Technical Documents
Description
Phosphonoacetate (PACE) modified oligonucleotides show great potential as biological modifiers in a wide variety of research applications. PACE monomers are part of a family of Phosphonocarboxylate monomers. The monomers can be easily incorporated into complex oligonucleotides and are compatible with a wide variety of other sugar or heterobase modifications. PACE DNA can be conjugated through the carboxylic acid functional group. They have been shown to be active in siRNA duplexes and accelerate the initial rate of cleavage by RNase H-1 when incorporated with phosphorothioates. However, the most interesting observation to date is that they exhibit an unprecedented enhancement in penetration of cultured cells. T
he phosphonoacetates are fully soluble in acetonitrile at a recommended concentration of 0.1M and are compatible with standard DNA synthesizers. A recommended coupling time of 33.3 minutes with 1H-Tetrazole is necessary when using the standard protocol. A modified LV cycle for AB instruments that reduces coupling time to 15 minutes with 1H-Tetrazole is available on our website. Oxidation must precede capping in the synthesis cycle. Reagents for oxidation depend on the type of synthesis. For fully modified oligos, we recommend the non-aqueous oxidizer camphorsulfonyloxaziridine (CSO) as a 0.1M solution. For mixed phosphodiester and phosphonoacetate modified oligos, a 0.5M CSO solution is recommended. Low water oxidizer, 40-4032, is an alternative oxidizing reagent although it has been reported that this can result in conversion of a small percentage of the phosphonoacetate to the phosphodiester. We also recommend the use of the Cap Mix B with DMAP (40-4020) instead of the standard Cap Mix B containing 1-Methylimidazole.
The standard protocol for cleavage and deprotection requires a two step method with pretreatment using 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and subsequent cleavage using methylamine. The DBU is used to deprotect the dimethylcyanoethyl (DMCE) protecting groups and to prevent alkylation of the bases during deprotection. Cleavage with 40% methylamine in water is recommended and we have also had good results when using AMA deprotection.
Details
Usage
- Coupling: 33 minutes with 1H-Tetrazole Activator.||Synthesis: Oxidize before capping.Use either low water, low iodine oxidizer (Cat.# 40-4032-xx) or 10-camphorsulfonyloxaziridine (CSO) in acetonitrile.When CSO is used, extend the oxidation time to 3 minutes.Use 0.5M CSO when oxidizing mixed PACE/phosphodiester linkages.When oxidizing only PACE linkages, 0.1 M CSO can be used.For Cap Mix B, use 6.5% DMAP in THF (Cat.# 40-4020-xx).An example of a PACE cycle for AB synthesizers can be seen at:|http://www.glenresearch.com/Technical/PACE_cycle.pdf
- Deprotection: Pretreat synthesis column with 1.5% DBU in anhydrous acetonitrile for 60 minutes (syringe method).Wash with acetonitrile and dry with argon.Deprotect with 40% Methylamine for 20 minutes at 55°C.
| Specifications | |
|---|---|
| Diluent | Anhydrous Acetonitrile |
| Storage | Freezer storage, -10 to -30°C, dry |
| Stability | 2-3 days |
Intellectual Property
Dilution/Coupling Data
The table below show pack size data and, for solutions, dilution and approximate coupling based on normal priming procedures.
ABI 392/394
| Catalog # | Pack Size | Grams/Pack | 0.1M Dil. (mL) | Approximate Number of Additions | |||||
|---|---|---|---|---|---|---|---|---|---|
| LV40 | LV200 | 40nm | 0.2μm | 1μm | 10μm | ||||
| 10-1150-02 | 0.25 g | .25grams | 2.97 | 85.67 | 51.4 | 32.13 | 23.36 | 17.13 | 4.28 |
| 10-1150-05 | 0.5 g | .5grams | 5.94 | 184.67 | 110.8 | 69.25 | 50.36 | 36.93 | 9.23 |
| 10-1150-10 | 1.0 g | 1grams | 11.88 | 382.67 | 229.6 | 143.5 | 104.36 | 76.53 | 19.13 |
Expedite
| Catalog # | Pack Size | Grams/Pack | Dilution (mL) | Approximate Number of Additions | ||||
|---|---|---|---|---|---|---|---|---|
| Molarity | 50nm | 0.2μm | 1μm | 15μm | ||||
| 10-1150-02 | 0.25 g | .25grams | 4.43 | 0.07 | 82.2 | 51.38 | 37.36 | 5.14 |
| 10-1150-05 | 0.5 g | .5grams | 8.86 | 0.07 | 170.8 | 106.75 | 77.64 | 10.68 |
| 10-1150-10 | 1.0 g | 1grams | 17.73 | 0.07 | 348.2 | 217.63 | 158.27 | 21.76 |
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FDAApprovesLenalidomideasMaintenanceTherapyforPatientsWithMultipleMyelomaFollowingAutologousStemCellTransplant
OnFebruary22,theU.S.FoodandDrugAdmiNISTration(FDA)expandedtheexistingindicationforlenalidomide(Revlimid)10mgcapsulestoincludeuseforpatientswithmultiplemyelomaasmaintenancetherapyfollowingautologoushematopoieticstemcelltransplant.TheexpandedindicationmakeslenalidomidethefirstandonlytreatmenttoreceiveFDAapprovalformaintenanceusefollowingautologoushematopoieticstemcelltransplant.
“Autologousstemcelltransplantafterinductiontherapyispartofthecontinuumofcarefortransplant-eligIBLe[patientswith]multiplemyeloma.However,mostpatientswillstillseetheirdiseaserecurorprogressafterthistreatment,”saidPhilipMcCarthy,MD,Director,BloodandMarrowTransplantCenter,DepartmentofMedicineatRoswellParkCancerInstitute.“Lenalidomidemaintenancetherapy,whichhasbeenshowntoincreaseprogression-freesurvivalfollowingautologousstemcelltransplantinclinicaltrials,canbeconsideredastandardofcareforthesepatients.”
ClinicalTrialFindings
Theapprovalwasbasedontwolargestudies—CALGB100104andIFM2005-02—includingmorethan1,000patientscomparinglenalidomidemaintenancetherapygivenuntildiseaseprogressionorunacceptabletoxicityafterautologoushematopoieticstemcelltransplantvsnomaintenance.Inbothstudies,theprimaryefficacyendpointwasprogression-freesurvival.
Inthemostcurrentprogression-freesurvivalanalysis,Study1(CALGB100104)demonstratedamedianprogression-freesurvivalof5.7years(95%confidenceinterval[CI]=4.4–notestimable)vs1.9years(95%CI=1.6–2.5)fornomaintenance,adifferenceof3.8years(hazardratio[HR]=0.38;95%CI=0.28–0.50).
Study2(IFM2005-02)alsoshowedabenefitwithamedianprogression-freesurvivalof3.9years(95%CI=3.3–4.7)vs2years(95%CI=1.8–2.3)fornomaintenance,adifferenceof1.9years(HR=0.53;95%CI=0.44–0.64).
Individualstudieswerenotpoweredforanoverallsurvivalendpoint.
AdescriptiveanalysisshowedthemedianoverallsurvivalinStudy1was9.3years(95%CI=8.5–notestimable)forpatientswhoreceivedlenalidomidevs7years(95%CI=5.9–8.6)fornomaintenance(HR=0.59;95%CI=0.4–0.78).InStudy2,medianoverallsurvivalwas8.8years(95%CI=7.4–notestimable)forpatientswhoreceivedlenalidomidevs7.3years(95%CI=6.7–9.0)fornomaintenance(HR=0.90;95%CI=0.72–1.13).
AdverseEvents
Themostfrequentlyreportedadversereactionsin≥20%(lenalidomidearm)acrossbothmaintenancestudies(Study1,Study2respectively)wereneutropenia(79%,61%);thrombocytopenia(72%,24%);leukopenia(23%,32%);anemia(21%,9%);upperrespiratorytractinfection(27%,11%);bronchitis(5%,47%);nasopharyngitis(2%,35%);cough(10%,27%);gastroenteritis(0%,23%);diarrhea(55%,39%);rash(32%,8%);fatigue(23%,11%);asthenia(0%,30%);musclespasm(0%,33%);andpyrexia(8%,21%).ThemostfrequentlyreportedGrade3or4reactions(morethan20%inthelenalidomidearm)includedneutropenia,thrombocytopenia,andleukopenia.
Thefrequenciesofonsetofadversereactionsweregenerallyhighestinthefirst6monthsoftreatmentandthenthefrequenciesdecreasedovertimeorremainedstablethroughouttreatment.
Inpatientsreceivinglenalidomidemaintenancetherapy,hematologicsecondprimarymalignanciesoccurredin7.5%ofpatientscomparedto3.3%inpatientsreceivingplacebo.Theincidenceofhematologicplussolidtumor(excludingsquamouscellcarcinomaandbasalcellcarcinoma)secondprimarymalignancieswas14.9%,comparedto8.8%inpatientsreceivingplacebowithamedianfollow-upof91.5months.Nonmelanomaskincancersecondprimarymalignancies,includingsquamouscellcarcinomaandbasalcellcarcinoma,occurredin3.9%ofpatientsreceivinglenalidomidemaintenance,comparedto2.6%intheplaceboarm.
果糖胺是血浆中的蛋白质与葡萄糖非酶糖化过程中形成的高分子酮胺结构类似果糖胺的物质，它的浓度与血糖水平成正相关，并相对保持稳定。它的测定却不受血糖的影响。由于血浆蛋白的半衰期为17～20天，故果糖胺可以反映糖尿病患者检测前1～3周内的平均血糖水平。从一定程度上弥补了糖化血红蛋白不能反映较短时期内血糖浓度变化的不足。果糖胺的测定快速而价廉（化学法），是评价糖尿病控制情况的一个良好指标，尤其是对血糖波动较大的脆性糖尿病及妊娠糖尿病，了解其平均血糖水平有实际意义。但果糖胺不受每次进食的影响，所以不能用来直接指导每日胰岛素及口服降糖药的用量。血清果糖胺正常值为1.64～2.64mmol/L，血浆中果糖胺较血清低0.3mmol/L。
如题，之前买的sigma的粉末，太贵。加培养基又不方便
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原文链接：http://www.ascopost.com/News/40561
AdditionofIxazomibtoLenalidomide/DexamethasoneImprovesProgression-FreeSurvivalinRelapsed/RefractoryMultipleMyeloma
Moreauetalfoundthataddingtheoralproteasomeinhibitorixazomib(Ninlaro)tolenalidomide(Revlimid)anddexamethasonesignificantlyprolongedprogression-freesurvivalamongpatientswithrelapsed,refractory,orrelapsedandrefractorymultiplemyeloma.TheyreportedthefindingsfromthephaseIIITOURMALINE-MM1trialinTheNewEnglandJournalofMedicine.ThetrialsupportedtherecentU.S.FoodandDrugAdmiNISTration(FDA)approvalofixazomibinpreviouslytreatedmultiplemyeloma,makingitthefirstapprovedoralproteasomeinhibitor.
StudyDetails
Inthedouble-blindtrial,722patientsfrom147sitesin26countrieswererandomizedbetweenAugust2012andMay272014toreceiveixazomib(n=360)orplacebo(n=362)pluslenalidomideanddexamethasone.Treatmentconsistedof28-daycyclesoforalixazomibat4mgorplaceboondays1,8,and15;orallenalidomideat25mgondays1through21(10mginthosewithcreatinineclearance≤60or≤50mL/min/1.73m2accordingtolocalprescribinginformation);andoraldexamethasoneat40mgondays1,8,15,and22.Theprimaryendpointwasprogression-freesurvival.
Fortheixazomibvsplacebogroups,medianagewas66yearsinboth(53%vs51%>65years);58%vs56%weremale;86%vs83%werewhite;EasternCooperativeOncologyGroupperformancestatuswas0or1in95%vs93%;InternationalStagingSystem(ISS)stagewasIin63%vs64%,IIin25%vs24%,andIIIin12%inboth;78%vs72%hadcreatinineclearance≥60mL/min/1.73m2;55%vs60%hadstandard-and21%vs17%hadhigh-riskcytogenetics;numberofpriortherapieswas1in62%vs60%,2in27%vs31%,and3in11%vs9%;59%vs55%hadpriorstemcelltransplantation;diseasecategorywasrelapsedin77%inboth,refractoryin12%vs11%,relapsedandrefractoryin11%vs12%,andprimaryrefractoryin7%vs6%;priorproteasomeinhibitortherapywasbortezomib(Velcade)in69%inbothandcarfilzomib(Kyprolis)in<1%vs1%,with1%vs2%ofpatientshavingdiseaserefractorytopriortreatment;andpriorimmunomodulatorytherapywaslenalidomidein54%vs56%andthalidomide(Thalomid)in44%vs47%,with21%vs25%havingdiseaserefractorytopriortherapy.
ImprovedProgression-FreeSurvival
Aftermedianfollow-upof14.7months,medianprogression-freesurvivalwas20.6monthsintheixazomibgroupvs14.7monthsintheplacebogroup(hazardratio[HR]=0.74,P=.01).Benefitofixazomibwasconsistentacrossprespecifiedsubgroups,includingpoor-prognosissubgroupssuchasthosewithhigh-riskcytogenetics(24.1vs9.7months,HR=0.54),ISSstageIIIdisease(18.4vs10.1months,HR=0.72),thoseaged>75years(18.5vs13.1months,HR=0.87),andthosewhohadreceivedtwo(17.5vs14.1months,HR=0.75)orthree(notestimablevs10.2months,HR=0.37)priortherapies.
Overallresponserateswere78%vs72%,withtheratesofcompleteresponseplusverygoodpartialresponseof48%vs39%.Mediantimetoresponsewas1.1vs1.9months.Mediandurationofresponsewas20.5vs15.0months.Atmedianfollow-upofapproximately23months,medianoverallsurvivalhadnotbeenreachedineithergroup.
AdverseEvents
Adverseeventsof≥grade3occurredin74%oftheixazomibgroupvs69%oftheplacebogroup,withthemostcommonintheixazomibgroupbeingneutropenia(23%vs24%)andthrombocytopenia(19%vs9%).Rashofanygradewasmorecommonintheixazomibgroup(36%vs23%),asweregastrointestinaladverseevents(mostlylowgrade);22%ofixazomibpatientsand19%ofplacebopatientsreceivedantidiarrhealagents,and21%and13%receivedantiemeticdrugs.Peripheralneuropathyofanygradeoccurredin27%vs22%(grade3in2%ineach).
Seriousadverseeventsoccurredin47%vs49%.Adverseeventsledtodosereductionofanydrugin56%vs50%,discontinuationofanydrugin25%vs20%,anddiscontinuationofthestudyregimenin17%vs14%.Deathoccurredduringthestudyperiodin4%vs6%.
Theinvestigatorsconcluded:“Theadditionofixazomibtoaregimenoflenalidomideanddexamethasonewasassociatedwithsignificantlylongerprogression-freesurvival;theadditionaltoxiceffectswiththisall-oralregimenwerelimited.”
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ICML2017:PhaseIIIbMAGNIFYStudyofLenalidomideandRituximabCombinationinRelapsed/RefractoryFollicularandMarginalZoneLymphoma
AninterimanalysisofMAGNIFY,aphaseIIIb,randomized,open-label,multicenterstudyoftheR2combinationregimen(lenalidomide[Revlimid]plusrituximab[Rituxan])inpatientswithrelapsedorrefractorymarginalzonelymphoma,waspresentedattheInternationalConferenceonMalignantLymphoma(ICML)inLugano,Switzerland.ThisanalysisexpandedupondatapresentedearlierinthemonthattheASCOAnnualMeeting(Abstract7502).
TheMAGNIFYstudycontinuestoevaluatetheclinicalactivityof12cyclesofR2combinationtherapyfollowedbyrandomizationtoeither18cyclesofR2maintenanceor18cyclesofrituximabmonotherapy,inpatientswithrelapsedorrefractoryfollicularlymphoma,marginalzonelymphoma,ormantlecelllymphoma.Approximately500patientsareplannedtobeenrolledinthestudy.
Theprimaryendpointisprogression-freesurvival.Secondaryendpointsincludeoverallsurvival,overallresponserate,completeresponse,improvementofresponse,durationofresponse,durationofcompleteresponse,timetonextlymphomatreatment,timetohistologictransformation,safety,andexploratoryquality-of-lifemeasures.EnrollmentintheMAGNIFYstudyisongoing.
ASCOData
AttheASCOAnnualMeeting,interimdatawerepresentedfromananalysisofasubsetofpatientsfromtheMAGNIFYstudywithrelapsedorrefractoryfollicularlymphoma(n=160)withearly-relapse(n=52)anddouble-refractory(n=50)disease.
AttheJanuary9,2017,datacutoff,the1-yearprogression-freesurvivalforallfollicularlymphomapatientswas70%,with65%fordouble-refractorypatientsand49%forearly-relapsepatients.Additionally,evaluablefollicularlymphomapatients(n=128)hadanoverallresponserateof66%withacompleteresponse/completeresponse–unconfirmedrateof38%.Fordouble-refractorypatients(n=42),overallresponseratewas45%withacompleteresponse/completeresponse–unconfirmedrateof21%andforearly-relapsepatients(n=43),overallresponseratewas47%withacompleteresponse/completeresponse–unconfirmedrateof21%.Mediandurationofresponsewasnotmetatamedianfollow-upof10.2months.
Themostcommongrade3or4adverseeventsobservedinthestudyforallfollicularlymphoma,double-refractory,andearly-relapsepatients,respectively,wereneutropenia(29%,42%,37%),fatigue(6%,4%,8%),leukopenia(5%,8%,10%),thrombocytopenia(4%,8%,4%),andlymphopenia(3%,6%,4%).
ICMLData
DatapresentedatICMLinaseparateanalysisfocusedonpatientswithmarginalzonelymphoma(n=38),includingnodalmarginalzonelymphoma(n=18),splenicmarginalzonelymphoma(n=10),andmucosa-associatedlymphoidtissuelymphoma(n=10).
Atamedianfollow-upof13.8monthsfrominitiationoftherapywiththeR2combination,evaluablepatientswithmarginalzonelymphoma(n=32)achievedanoverallresponserateof66%withacompleteresponse/completeresponse–unconfirmedrateof44%.Evaluablenodalmarginalzonelymphomapatients(n=14)hadanoverallresponserateof57%withacompleteresponse/completeresponse–unconfirmedrateof57%.Evaluablesplenicmarginalzonelymphomapatients(n=8)hadanoverallresponserateof63%withacompleteresponserateof25%;andevaluablemucosa-associatedlymphoidtissuelymphomapatients(n=10)hadanoverallresponserateof80%withacompleteresponse/completeresponse–unconfirmedrateof40%.Mediandurationofresponsewasnotreachedforanygroup.
Themostcommongrade3or4adverseeventsobservedinpatientswithmarginalzonelymphomawereneutropenia(32%),thrombocytopenia(16%),andleukopenia(11%).
“Thechemotherapy-freecombinationoflenalidomideandrituximab,withcomplementarymechanismsofactionthatarethoughttoenhanceantibodydependentcellularcytotoxicity,continuestoshowencouragingactivityandatolerablesafetyprofileinindolentlymphomas,andparticularlyindifficult-to-treatpatientsubsets,”saidDavidJ.Andorsky,MD,co–principalinvestigatorofthestudyandmedicaloncologistattheRockyMountainCancerCentersinBoulder,Colorado.“Theseresultsinpatientswhohadfailedmultipletherapiesorrelapsedearly,aswellastheactivityinmarginalzonepatientsmeritfurtherstudyinthisareaofindolentlymphoma.”
AboutMAGNIFY
MAGNIFYisaphaseIIIb,multicenter,open-labelstudyofpatientswithgrades1–3bortransformedfollicularlymphoma,marginalzonelymphoma,ormantlecelllymphomawhoreceivedatleast1priortherapyandhadstageI–IV,measurabledisease.Approximately500patientsareplannedforenrollmentin12cyclesofR2induction,withaprojected314patientswithatleaststablediseaseafterinductionrandomized(1:1)to2maintenancearms.
Inductionincludesorallenalidomideat20mg/d,days1–21per28-daycycle(d1–21/28)plusintravenousrituximabat375mg/m2,days1,8,15,and22ofcycle1andday1ofcycles3,5,7,9,and11(28-daycycles).Patientsarethenrandomizedtomaintenancelenalidomideat10mg/d,days1to21/28,cycles13to30,plusrituximabat375mg/m2,day1ofcycles13,15,17,19,21,23,25,27,and29(R2,armA),orrituximabalone(sameschedule,armB).PatientsreceivingR2maintenanceafter18cyclesmaycontinuemaintenancelenalidomidemonotherapyat10mg/d,days1–21/28(perpatientand/orinvestigatordiscretion),untildiseaseprogressionastolerated.Patientswillbefollowedfor≥5yearsafterthelastpatientinitiatesinductiontherapy.
