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1.
AJNR Am J Neuroradiol ; 44(3): 283-290, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36797033

RESUMO

BACKGROUND AND PURPOSE: Tractography of the corticospinal tract is paramount to presurgical planning and guidance of intraoperative resection in patients with motor-eloquent gliomas. It is well-known that DTI-based tractography as the most frequently used technique has relevant shortcomings, particularly for resolving complex fiber architecture. The purpose of this study was to evaluate multilevel fiber tractography combined with functional motor cortex mapping in comparison with conventional deterministic tractography algorithms. MATERIALS AND METHODS: Thirty-one patients (mean age, 61.5 [SD, 12.2] years) with motor-eloquent high-grade gliomas underwent MR imaging with DWI (TR/TE = 5000/78 ms, voxel size = 2 × 2 × 2 mm3, 1 volume at b = 0 s/mm2, 32 volumes at b = 1000 s/mm2). DTI, constrained spherical deconvolution, and multilevel fiber tractography-based reconstruction of the corticospinal tract within the tumor-affected hemispheres were performed. The functional motor cortex was enclosed by navigated transcranial magnetic stimulation motor mapping before tumor resection and used for seeding. A range of angular deviation and fractional anisotropy thresholds (for DTI) was tested. RESULTS: For all investigated thresholds, multilevel fiber tractography achieved the highest mean coverage of the motor maps (eg, angular threshold = 60°; multilevel/constrained spherical deconvolution/DTI, 25% anisotropy threshold = 71.8%, 22.6%, and 11.7%) and the most extensive corticospinal tract reconstructions (eg, angular threshold = 60°; multilevel/constrained spherical deconvolution/DTI, 25% anisotropy threshold = 26,485 mm3, 6308 mm3, and 4270 mm3). CONCLUSIONS: Multilevel fiber tractography may improve the coverage of the motor cortex by corticospinal tract fibers compared with conventional deterministic algorithms. Thus, it could provide a more detailed and complete visualization of corticospinal tract architecture, particularly by visualizing fiber trajectories with acute angles that might be of high relevance in patients with gliomas and distorted anatomy.


Assuntos
Neoplasias Encefálicas , Glioma , Córtex Motor , Humanos , Pessoa de Meia-Idade , Tratos Piramidais/diagnóstico por imagem , Tratos Piramidais/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/patologia , Imagem de Tensor de Difusão/métodos , Córtex Motor/patologia , Glioma/diagnóstico por imagem , Glioma/cirurgia , Glioma/patologia
2.
Phys Rev Lett ; 121(2): 022002, 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30085700

RESUMO

We compute the leading, strong-interaction contribution to the anomalous magnetic moment of the electron, muon, and tau using lattice quantum chromodynamics (QCD) simulations. Calculations include the effects of u, d, s, and c quarks and are performed directly at the physical values of the quark masses and in volumes of linear extent larger than 6 fm. All connected and disconnected Wick contractions are calculated. Continuum limits are carried out using six lattice spacings. We obtain a_{e}^{LO-HVP}=189.3(2.6)(5.6)×10^{-14}, a_{µ}^{LO-HVP}=711.1(7.5)(17.4)×10^{-10} and a_{τ}^{LO-HVP}=341.0(0.8)(3.2)×10^{-8}, where the first error is statistical and the second is systematic.

3.
Nervenarzt ; 89(6): 648-657, 2018 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-29679126

RESUMO

BACKGROUND: Adult spinal deformity (ASD) is mostly a progressive disease which usually leads to chronic pain. Due to increased prevalence in older people many patients suffer from comorbidities, which make conservative and surgical treatment even more complex. OBJECTIVE: This article provides an overview on the current conservative and surgical treatment options. MATERIAL AND METHODS: An extensive literature search was carried out via Medline plus an additional evaluation of the authors' personal experiences was performed. RESULTS: The current conservative and surgical treatments are outlined and potential risk factors and predictors which may lead to inferior clinical outcome are discussed. CONCLUSION: Patients for whom even conservative treatment leads to success should be identified earlier and better. The surgical treatment ranges from minimally invasive decompression to multilevel fusions. Complications in large corrective interventions can be substantial but if the indications are correctly assessed, such complex surgical treatment has excellent clinical results in terms of pain and quality of life.


Assuntos
Procedimentos Neurocirúrgicos , Doenças da Coluna Vertebral , Descompressão Cirúrgica , Humanos , Dor , Qualidade de Vida , Doenças da Coluna Vertebral/cirurgia , Resultado do Tratamento
4.
Orthopade ; 47(6): 483-488, 2018 06.
Artigo em Alemão | MEDLINE | ID: mdl-29632972

RESUMO

BACKGROUND: Anterior cervical discectomy and fusion (ACDF) as well as posterior instrumentation of the cervical spine are frequently performed surgeries for cervical disc prolapse or spinal stenosis. Surgery itself harbors a very low risk of adverse events. Postoperative palsy of the C5 nerve root, however, is a severe complication and its origin is still not fully understood. The risk of such a C5 palsy is reported to be between 0 and 30%; 5% on average according to the literature. OBJECTIVES: To describe underlying pathomechanisms and to recommend strategies for risk reduction. MATERIALS AND METHODS: An extensive literature research via Medline was performed. RESULTS: Potential risk factors are male gender, sagittal diameter below 5.6 mm, anterior approach, and higher age. CONCLUSIONS: Currently available data only originates from retrospective or anatomical studies. A prospective register study with the goal to put light on the pathogenesis is currently being performed.


Assuntos
Vértebras Cervicais , Paralisia , Fusão Vertebral , Descompressão Cirúrgica , Humanos , Masculino , Estudos Prospectivos , Estudos Retrospectivos
5.
Nervenarzt ; 88(12): 1402-1410, 2017 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-28956079

RESUMO

Migraine as primary headache is a life-long disease which is relevant for the quality of life and is based on complex genetics. It often starts in childhood with symptoms typical for the specific age. These show different nuances compared to the migraine symptoms in adults, for example, regarding (bilateral/unilateral) localization of the acute migraine headache. Only over the course of years-during adolescence and young adulthood-do the more specific symptoms as defined by the International Classification of Headache Disorders (ICHD 3 beta) develop. In this article we focus on the clinical specifics of children and adolescents with migraine. We elaborately refer to the trigeminocervical complex (TCC) because it forms a conceptual bridge for the understanding of migraine, for psychoeducation, and for therapeutic options. We pragmatically discuss options and limits of treatments.


Assuntos
Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/fisiopatologia , Músculos do Pescoço/fisiopatologia , Analgésicos/uso terapêutico , Terapia Combinada , Traumatismos Craniocerebrais/complicações , Traumatismos Craniocerebrais/fisiopatologia , Diagnóstico Diferencial , Humanos , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/terapia , Fatores de Risco , Estimulação Magnética Transcraniana , Nervo Trigêmeo/fisiopatologia
6.
Phys Rev Lett ; 117(8): 082001, 2016 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-27588847

RESUMO

In a previous Letter [Borsanyi et al., Phys. Rev. Lett. 111, 252001 (2013)] we determined the isospin mass splittings of the baryon octet from a lattice calculation based on N_{f}=2+1 QCD simulations to which QED effects have been added in a partially quenched setup. Using the same data we determine here the corrections to Dashen's theorem and the individual up and down quark masses. Our ensembles include 5 lattice spacings down to 0.054 fm, lattice sizes up to 6 fm, and average up-down quark masses all the way down to their physical value. For the parameter which quantifies violations to Dashen's theorem, we obtain ϵ=0.73(2)(5)(17), where the first error is statistical, the second is systematic, and the third is an estimate of the QED quenching error. For the light quark masses we obtain, m_{u}=2.27(6)(5)(4) and m_{d}=4.67(6)(5)(4) MeV in the modified minimal subtraction scheme at 2 GeV and the isospin breaking ratios m_{u}/m_{d}=0.485(11)(8)(14), R=38.2(1.1)(0.8)(1.4), and Q=23.4(0.4)(0.3)(0.4). Our results exclude the m_{u}=0 solution to the strong CP problem by more than 24 standard deviations.

7.
Orthopade ; 45(9): 732-7, 2016 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-27541352

RESUMO

BACKGROUND: Post-nucleotomy syndrome includes all existing sequelae after surgical nucleotomy for the resection of a lumbar disc herniation, such as axial lumbar back pain and persisting radiculopathy. OBJECTIVES: To describe underlying pathologies and to determine operative treatment options. MATERIALS AND METHODS: Extensive literature research was carried out on Medline. RESULTS: Various devices and approaches have been developed in the last decades. Nonetheless, surgical and non-surgical therapy of post-nucleotomy syndrome remains complex and frequently fails. CONCLUSIONS: Better studies providing a better level of evidence for each sub-entity of post-nucleotomy syndrome are required.


Assuntos
Descompressão Cirúrgica/métodos , Síndrome Pós-Laminectomia/diagnóstico , Síndrome Pós-Laminectomia/cirurgia , Laminectomia/métodos , Medição da Dor/métodos , Fusão Vertebral/métodos , Terapia Combinada/métodos , Discotomia/efeitos adversos , Discotomia/métodos , Medicina Baseada em Evidências , Síndrome Pós-Laminectomia/etiologia , Humanos , Manejo da Dor/métodos , Resultado do Tratamento
8.
Phys Rev Lett ; 116(17): 172001, 2016 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-27176514

RESUMO

We present a QCD calculation of the u, d, and s scalar quark contents of nucleons based on 47 lattice ensembles with N_{f}=2+1 dynamical sea quarks, 5 lattice spacings down to 0.054 fm, lattice sizes up to 6 fm, and pion masses down to 120 MeV. Using the Feynman-Hellmann theorem, we obtain f_{ud}^{N}=0.0405(40)(35) and f_{s}^{N}=0.113(45)(40), which translates into σ_{πN}=38(3)(3) MeV, σ_{sN}=105(41)(37) MeV, and y_{N}=0.20(8)(8) for the sigma terms and the related ratio, where the first errors are statistical and the second errors are systematic. Using isospin relations, we also compute the individual up and down quark contents of the proton and neutron (results in the main text).

9.
Chirurg ; 87(3): 202-7, 2016 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-26779646

RESUMO

Non-fusion spinal implants are designed to reduce the commonly occurring risks and complications of spinal fusion surgery, e.g. long duration of surgery, high blood loss, screw loosening and adjacent segment disease, by dynamic or movement preserving approaches. This principle could be shown for interspinous spacers, cervical and lumbar total disc replacement and dynamic stabilization; however, due to the continuing high rate of revision surgery, the indications for surgery require as much attention and evidence as comparative data on the surgical technique itself.


Assuntos
Próteses e Implantes , Doenças da Coluna Vertebral/cirurgia , Parafusos Ósseos , Vértebras Cervicais/cirurgia , Humanos , Vértebras Lombares/cirurgia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Reoperação , Fatores de Risco , Fusão Vertebral/instrumentação , Estenose Espinal/cirurgia
10.
Science ; 347(6229): 1452-5, 2015 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-25814578

RESUMO

The existence and stability of atoms rely on the fact that neutrons are more massive than protons. The measured mass difference is only 0.14% of the average of the two masses. A slightly smaller or larger value would have led to a dramatically different universe. Here, we show that this difference results from the competition between electromagnetic and mass isospin breaking effects. We performed lattice quantum-chromodynamics and quantum-electrodynamics computations with four nondegenerate Wilson fermion flavors and computed the neutron-proton mass-splitting with an accuracy of 300 kilo-electron volts, which is greater than 0 by 5 standard deviations. We also determine the splittings in the Σ, Ξ, D, and Ξcc isospin multiplets, exceeding in some cases the precision of experimental measurements.

11.
Phys Rev Lett ; 113(5): 052301, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-25126910

RESUMO

Recent results for moments of multiplicity distributions of net protons and net-electric charge from the STAR Collaboration are compared to lattice QCD results for higher order fluctuations of baryon number and electric charge by the Wuppertal-Budapest Collaboration, with the purpose of extracting the freeze-out temperature and chemical potential. All lattice simulations are performed for a system of 2+1 dynamical quark flavors, at the physical mass for light and strange quarks; all results are continuum extrapolated. We show that it is possible to extract an upper value for the freeze-out temperature, as well as precise baryochemical potential values corresponding to the four highest collision energies of the experimental beam energy scan. Consistency between the freeze-out parameters obtained from baryon number and electric charge fluctuations is found. The freeze-out chemical potentials are now in agreement with the statistical hadronization model.

12.
Acta Neurochir (Wien) ; 156(2): 415-9; discussion 419, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24322583

RESUMO

BACKGROUND: The optic nerve within the optic canal, the parophthalmic segment of the carotid artery, and the oculomotor nerve in the superior orbital fissure all lay against the anterior clinoid process. Bone resection uncovers these structures. METHOD: For extradural resection of the anterior clinoid process and surrounding bone, two key steps are recommended: bony opening of the superior orbital fissure, and transection of the orbitotemporal periosteal fold. CONCLUSION: Anterior clinoidectomy is technically challenging. Following a sequence of surgical steps to expose clearly-defined surgical landmarks helps to make this procedure simple and safe. KEY POINTS: • Pterional craniotomy • Complete extradural anterior clinoidectomy • Slit dura (3 mm) to drain cerebrospinal fluid • Peel dura from orbital roof and lateral wall • Bony opening of superior orbital fissure to use it as surgical corridor • Drilling of optic canal • Transection of orbitotemporal periosteal fold • Hollow anterior clinoid process and piece-meal resection • Transection of falciforme ligament to free optic nerve • Replace falciforme ligament by extradural free pericranial flap.


Assuntos
Procedimentos Neurocirúrgicos , Nervo Óptico/cirurgia , Órbita/cirurgia , Osso Esfenoide/cirurgia , Craniotomia/métodos , Humanos , Aneurisma Intracraniano/cirurgia , Procedimentos Neurocirúrgicos/métodos
13.
Phys Rev Lett ; 111(6): 062005, 2013 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-23971565

RESUMO

We present our results for ratios of higher order fluctuations of electric charge as functions of the temperature. These results are obtained in a system of 2+1 quark flavors at physical quark masses and continuum extrapolated. We compare them to preliminary data on higher order moments of the net electric charge distribution from the STAR collaboration. This allows us to determine the freeze-out temperature and chemical potential from first principles. We also show continuum-extrapolated results for ratios of higher order fluctuations of baryon number. These will allow us to test the consistency of the approach, by comparing them to the corresponding experimental data (once they become available) and thus, extracting the freeze-out parameters in an independent way.

14.
Phys Rev Lett ; 111(25): 252001, 2013 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-24483739

RESUMO

While electromagnetic and up-down quark mass difference effects on octet baryon masses are very small, they have important consequences. The stability of the hydrogen atom against beta decay is a prominent example. Here, we include these effects by adding them to valence quarks in a lattice QCD calculation based on Nf=2+1 simulations with five lattice spacings down to 0.054 fm, lattice sizes up to 6 fm, and average up-down quark masses all the way down to their physical value. This allows us to gain control over all systematic errors, except for the one associated with neglecting electromagnetism in the sea. We compute the octet baryon isomultiplet mass splittings, as well as the individual contributions from electromagnetism and the up-down quark mass difference. Our results for the total splittings are in good agreement with experiment.

15.
Mol Hum Reprod ; 18(9): 442-50, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22505054

RESUMO

Recurrent pregnancy loss (RPL) occurs in ∼5% of women. However, the etiology is still poorly understood. Defects in decidualization of the endometrium during early pregnancy contribute to several pregnancy complications, such as pre-eclampsia and intrauterine growth restriction (IUGR), and are believed to be important in the pathogenesis of idiopathic RPL. We performed microarray analysis to identify gene expression alterations in the deciduas of idiopathic RPL patients. Control patients had one antecedent term delivery, but were undergoing dilation and curettage for current aneuploid miscarriage. Gene expression differences were evaluated using both pathway and gene ontology (GO) analysis. Selected genes were validated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). A total of 155 genes were found to be significantly dysregulated in the deciduas of RPL patients (>2-fold change, P < 0.05), with 22 genes up-regulated and 133 genes down-regulated. GO analysis linked a large percentage of genes to discrete biological functions, including immune response (23%), cell signaling (18%) and cell invasion (17.1%), and pathway analysis revealed consistent changes in both the interleukin 1 (IL-1) and IL-8 pathways. All genes in the IL-8 pathway were up-regulated while genes in the IL-1 pathway were down-regulated. Although both pathways can promote inflammation, IL-1 pathway activity is important for normal implantation. Additionally, genes known to be critical for degradation of the extracellular matrix, including matrix metalloproteinase 26 and serine peptidase inhibitor Kazal-type 1, were also highly up-regulated. In this first microarray approach to decidual gene expression in RPL patients, our data suggest that dysregulation of genes associated with cell invasion and immunity may contribute significantly to idiopathic recurrent miscarriage.


Assuntos
Aborto Habitual/genética , Aborto Habitual/imunologia , Decídua/metabolismo , Implantação do Embrião/genética , Regulação da Expressão Gênica no Desenvolvimento , Adulto , Movimento Celular/genética , Decídua/citologia , Regulação para Baixo , Endométrio/imunologia , Endométrio/metabolismo , Feminino , Retardo do Crescimento Fetal , Perfilação da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/imunologia , Interleucina-1/genética , Interleucina-8/genética , Metaloproteinases da Matriz/biossíntese , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Pré-Eclâmpsia , Gravidez , Complicações na Gravidez/genética , Proteínas Secretadas Inibidoras de Proteinases/biossíntese , Regulação para Cima
17.
Science ; 322(5905): 1224-7, 2008 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-19023076

RESUMO

More than 99% of the mass of the visible universe is made up of protons and neutrons. Both particles are much heavier than their quark and gluon constituents, and the Standard Model of particle physics should explain this difference. We present a full ab initio calculation of the masses of protons, neutrons, and other light hadrons, using lattice quantum chromodynamics. Pion masses down to 190 mega-electron volts are used to extrapolate to the physical point, with lattice sizes of approximately four times the inverse pion mass. Three lattice spacings are used for a continuum extrapolation. Our results completely agree with experimental observations and represent a quantitative confirmation of this aspect of the Standard Model with fully controlled uncertainties.

18.
Nervenarzt ; 74(7): 581-6, 2003 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-12940243

RESUMO

Due to cultural and social barriers, immigrants seldom frequent centers for information, counseling, and treatment of addictive disorders. We examine cultural differences in the explanatory models of addictive behavior among Turkish and German youths in Germany with statistical devices that map the concepts associated with problems of addiction. Relevant differences were found between the disorder concepts of Turkish and German youth. German but not Turkish youths classified eating disorders among severe addictive disorders and associated them with embarrassment and shame. Concerning substance abuse, German but not Turkish youths clearly differentiated between illegal drug abuse and the abuse of alcohol and nicotine. Nearly half of all Turkish youths rejected central medical concepts such as "physical dependence" or "reduced control of substance intake" as completely inadequate to characterize problems of addictive behavior. Preventive information programs must consider these differences and use concepts that are accepted and clearly associated with addictive behavior by immigrant populations.


Assuntos
Atitude Frente a Saúde , Comportamento Aditivo/psicologia , Comparação Transcultural , Emigração e Imigração , Etnicidade/psicologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adolescente , Comportamento Aditivo/prevenção & controle , Comportamento Aditivo/reabilitação , Análise por Conglomerados , Emigração e Imigração/estatística & dados numéricos , Etnicidade/estatística & dados numéricos , Transtornos da Alimentação e da Ingestão de Alimentos/prevenção & controle , Transtornos da Alimentação e da Ingestão de Alimentos/psicologia , Transtornos da Alimentação e da Ingestão de Alimentos/reabilitação , Feminino , Alemanha , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle , Transtornos Relacionados ao Uso de Substâncias/reabilitação , Turquia/etnologia
19.
Mol Endocrinol ; 15(11): 1971-82, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11682627

RESUMO

Recently, proteinase inhibitor 9 (PI-9) was identified as the first endogenous inhibitor of caspase 1 (IL-1beta-converting enzyme). The regulation of PI-9 expression, therefore, has great importance in the control of inflammatory processes. We reported that PI-9 mRNA and protein are rapidly and directly induced by estrogen in human liver cells. Using transient transfections to assay PI-9 promoter truncations and mutations, we demonstrate that this strong estrogen induction is mediated by a unique downstream estrogen responsive unit (ERU) approximately 200 nucleotides downstream of the transcription start site. Using primers flanking the ERU in chromatin immunoprecipitation assays, we demonstrate estrogen-dependent binding of ER to the cellular PI-9 promoter. The ERU consists of an imperfect estrogen response element (ERE) palindrome immediately adjacent to a direct repeat containing two consensus ERE half-sites separated by 13 nucleotides (DR13). In transient transfections, all four of the ERE half-sites in the imperfect ERE and in the DR13 were important for estrogen inducibility. Transfected chicken ovalbumin upstream transcription factor I and II down-regulated estrogen-mediated expression from the ERU. EMSAs using purified recombinant human ERalpha demonstrate high-affinity binding of two ER complexes to the ERU. Further EMSAs showed that one ER dimer binds to an isolated DR13, supporting the view that one ER dimer binds to the imperfect ERE and one ER dimer binds to DR13. Deoxyribonuclease I footprinting showed that purified ER protected all four of the half-sites in the ERU. Our finding that a direct repeat can function with an imperfect ERE palindrome to confer estrogen inducibility on a native gene extends the repertoire of DNA sequences able to function as EREs.


Assuntos
Caspase 1/metabolismo , Estrogênios/metabolismo , Receptores de Esteroides , Elementos de Resposta , Serpinas/genética , Serpinas/metabolismo , Fator I de Transcrição COUP , Fatores de Transcrição COUP , Caspase 1/efeitos dos fármacos , Inibidores de Caspase , Células Cultivadas , Cromatina/metabolismo , Pegada de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Desoxirribonuclease I/genética , Desoxirribonuclease I/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Estrogênios/farmacologia , Humanos , Fígado/citologia , Mutação , Regiões Promotoras Genéticas , Serpinas/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Sítio de Iniciação de Transcrição
20.
J Biol Chem ; 275(8): 5867-73, 2000 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-10681578

RESUMO

Although liver is an estrogen target tissue, the number of hepatic genes known to be directly induced by estrogen is very small. We identified proteinase inhibitor 9, or PI-9, as being rapidly and strongly induced by estrogen in an estrogen receptor-positive human liver cell line (HepG2-ER7). Since PI-9 mRNA was also induced by estrogen in a human liver biopsy sample, PI-9 is a genuine estrogen-regulated human gene. PI-9 is a potent inhibitor of granzyme B and of granzyme B-mediated apoptosis. Estrogens induced PI-9 mRNA within 2 h, PI-9 mRNA levels reached a plateau of 30-40-fold induction in 4 h, and induction was not blocked by cycloheximide, indicating that induction of PI-9 mRNA is a primary response. The antiestrogen trans-hydroxytamoxifen was a partial agonist for PI-9 mRNA induction, whereas the antiestrogen ICI 182, 780 was a pure antagonist. Western blot analysis showed that estrogen strongly increases PI-9 protein levels. Inhibition of transcription with actinomycin D resulted in identical rates of PI-9 mRNA decay in the presence and absence of estrogen. We isolated genomic clones containing the PI-9 promoter region, identified a putative transcription start site, and carried out transient transfections of PI-9-luciferase reporter gene constructs. The estrogen, moxestrol, elicited a robust induction from the PI-9-luciferase reporter. Mutational inactivation of three potential imperfect estrogen response elements in the PI-9 5'-flanking region had no effect on moxestrol estrogen receptor induction.


Assuntos
Apoptose/efeitos dos fármacos , Estrogênios/farmacologia , Serina Endopeptidases/metabolismo , Serpinas/fisiologia , Sequência de Bases , Northern Blotting , Carcinoma Hepatocelular/metabolismo , Relação Dose-Resposta a Droga , Antagonistas de Estrogênios/farmacologia , Etinilestradiol/análogos & derivados , Etinilestradiol/farmacologia , Regulação da Expressão Gênica , Granzimas , Humanos , Fígado/metabolismo , Dados de Sequência Molecular , Regiões Promotoras Genéticas , RNA Mensageiro/efeitos dos fármacos , Elementos de Resposta , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Inibidores de Serina Proteinase/genética , Inibidores de Serina Proteinase/fisiologia , Serpinas/genética , Fatores de Tempo , Transcrição Gênica/efeitos dos fármacos , Células Tumorais Cultivadas
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