eliminats physiological input from other parts of the system. So it’s a simpler and more controlled approach. Re-cently, there are reports from pharmaceutical researchers using isolated guinea pig hearts to screen for potential cardiac side effect of drug candidates 3.

In vitro assay for action potential duration (APD)

Multi-cellular tissues such as papillary muscles and Purkinje fibers have also been used to evaluate the drug effect. Action potentials (AP) from these tissues can be recorded and drug effect on AP can be directly monitored. APD assay with these cultured tissue provide a good mixture of physiological close-ness to the in vivo environments and easy of control of the experiment.

To further simplify the model, APD from dissociated individ-ual cardio myocyte can also be monitored to evaluate the drug effect. Compared with the recombinant hERG channel assay as discussed below, dissociated tissues and myocytes have the advantage of having all relevant physiological currents. Thus they are suitable for assessing effects on both action potential duration and physiological ionic currents.

Assaying compound activity on hERG

Since hERG is the single most common contributor of LQT and TdP, a compound’s potential of inducing TdP and LQT can be directly evaluated with hERG channel in vitro and in recombinant expression systems. There are many traditional methods for assaying ion channels, as well as some newly developed technologies. Most of traditional ion channel assay methods can be applied to hERG assays. The most commonly used high throughput assays in the pharmaceutical industry are discussed below.

Radioligand-displacement assay

Since most of the hERG ligands occupy the same binding site on the channel protein, a ligand displacement assay can be designed. A [H3]-labeled ligand, such as dofetilide 6 or astermi-zole is used to pre-incubate with cells or membrane fractions containing the ion channel protein complex. The compounds being assayed can then be applied to the cells or membrane fractions. Assay compounds will compete for the binding site with the radio-labeled ligand ([H3]-dofetilide). The competi-tive binding obeys mass-action law. By knowing the binding affinity of the labeled ligand, the binding affinities of assay ligands can then be calculated 2.4.

Flux assay

One way to measure the ion channel activity is to trace the amount of ions flow through the channel. Since rubidium ions can permeate through most potassium channels, hERG channel activity can be assayed using rubidium as a tracer, as well. Radioactive 86Rb+ was used in the past. But the strong radioactivity made it less favorable in the industry. Instead, an atomic absorption spectrum measurement of non-radioactive 87Rb+assay was developed by Bayer AG 10 and later commer-cialized by Aurora Biomed (Canada) with the ICR 8000/12000 systems.

The flux assay measures the end results of ions flowing through the open channel. It is a fast and economic way of measuring ion channel activity. The limitation of the assay is that no kinetic information of channel activity can be derived. Membrane potential assay

Ion channel activity induces cell membrane potential changes. Monitoring the membrane potential of a cell can deduce additional kinetic information of channel activity. In the case of hERG, activation of the channels will repolarize the cell membrane, just as any potassium channel does. Fluorescent membrane potential indicators, e.g. Oxonols, DiBACs, or other dyes can be employed on FLIPR? (Molecular Devices, USA) or VIPR? (Aurora Discovery, USA) systems to indicate channel activity. In general, membrane potential dye based as-says have the advantage of high throughput and low cost per data point. But it also comes with high rates of false positives and false negatives.

Electrophysiology and voltage-clamp assay

Ion channel activity can also be directly assayed by record-

ing ionic current flow through ion channels by electrically controlling the cell membrane potential (voltage-clamp the cell membrane). Voltage-clamp technology, a very laborious process requiring a skilled operator and specialized instru-ments, was invented in the 1950’s. It gained wide acceptance in the 1980’s. Until now, it is still considered the “gold standard” of ion channel assays.

Drug efficacy on hERG channels can be assayed on ion channel bearing mammalian cell lines (common parental cell lines such and CHO-K1 or HEK-293), or Xenopus oocytes transiently expressing the ion channel gene through mRNA in-jection. Limitations of traditional electrophysiology is inherent to its complicated assay set ups and assay procedures. It’s slow, labor-intensive, and hence expensive too.

Automatic (high throughput) electrophysiology To address the limitations of manual voltage clamping tech-nology, a number of automatic electrophysiology technologies have been introduced in recent years. Most of these technolo-gies are based on planar electrodes, which include marketed products such as IonWorks? Quattro? and PatchXpress? 7000A systems from Molecular Devices Corporation (USA), QPatch? 16/48 system from Sophion AG (Germany), Cytopatch? 100 from Cytocentrix (Germany) and NPC?-16 from Nanion Technologies (Goffering a unique solution for automatic patch clamping is Flyion. It marketed an inverted patch clamp system employs a pipette tip, back filled with sus-pension cells to achieve automatic seal formation. A compari-son of the throughputs and costs of the available automatic electrophysiology systems is listed in table 2 5. In general, these automatic patching systems provide assay values show good correlation with that collected with traditional manual patch clamp systems 7.

Table 2 Comparison of planar Patch Clamp systems

Besides these mammalian cell patch clamping systems, there are also a few automatic Xenopus oocyte based two-electrodes voltage-clamp systems. Molecular Devices is marketing

an eight channel OpusXpress? 6000A system and Multi Channel Systems (Germany) is currently marketing a desktop solution, called Roboocyte?, which also has built-in mRNA injection function. Oocyte systems have their own unique applications, such as working with transiently expressing RNA- injected oocytes. This eliminates the relatively long process of generating stable cell lines. Besides this advantage, the oocyte system is also known to be easier to assay mutated ion channels.

Conclusion

Cardiac safety pharmacology and hERG liability is quickly becoming a must-have data point in the toxicity studies. More and more pharmaceutical and biotech companies are mov-ing the hERG liability assay to the early stage of the discov-ery pipeline. As the assays become faster, cheaper and more reliable, it makes financial sense to screen any potential lead compounds before even getting into in vivo animal testing.

References

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2004 Jun;35(6):543-7

2 Chiu PJ, Marcoe KF, Bounds SE, Lin CH, Feng JJ, Lin

A, Cheng FC, Crumb WJ, Mitchell R. Validation of a

[3H]astemizole binding assay in HEK293 cells expressing HERG K+ channels J Pharmacol Sci. 2004 Jul;95(3):311-9.

3 Cheng HC, Incardona J, McCullough B. Isolated perfused

and paced guinea pig heart to test for drug-induced

changes of the QT interval. J Pharmacol Toxicol

Methods. 2006 Feb 25

4 Cheng and Prusoff, Relationship between the inhibition

constant (K1) and the concentration of inhibitor which

causes 50 percent inhibition (I50) of an enzymatic

reaction Biochem Pharmacol. 1973 Dec 1;22(23):3099 108 1973

5 Comley J. Automated patch clamping, setting a new

standard for early hERG Drug Discovery World

(2005/6 winter: 62-79)

6 Diaz GJ, K Daniell, S T Leitza, R L Martin, Z Su,

J S. McDermott, B F. Cox and G A. Gintant, The

[3H]dofetilide binding assay is a predictive screening

tool for hERG blockade and proarrhythmia: Compar son of intact cell and membrane preparations and

effects of altering [K+]oJ Pharmacol Toxicol Met

ods. 2004 Nov-Dec;50(3):187-99

7 Dubin AE, Nasser N, Rohrbacher J, Hermans AN, Mar-

rannes R, Grantham C, Van Rossem K, Cik M, Chaplan

SR, Gallacher D, Xu J, Guia A, Byrne NG, Mathes C.

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Mar;10(2):168-81.

8 Milan DJ., IL. Jones, PT. Ellinor and CA. MacRae In vivo

recording of adult zebrafish electrocardiogram and assess-ment of drug-induced QT prolongation, Am J Physiol

Heart Circ Physiol 2006; 291: H269-H273

9 Perry M, de Groot MJ, Helliwell R, Leishman D, Tristani-

Firouzi M, Sanguinetti MC, Mitcheson J. Structural

determinants of HERG channel block by clofilium and

ibutilide, Mol Pharmacol. 2004 Aug;66(2):240-9

10 Terstappen GC. Functional analysis of native and

recombinant ion channels using a high-capacity

nonradioactive rubidium efflux assay. Anal Biochem. 1999 Aug 1;272(2):149-55

11 Trudeau MC, Warmke JW, Ganetzky B, Robertson GA.

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potassium channel family. Science 1995 Jul 7;269(5220):92

5.

12 Vincent GM, Timothy K, Zhang L., Congenital Long QT

syndrome. Card Electrophysiol Rev. 2002 Feb;6(1-2):57-60 13 Yap YG and Camm AJ Drug induced QT prolongation

and Torsades De Pointes, Heart 2003; 89:1363-1372

14 Yamamoto K, T Tamura, R Imai and M Yamamoto Acute

Canine Model for Drug-Induced Torsades de Pointes in Drug Safety Evaluation - Influences of Anesthesia and

Validation with Quinidine and Astemizole Toxicol Sc

ences 2001; 60, 165-176

Vendor Product name # of

assay

/chip

Chip

cost

(US$)

Datapoints

/8HR day

Cost (US$)

/ datapoint

Cytocentrics CytoPatch?

10011013414

Flyion Flyscreen?

850015100~5007.5~10

Molecular Devices IonWorks?

Quattro?38424023000.75

Molecular Devices PatchXpress?

7000A161302408.13

Nanion NPC?

-Port-a-Patch15405

广东省职称评审申报系统-个人操作指引

年广东省职称评审申报系统-个人操作指引

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广东省专业技术人才管理信息系统个人用户操作指南

目录 1.系统功能 (2) 2.系统登录地址 (2) 3.操作指引 (3) 3.1.个人用户注册 (3) 3.2.登录系统 (5) 3.3.个人信息维护 (5) 3.4.网上业务办理 (10) 3.4.1.人事管理单位变更申请 (10) 3.4.2.职称考核认定申请 (11) 3.4.3.职称评审申请 (13) 3.4.4.省外来粤资格确认申请....................................................................................... 错误!未定义书签。 3.4.5.职称证书补换发申请........................................................................................... 错误!未定义书签。 3.4.6.省外委托评审申请 (17) 3.4.7.业务办理查询 (20) 4.其他功能 (24) 4.1.办理事项跟踪 (24) 4.2.密码修改 (27) 4.3.密码申诉 (28) 4.4.找回用户名 (31) 5.常见问题 (32) 5.1.信息不完整 (32) 5.2.退回修改与提交 (33)

1.系统功能 广东省专业技术人才管理信息系统功能如下: ?用户管理 1)个人用户注册 2)个人信息维护 3)密码修改 4)密码申诉 5)找回用户名 ?业务办理 1)人事管理单位变更申请 2)评审申请 3)考核认定申请 4)省外来粤资格确认申请 5)省外委托评审申请 6)证书补换发申请 7)业务办理查询 2.系统登录地址 在IE浏览器下登录,建议使用IE8.0及以上版本浏览器。 正式系统地址:http://210.76.66.109:7006/gdweb/ggfw/web/pub/ggfwzyjs.do

职称申报评审须知ppt】

?单击此处编辑母版文本样式–第二级 ?第三级–第四级?第五级LOGO 1/12 一般申报评审各级别职称的学历资历要求(年限截止时间算至2011年12月31日):初级:普通中专学历,2007年(含)之前取得技术员职称或2006年(含)之前毕业、非因本人原因未能及时办理初定技术员职称(所在单位需出具有效证明,证明无固定格式,说明原因即可。),并一直从事本专业技术工作。中级:2007年(含)之前取得助理工程师职称,专科、本科学历,或普通中专学历 毕业后从事本专业技术工作满15年(工作后取得的中专学历需累计从事本专业技术 工作满20年),并一直从事本专业技术工作;或2004年(含)之前专科、2006年(含)之前本科毕业后一直从事本专业技术工作,且非因本人原因未能及时办理初定助理工程师职称。(所在单位需出具有效证明,证明无固定格式,说明原因即可。)高级:2006年(含)之前取得工程师职称(外地的中级职称证书先转评中级,通过后次年再申报高级;硕士学位需2007年取得,博士学位需2009年取得),本科学历,或专科学历毕业后从事本专业技术工作满15年(工作后取得的专科学历需累计从事本专业技术工作满20年),并一直从事本专业技术工作。

?单击此处编辑母版文本样式 –第二级 ?第三级 –第四级 ?第五级 LOGO 学历/学位高级中级助理级员级博士 担任中级职务后从事本 专业技术工件二年以上 【评审】 毕业后考核合格【初定】 硕士 担任中级职务后从事本 专业技术工作四年以上 【评审】 毕业后从事本专业技术工 作三年以上【初定】 本科 担任中级职务后从事本 专业技术工作五年以上 【评审】 担任助理级职务后从事本 专业技术工作四年以上 【评审】 毕业后从事本专业 技术工作一年以上 考核合格【初定】 1/12 【初定】的具体流程

Review 1(Period 1)

Review 1(Period 1) Objectives: 1. Review words and simple sentence. 2. Review simple conversations between classmates. 3. Review the new words and simple sentence. Notes: Key points: 1.Review the new words and sentence patterns. 2.Can use these new words and sentence patterns in the daily life. Difficult points:1.Review simple sentences:what can you see? May I use your crayon? I can run fast! 2. To know more greeting. Teaching Procedures: Step 1:Warming up 1.Greetings: Step 2:Lead-in T:Look page 19. Can you …? Yes, I can. /No, I can’t. What can you do? I can … Can he/she …? Yes, he/she can. /No, he/she can’t. It’s easy/fun. Step 3:Presentation and drills 1. Open the book page 68.

Teach new words and let the Ss to read and say. 2. Teach part 1. Open the book page 20. Listen to the tape. Listen and say. 3. Teach part 2. Listen to the tape then circle the right words. Look and match. Step 4:Practice 1.Team work. Act and guess. Work in pairs or groups. Step 5:Consolidation Do the exercise on the book and talk about with the classmate.

职称评审申报须知

职称评审申报须知 一、专业技术资格评审时间 专业技术资格评审工作只在每年的7-9月开展。 广州市人事局于2008年、2009年分别开通了“职称业务申报与管理系统”和“专业技术人员继续教育管理系统”,自2008年起在全市高、中、初级各专业技术资格评审工作中(含送省高、中级专业技术资格评委会评审、委托评审、破格申报),全面采用网上申报。 注:因这两个系统是相通的,如“专业技术人员继续教育管理系统”未通过,则“职称业务申报与管理系统”中的相关材料送至上级主管部门审批后无法再往上一级提交,故建议客户能从评审当年的三月份起开始准备相关工作及材料; 二、中、高级职称评审条件

注:1、从省内的其他市调入或安置到我市企事业单位(人事关系、户口均在我市)工作且持有我省专业技术资格证的专业技术人员,如未现持有2000年7月31日以前发的《广东省高(中、初)级专业技术职务资格证》(下称"旧版资格证"),还须参加我市专业技术人员普查换证; 2、专业技术人员申报评审,其工作资历计算的截止时间为评审当年8月31日。由此日上推,凡未满规定年限的,请勿申报。 二、所需材料 初级职称评审 1、参加全国计算机专业技术人员应用能力考试并合格(该考试可登录广州考试信息网,每月都可报名参加); 2、完成从事专业技术工作年限内继续教育学时,并由所在继续教育基地或办学单位负责将学员接受继续教育的基本情况登记在《专业同技术人员继 续教育证书》上。继续教育学时的有效期限为五年,其中,2008年1月1日之前每年必须完成90个学时,之后每年必须完成72个学时。含2门公修课、2门以上不同内容课题(课程)的专业课培训。自2009年起,凡在广州市申报职称评审的继续教育全面采用网上申报。请申报人以及各有关单位登录中国广州人事网(https://www.wendangku.net/doc/c116963539.html,)“专业技术人员继续教育管理系统”进行网上申报和审核。未在该系统申报或已申报但未通过的人员,其“职称业务申报与管理系统”中申报的材料将无法提交终审部门,从而影响当年评审工作的进行。接广州市人力资源和社保保障局通知,2010年继续教育网上申报工作要求,专业技术人员在6月30日前按以上要求申报完成继续教育任务验证的(即完成上页总流程的第三步),验证周期年度时间计算截止到上一年的12月31日,申请验证时间之前本年度完成的学时可累计计算到上一年度。6月30日之后申请验证的,验证周期年度时间计算截止到本年,申请验证时间之前本年度完成的学时累计计算到本年度。例:某申报人未取得初级职称,参加2010年评审工作,该申报人在2010年6月30日前完成“个人:继续教育情况复验(周期验证)申请”,则该申报人需完成的学时为评前五年即2005-2009年共计414个学时。如该申报人未能在2010年6月30日前完成“个人:继续教育情况复验(周期验证)申请”,则该申报人需完成的学时需加多一年的学时,即414+72=486个学时,否则无法参加本年度职称评审工作。 3、与从事的专业技术工作相关的解决技术问题而撰写的专项技术分析(论证)报告1篇。

职称申报评审管理系统

职称申报评审管理系统 使用说明书 ----职称申报人员 甘肃省职称办 2018.11

目录 1.申报须知 (3) 1.1 必看文件 (3) 1.2 诚信要求 (3) 1.3 上传电子版材料规格要求 (3) 2.系统登录 (3) 3.填报基础信息(必填) (5) 4.填报信息 (9) 4.1 基本信息 (9) 4.1.1 个人信息 (10) 4.1.2 考核情况 (12) 4.2 学历资历 (13) 4.2.1 学习经历 (13) 4.2.2 专业技术资格证书 (17) 4.2.3 专业技术职务聘用证明 (17) 4.2.4 相关材料 (18) 4.2.5 工作履历 (20) 4.2.6 参加学术团体(社会兼职)经历 (20) 4.3 专业技术工作经历 (21) 4.4 业绩成果 (23) 4.4.1论文 (23) 4.4.2 论著 (24) 4.4.3 课题(项目) (24) 4.4.4 奖励和荣誉 (24) 4.4.5 专利 (24) 4.4.6 其他业绩 (25) 4.5 小结 (26) 5.关注申报状态 (28)

职称申报人员使用手册 1. 申报须知 1.1 必看文件 全省申报高级资格人员和省直单位申报中级资格人员须认真阅读年度省职称评审工作的通知、相应评委会组建单位会同省人社厅下发的申报工作的通知、所申报系列专业执行的专业技术资格条件。 设区市申报中级资格人员须认真阅读设区市下发的年度职称评审工作的通知、申报工作的通知、所申报系列专业执行的专业技术资格条件。 1.2 诚信要求 按系统规定和文件的要求实事求是填报信息,填报信息或上传材料弄虚作假的,将列入系统“黑名单”,三年内不得再申报职称,并影响个人社会信用。 1.3 上传电子版材料规格要求 ●证件照 照片必须为近期彩色标准1寸的半身免冠正面证件照(尺寸25mmX35mm, 像素295pxX413px), 红色或蓝色或白色背景,jpg或jpeg格式,大小不能超过2M。照片要求清晰,表情自然,该照片将作为评审表和电子资格证书中的照片使用。 ●证明材料。 上传材料类型为JPG、JPEG或PDF格式,单个文件大小不超过2M。若上传的单个文件是多个有序的图片,建议将这些图片转换为一个PDF文件上传。 因申报个人上传材料不清晰或出现漏报、错报、未放指定位置导致的后果,由申报个人承担。申报材料报至评委会后原则上不再补充材料。 2. 系统登录 首先,申报单位和基层单位为本单位职称申报者建立申报帐户(即其本人身份证号),开通申报流程。 申报人员根据本年度甘肃省人事厅职称办的通知,获取职称申报系统地址。 在360浏览器(极速模式)或谷歌浏览器下登录,界面如图1所示。

职称网上申报操作流程(个人)及填写模板

人事网职称业务申报与管理系统操作流程(1)(用户类型:个人;业务类型:专业技术资格认定) 一、注册 1、登录中国广州人事网(https://www.wendangku.net/doc/c116963539.html,)------进入“职称业务申报与管理系统”(人事网首页----业务直通车菜单----专业技术人员) 2、点击“用户注册”(蓝色字体,在用户登录的下方),进入注册页面。 3、在“申请应用系统”步骤建议选择:①职称业务申报与管理系统;②专业技术人员继续教育管理系统;③专业技术资格考试系统。共三项。 4、在“填写帐号信息”步骤:“姓名”与“公民身份号码”必须使用真实的姓名和身份证号码,请记住“用户名”和“密码”,方便以后登录系统时使用。 二、登录 1、登录中国广州人事网(https://www.wendangku.net/doc/c116963539.html,)------进入“职称业务申报与管理系统”界面(在人事网首页----业务直通车菜单----专业技术人员),界面左面是用户登录选项,右面是职称的相关文件及申报职称提示。 2、“用户类型”请选择“个人”,使用注册时的“用户名”及“密码”

进行登录。 三、填写资料 1、登录后,界面左面是业务操作的目录树,右面是相关的职称文件、操作指引等。 2、根据要求选择“专业技术资格认定”。 3、专业技术资格认定: (1)路径:正常申报/ 中级或初级(区县含南方人才市场)(2)点击“基本信息”后:请慎重填写“认定专业”栏。具体可参照《专业技术资格评审委员会情况一览表》的相关专业。 (3)点击“学历(学位)教育情况/非学历教育情况”后:①“学历(学位)教育情况”添加栏,学历“结束时间”是指学历证书的发证时间;“专业名称”选项有相应的毕业专业时,“详细专业”栏可不填写,若“专业名称”没有相应的毕业专业,请在“详细专业”栏手工录入毕业证或学位证的专业。②“非学历教育情况”栏不作要求,若填写,请在提交材料时提供相关的证书复印件。 (4)点击“专业技术工作经历”添加栏,“工作单位及部门”,若劳务派遣请注明派遣单位及工作单位;“专业技术岗位”申报认定专业必须与现从事专业技术工作一致,并且满足申报认定的工作年限;工作岗位尚未结束时,“结束时间”为空值;“主要工作内容”简述岗位工作内容,建议每个岗位不超过30个字。 (5)点击“见习期奖惩情况/个人专业技术工作小结”后,“见习

职称评审材料填报须知

附件2: 职称评审材料填报须知 职称评审申报表格由原广东省人事厅制,共9件。表格的填报注意事项简要说明如下,供广大专业技术人员参考: 评审表一:A4纸单面打印,请申报人根据本人实际情况填写好后粘贴在牛皮纸档案袋上(建议在姓名旁边写上本人的联系电话)。评审表一是送评材料的目录单,是申报材料内容的高度概括,因此,此表填写的内容应与申报材料相对应。如某项无内容则应在该栏注明“无”字样(例如:张三没有提交著作,则应在表一“著作①②”对应的栏目处写上“无”)。申报材料应按要求装订好并按表二至表九的顺序摆放后装袋,装订要求如下: 1.评审表二(共16页)用订书钉或装订线装订成册; 2.评审表三(高级一式20份、中级一式15份、初级一式10份)用夹子夹起来; 3.评审表四单独一页; 4.评审表五(共6页)用订书钉或装订线装订成册,证书、证明材料附件粘贴后可折叠; 5.评审表六(1)与获奖材料装订成册,评审表六(2)与科研成果、专利材料装订成册,评审表六(3)与论文、论著装订成册,评审表六(4)与其他业绩成果材料装订成册; 6.评审表七单独一页; 7.评审表八单独一页; 8.评审表九单独一页。 评审表二:A4纸双面打印,请不要改变表格原有的结构、字体、字号。申报人填写用的字体、字号则可以根据需要调整。表内各栏项目不得空白,如某项无内容则应在该栏注明“无”字样。 第1页:(1)注意检查是否有贴照片(小一寸)。 (2)最高学历、最高学位以取得学历、学位证书为准。虽已毕业但尚未取得证书的学历、学位请不要填写。 (3)“现专业技术资格名称”填现职称名称,例如:建筑结构助理工程师;“取得时间”填评定、考试通过的时间,“现资格取得方式”填:评审、认定、考试。 (4)学历教育:请自中专开始填起,无中专以上学历从初中填起;办学形式指全日制、在职或电大、函大、业余大、职大、夜大、自学考试等。 (5)非学历教育:指用大、中专学校或相同水平教材进行的基础教育,如专业证书班等。 (6)主要工作简历:从参加工作开始填写,重要兼职亦应填写,所列各项时间段应前后衔接。 第3页:(1)“公共必修课”、“专业必修课”请填2014、2015、2016年每年的公需科目、专业必修科目学习情况。(2)“所在单位对申报人完成继续教育情况的审核意见”应体现经单位审核申报人是否已按《广东省专业技术人员继续教育条例》的要求,完成哪些年度的继续教育任务。 第4页:获现资格之前主要专业技术工作及取得的业绩成果情况:填获现职称之前所承担的主要专业技术工作任务及取得的业绩成果、获奖情况等,项目如系多方合作、多人合作,或发包承揽关系的甲方乙方项目,必须如实注明,并说明本人承担部分及所起作用。若申报人目前无职称,此页请填“无”。 第5页:获现资格以来获奖情况、承担已完成或结项的科研项目情况、发明专利情况:填获得现职称至今年8月31日的获奖项目、专利及完成(结项)的科研项目情况。若申报人目前无职称,请按从事现专业技术岗位工作开始填起。 第6页:获现资格以来独立完成的专业技术工作及取得的业绩成果情况:填获得现职称后至今年8月31日已独立完成的专业技术工作及取得符合我省相应专业技术资格条件的业绩成果(不含获奖情况、科研项目情况、发明专利情况)。若申报人目前无职称,请按从事现专业技术岗位工作开始填起。

职称网上申报操作流程及填写模板

人事网职称业务申报与管理系统操作流程(1) (用户类型:个人;业务类型:专业技术资格认定) 一、注册 1、登录中国广州人事网()------进入“职称业务申报与管理系统”(人事网首页----业务直通车菜单----专业技术人员) 2、点击“用户注册”(蓝色字体,在用户登录的下方),进入注册页面。 3、在“申请应用系统”步骤建议选择:①职称业务申报与管理系统;②专业技术人员继续教育管理系统;③专业技术资格考试系统。共三项。 4、在“填写帐号信息”步骤:“姓名”与“公民身份号码”必须使用真实的姓名和身份证号码,请记住“用户名”和“密码”,方便以后登录系统时使用。 二、登录 1、登录中国广州人事网()------进入“职称业务申报与管理系统”界面(在人事网首页----业务直通车菜单----专业技术人员),界面左面是用户登录选项,右面是职称的相关文件及申报职称提示。 2、“用户类型”请选择“个人”,使用注册时的“用户名”及“密码”进行登录。

三、填写资料 1、登录后,界面左面是业务操作的目录树,右面是相关的职称文件、操作指引等。 2、根据要求选择“专业技术资格认定”。 3、专业技术资格认定: (1)路径:正常申报 / 中级或初级(区县含南方人才市场)(2)点击“基本信息”后:请慎重填写“认定专业”栏。具体可参照《专业技术资格评审委员会情况一览表》的相关专业。(3)点击“学历(学位)教育情况/非学历教育情况”后:①“学历(学位)教育情况”添加栏,学历“结束时间”是指学历证书的发证时间;“专业名称”选项有相应的毕业专业时,“详细专业”栏可不填写,若“专业名称”没有相应的毕业专业,请在“详细专业”栏手工录入毕业证或学位证的专业。②“非学历教育情况”栏不作要求,若填写,请在提交材料时提供相关的证书复印件。 (4)点击“专业技术工作经历”添加栏,“工作单位及部门”,若劳务派遣请注明派遣单位及工作单位;“专业技术岗位”申报认定专业必须与现从事专业技术工作一致,并且满足申报认定的工作年限;工作岗位尚未结束时,“结束时间”为空值;“主要工作内容”简述岗位工作内容,建议每个岗位不超过30个字。(5)点击“见习期奖惩情况/个人专业技术工作小结”后,“见

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