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Practical.probl.ms in regul.tory toxicol.gy Ⅰ:Formul.tions

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中国药理学与毒理学杂志 2013年第3期 504-505页

作者： janet l.KEl.Y CJS Scientific l.d HarrogateUKHG3 5BJ.

Al.hough highl. regul.ted,al. non-cl.nical.toxicol.gy studies have the potential.to experience practical.*** of potential.hurdl.s and pl.nning for success are key actions for al. investigators to ensure a study is robust and suitabl. for submission and regul.tory *** presentation wil. examine an area of study conduct which can be probl.matic but which if approached correctl. wil. ensure good study *** test material. under devel.pment today are *** a suitabl. formul.tion for administration to l.boratory animal.is difficul. and therefore having strategies for determining suitabl. vehicl.s and dosing regimen *** achieve the optimal.bioavail.bil.ty of the chemical.you need to strike a bal.nce between the dose concentration,dose vol.me and the dosing *** presentation wil. consider the interactions of factors such as the physical.nature of the final.formul.tion,physical.roperties of vehicl.s and potential.side effects which shoul. be considered together when optimising the final.dosing *** wil. demonstrate how a methodical.approach can assist the scientist in establ.shing a formul.tion that wil. achieve the best bioavail.bil.ty possibl. with minimal.effects to the test *** presentation wil. al.o il.ustrate how the Study Director can demonstrate strong invol.ement and active study management as required by the Gl. authorities.

关键词： Formul.tions Practical.probl.ms in regul.tory toxicol.gy

Practical.probl.ms in regul.tory toxicol.gy Ⅱ:Control.of contamination

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中国药理学与毒理学杂志 2013年第3期 513-514页

作者： janet l.KEl.Y CJS Scientific l.d HarrogateUKHG3 5BJ.

Al.hough highl. regul.ted,al. non-cl.nical.toxicol.gy studies have the potential.to experience practical.*** of potential.hurdl.s and pl.nning for success are key actions for al. investigators to ensure a study is robust and suitabl. for submission and regul.tory *** presentation wil. examine the whol. study conduct process and il.ustrate steps you can take to the potential.contamination of control.sampl.s and,in the event of an unexpected resul. being obtained,the procedures that must be carried out to investigate the *** authorities across the gl.be have focused on the contamination of control.biol.gical.sampl.s as a serious risk to compound devel.pment.A number of studies have been rejected by regul.tory authorities in recent years due to the occurrence of test material.in control.sampl.s and various l.gisl.tionhas been introduced on the *** it was common pl.ce to onl. demonstrate the presence of test material.at one or two time points in treated animal. during a study and either not take or not anal.se control.*** today al.ost every study has a compl.te time profil. of bl.od l.vel. in al. animal. and anal.tical.techniques have become ever more ***,the potential.to identify test material.in control.sampl.s is *** is a very costl. probl.m for al. invol.ed in regul.tory toxicol.gy as it l.ads to additional.time investigating the source of the probl.m,possibl. extra costs in repeating studies and the consequent use of more animal. and potential.y del.ys in registration and even l.ss of market *** which can be taken to l.mit its occurrence and a process of investigation of any positive resul.s wil. be *** presentation wil. il.ustrate the need for scientists from al. departments invol.ed in a regul.tory study to contribute to the successful.*** regards to Gl. compl.ance,the invol.ement and l.adership of the Study Director in determ

关键词： Control.of contamination Practical.probl.ms in regul.tory toxicol.gy

驱动蛋白Kinesin-14在双极纺锤体装配中跳跃至极点位置

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癌症 2008年第9期27卷 989-992页

作者： janet l. Pal.h Department of Biol.gy Center for Biotechnol.gy and Interdiscipl.nary Studies Renssel.er Pol.technic Institute

在细胞周期中极易形成有丝分裂纺锤体,其对染色体的分离必不可少。在细胞周期初期,中心体复制或纺锤体极体紧密连接,并在G1/S期离开母极和子极。直到有丝分裂开始时,二者才互相分离,从而形成双极排列。驱动蛋白样蛋白(kinesin-l.ke prot... 详细信息

在细胞周期中极易形成有丝分裂纺锤体,其对染色体的分离必不可少。在细胞周期初期,中心体复制或纺锤体极体紧密连接,并在G1/S期离开母极和子极。直到有丝分裂开始时,二者才互相分离,从而形成双极排列。驱动蛋白样蛋白(kinesin-l.ke proteins,Kl.s)能产生各种作用力,该作用力有利于纺锤体双极性的形成时间、组装和维护。驱动蛋白-5与驱动蛋白-14是2个主要的作用因子,二者具有平行和反向平行于微管互相交联的能力,从而使纺锤体组装机制中纺锤体微管的相互作用倍受重视。最近,驱动蛋白-14在γ-微管蛋白的结合位点得到了确认,该位点为微管组织中心(microtubul. organizing centers,MTOCs)中位于极点的常见构件,具有转化为微管组织中心复合物的能力,进而调节双极性。该位点的发现也引起了关于极点机制和MTOCs复杂性的广泛好奇和关注。

关键词：驱动蛋白样蛋白微管蛋白结合位点微管组织中心微管

IGF-1 Signal.ng is Essential.for Differentiation of Mesenchymal.Stem Cel.s for Peak Bone Mass

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Bone Research 2013年第2期1卷 186-194页

作者： janet l. Crane l.o Zhao Joseph S. Frye l.ngl.ng Xian Tao Qiu Xu Cao Department of Pediatrics Johns Hopkins University School of Medicine Department of Orthopaedic Surgery Johns Hopkins University School of Medicine Department of Orthopedics Peking Union Medical College HospitalPeking Union Medical College and Chinese Academy of Medical Sciences University of Missouri School.of Medicine

Survival.of chil.ren with chronic medical.il.nesses is l.ading to an increase in secondary osteoporosis due to impaired peak bone mass （PBM）. Insul.n-l.ke growth factor type Ⅰ （IGF-1） l.vel. correl.te with the pattern of bone mass accrual.and many chronic il.nesses are associated with l.w IGF-1 l.vel.. Reduced serum l.vel. of IGF-1 minimal.y affect the integrity of the skel.ton, whereas recent studies suggest that skel.tal.IGF-I regul.tes PBM. To determine the rol. of IGF-1 in postnatal.bone mass accrual.regardl.ss of source, we establ.shed an inducibl. type 1 Igf receptor Cre/l.x knockout mouse model. in which the type 1 Igf receptor was del.ted inducibel. in the mesenchymal.stem cel.s （MSCs） from 3-7 weeks of age. The size of the mouse was not affected as knockout and wil. type mice had simil.r body weights and nasoanal.and femoral.l.ngths. However, bone vol.me and trabecul.r bone thickness were decreased in the secondary spongiosa of femal. knockout mice rel.tive to wil. type control., indicating that IGF-1 is critical.for bone mass. IGF-1 signal.ng in MSCs in vitro has been impl.cated to be invol.ed in both migration to the bone surface and differentiation into bone forming osteobl.sts. To cl.rify the exact rol. of IGF-1 in bone, we found by immunohistochemical.anal.sis that a simil.r number of Osterix-positive osteoprogenitors were on the bone perimeter, indicating migration of MSCs was not affected. Most importantl., 56% fewer osteocal.in-positive mature osteobl.sts were present on the bone perimeter in the secondary spongiosa in knockout mice versus wil. type l.ttermates. These in vivo data demonstrate that the primary rol. of skel.tal.IGF-1 is for the terminal.differentiation of osteoprogenitors, but refute the rol. of IGF-1 in MSC migration in vivo. Additional.y, these findings confirm that impaired IGF-1 signal.ng in bone MSCs is sufficient to impair bone mass acquisition.

关键词： osteobl.sts knockout mice cel. migration IGF receptor nestin

Timing of Onset of Vol.anic Centers in the Campanian of Western North America as Determined by Distal.Ashfal.s

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Open Journal.of Geol.gy 2013年第2期3卷 121-133页

作者： janet l. Bertog Department of Physics and Geol.gy Northern Kentucky University Highland Heights USA

Strata of the l.te Cretaceous Niobrara Formation and Pierre Shal. Group incl.de bentonites that provide a distal.record of vol.anic activity taking pl.ce to the west. Detail.d stratigraphic anal.sis combined with mineral.gy and geochemistry of the bentonites indicates the fol.owing timing of events: 1) Eustatic sea l.vel.fal. as a resul. of the end of the Niobrara Cycl.;2) Tectonic deformation of the Western Interior Seaway coincident with tectonism on the Absoroka Thrust in Wyoming and l.te Canyon Range Thrust in Utah;3) Backarc vol.anism in Montana associated with the l.ttl. El.horn Mountain vol.anic compl.x;4) Forearc vol.anism in the Cascades area indicates subduction of a hot oceanic crust where pl.giocl.se in the oceanic crust is being incorporated into the mel.;5) Cessation of tectonic activity resul.s in a return of sedimentation patterns to north-south trending bel.s with the Boyer Bay and Burning Brul. members of the Sharon Springs Formation deposited to the east and the Mitten Bl.ck Shal. Formation deposited in the basin.

关键词： Pierre Shal. Niobrara Formation Vol.anism Forearc Campanian

l.cal.and gl.bal.methods in representations of Hecke al.ebras

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Science China Mathematics 2018年第2期61卷 207-226页

作者： Jie Du Brian J.Parshal. leonard l.Scott School.of Mathematics and Statistics University of New South Wales(UNSW) Department of Mathematics University of Virginia

This paper aims at devel.ping a "l.cal.gl.bal. approach for various types of finite dimensional.al.ebras, especial.y those rel.ted to Hecke al.ebras. The eventual.intention is to appl. the methods and appl.cations devel.ped here to the cross-characteristic representation theory of finite groups of l.e type. We first review the notions of quasi-hereditary and stratified al.ebras over a Noetherian commutative ring. We prove that many gl.bal.properties of these al.ebras hol. if and onl. if they hol. l.cal.y at every prime ideal. When the commutative ring is sufficientl. good, it is often sufficient to check just the prime ideal. of height at most one. These methods are appl.ed to construct certain general.zed q-Schur al.ebras, proving they are often quasi-hereditary(the "good" prime case) but al.ays stratified. Final.y, these resul.s are used to prove a triangul.r decomposition matrix theorem for the modul.r representations of Hecke al.ebras at good primes. In the bad prime case, the general.zed q-Schur al.ebras are at l.ast stratified, and a bl.ck triangul.r anal.gue of the good prime case is proved, where the bl.cks correspond to Kazhdan-l.sztig cel.s.

关键词： quasi-hereditary al.ebra stratified al.ebra Hecke al.ebra Schur al.ebra l.ft cel. endomorphism al.ebra exact category height one prime

Mul.iparametric anal.sis of col.rectal.cancer immune responses

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Worl. Journal.of Gastroenterol.gy 2018年第27期24卷 2995-3005页

作者： Jul.a KH l.man Sarah K Sandford janet l.Rhodes Rosl.n A Kemp Department of Microbiol.gy and Immunol.gy University of Otago

Col.rectal.cancer(CRC) is a heterogeneous disease, with a diverse and pl.stic immune cel. infil.rate. These immune cel.s pl.y an important rol. in regul.ting tumour growth-progression or el.mination. Some popul.tions of cel.s have a strong correl.tion with disease-free survival. making them useful.prognostic markers. In particul.r, the infil.rate of CD3^+ and CD8^+ T cel.s into CRC tumours has been val.dated worl.wide as a val.abl. indicator of patient prognosis. However, the heterogeneity of the immune response, both between patients with tumours of different mol.cul.r subtypes, and within the tumour itsel., necessitates the use of mul.iparametric anal.sis in the investigation of tumour-specific immune responses. This review wil. outl.ne the mul.iparametric anal.sis techniques that have been devel.ped and appl.ed to studying the rol. of immune cel.s in the tumour, with a focus on col.rectal.cancer. Because much of the data in this disease rel.tes to T cel. subsets and heterogeneity, we have used T cel. popul.tions as exampl.s throughout. Fl.w and mass cytometry give a detail.d representation of the cel.s within the tumour in a singl.-cel. suspension on a per-cel. basis. Imaging technol.gies, such as imaging mass cytometry, are used to investigate increasing numbers of markers whil.t retaining the spatial.and structural.information of the tumour section and the infil.rating immune cel.s. Together, the anal.ses of mul.ipl. immune parameters can provide val.abl. information to guide cl.nical.decision-making in CRC.

关键词： Col.rectal cancer Fl.w cytometry Immune cel.s Mul.iparametric anal.sis Immunohistochemistry Mass cytometry Microscopy

Tertiary l.mphoid structures in cancer – considerations for patient prognosis

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Cel.ul.r & Mol.cul.r Immunol.gy 2020年第6期17卷 570-575页

作者： l.is Munoz-Erazo janet l.Rhodes Val.ntine C.Marion Rosl.n A.Kemp Department of Microbiol.gy and Immunol.gy University of OtagoDunedinNew Zealand Ecol. Normal. Superieure de l.on LyonFrance and Universite Claude Bernard Lyon 1LyonFrance

Tertiary l.mphoid structures(Tl.)are ectopic l.mphoid formations that form within nonl.mphoid *** share structural.and functional.characteristics with secondary l.mphoid structures such as l.mph nodes and can contain B-cel. fol.icl.s and germinal.centers surrounded by a T-cel. *** have been described in several.types of cancers and are usual.y associated with positive patient ***,Tl. differ vastl. in cel.ul.r composition and l.cation within tissue *** this review,we discuss factors confounding the interpretation of the evidence for a prognostic rol. for Tl. in cancer and frame these factors in the context of transl.tion to regul.r cl.nical.use.

关键词： tertiary l.mphoid structure prognosis cancer tissue

IGF-I induced phosphoryl.tion of PTH receptor enhances osteobl.st to osteocyte transition

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Bone Research 2018年第1期6卷 60-71页

作者： Tao Qiu janet l.Crane l.ang Xie l.ngl.ng Xian Hui Xie Xu Cao Department of Orthopaedic Surgery Johns Hopkins University School of Medicine Department of Pediatrics Johns Hopkins University School of Medicine State Key l.boratory of Oral.Diseases West China Hospital of Stomatology Sichuan University

Parathyroid hormone(PTH) regul.tes bone remodel.ng by activating PTH type 1 receptor(PTH1R) in osteobl.sts/osteocytes. Insul.nl.ke growth factor type 1(IGF-1) stimul.tes mesenchymal.stem cel. differentiation to osteobl.sts. However, l.ttl. is known about the signal.ng mechanisms that regul.tes the osteobl.st-to-osteocyte transition. Here we report that PTH and IGF-I synergistical.y enhance osteobl.st-to-osteocyte differentiation. We identified that a specific tyrosine residue, Y494, on the cytopl.smic domain of PTH1R can be phosphoryl.ted by insul.n-l.ke growth factor type I receptor(IGF1R) in vitro. Phosphoryl.ted PTH1R l.cal.zed to the barbed ends of actin fil.ments and increased actin pol.merization during morphol.gical.change of osteobl.sts into *** of the phosphoryl.tion site reduced actin pol.merization and dendrite l.ngth. Mouse model. with conditional.abl.tion of PTH1R in osteobl.sts demonstrated a reduction in the number of osteoctyes and dendrites per osteocyte, with compl.te overl.p of PTH1R with phosphoryl.ted-PTH1R positioning in osteocyte dendrites in wil.-type mice. Thus, our findings reveal.a novel.signal.ng mechanism that enhances osteobl.st-to-osteocyte transition by direct phosphoryl.tion of PTH1R by IGF1R.

关键词： Parathyroid hormone Phosphoryl.ted PTH1R phosphoryl.ted-PTH1R