RESUMO
Notch is a highly conserved transmembrane protein that is involved in cell fate decisions and is found in organisms ranging from Drosophila to humans. A human homologue of Notch, TAN1, was initially identified at the chromosomal breakpoint of a subset of T-cell lymphoblastic leukemias/lymphomas containing a t(7;9) chromosomal translocation; however, its role in oncogenesis has been unclear. Using a bone marrow reconstitution assay with cells containing retrovirally transduced TAN1 alleles, we analyzed the oncogenic potential of both nuclear and extranuclear forms of truncated TAN1 in hematopoietic cells. Although the Moloney leukemia virus long terminal repeat drives expression in most hematopoietic cell types, retroviruses encoding either form of the TAN1 protein induced clonal leukemias of exclusively immature T cell phenotypes in approximately 50% of transplanted animals. All tumors overexpressed truncated TAN1 of the size and subcellular localization predicted from the structure of the gene. These results show that TAN1 is an oncoprotein and suggest that truncation and overexpression are important determinants of transforming activity. Moreover, the murine tumors caused by TAN1 in the bone marrow transplant model are very similar to the TAN1-associated human tumors and suggest that TAN1 may be specifically oncotropic for T cells.
Assuntos
Transplante de Medula Óssea , Medula Óssea/patologia , Leucemia de Células T/patologia , Linfoma de Células T/patologia , Proteínas de Membrana/biossíntese , Receptores de Superfície Celular , Fatores de Transcrição , Animais , Células da Medula Óssea , Cromossomos Humanos Par 7 , Cromossomos Humanos Par 9 , Drosophila , Proteínas de Drosophila , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Leucemia de Células T/genética , Linfoma de Células T/genética , Camundongos , Vírus da Leucemia Murina de Moloney/genética , Receptor Notch1 , Receptores Notch , Sequências Repetitivas de Ácido Nucleico , Deleção de Sequência , Translocação Genética , Transplante Isogênico , Integração ViralRESUMO
The purpose of this multicenter trial was to compare the antihypertensive efficacy and safety of losartan potassium (losartan), a selective angiotensin II receptor antagonist, when added to hydrochlorothiazide in hypertensive patients whose blood pressure was not adequately controlled by 25 mg hydrochlorothiazide monotherapy. After a 4-week monotherapy period of 25 mg hydrochlorothiazide, 304 patients with trough (22 to 26 hours postdose) sitting diastolic pressure between 93 and 120 mm Hg were maintained on 25 mg hydrochlorothiazide and randomized double-blind into treatment arms consisting of either 25, 50, or 100 mg losartan or placebo once daily for 12 weeks. The reductions in sitting diastolic pressure for patients treated with 25, 50, or 100 mg losartan concomitantly administered with 25 mg hydrochlorothiazide were significantly greater (P < or = .05) than the reductions observed in the 25 mg hydrochlorothiazide plus placebo group beginning 1 week after randomization. The antihypertensive response in all groups was greater at week 3 than week 1, with some additional decrease in blood pressure in some groups at later times. Sitting systolic pressures were also significantly reduced in each group over time. Standing blood pressures at week 12 were similar to sitting blood pressures. A dose-response relationship to losartan was observed in this patient population. The percentages of the total drug-related clinical adverse experiences as assessed by the investigator were generally similar in the 25, 50, and 100 mg losartan plus 25 mg hydrochlorothiazide groups (10.3%, 24.4%, and 20.0%, respectively) compared with the placebo plus 25 mg hydrochlorothiazide group (24.7%).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Angiotensina II/antagonistas & inibidores , Antagonistas de Receptores de Angiotensina , Anti-Hipertensivos/uso terapêutico , Compostos de Bifenilo/administração & dosagem , Hidroclorotiazida/administração & dosagem , Hipertensão/tratamento farmacológico , Imidazóis/administração & dosagem , Tetrazóis/administração & dosagem , Anti-Hipertensivos/farmacologia , Compostos de Bifenilo/farmacologia , Diástole/efeitos dos fármacos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Hidroclorotiazida/farmacologia , Imidazóis/farmacologia , Losartan , Masculino , Pessoa de Meia-Idade , Postura , Potássio/sangue , Sístole/efeitos dos fármacos , Tetrazóis/farmacologia , Fatores de Tempo , Ácido Úrico/sangueRESUMO
The objective of this study was to determine the incidence of dry cough in hypertensive patients with a history of angiotensin-converting enzyme (ACE) inhibitor-induced cough after treatment with losartan (an angiotensin II-receptor antagonist), lisinopril (an ACE inhibitor), or placebo. One hundred patients from 16 outpatient treatment centers in the United States were included in this double-masked, randomized, parallel-group, active- and placebo-controlled study, with stratification according to sex. After a challenge phase with lisinopril and a placebo washout phase, patients were randomly allocated to receive losartan 50 mg once daily, lisinopril 20 mg once daily, or placebo for a maximum of 8 weeks. The primary efficacy end point of the study was the presence or absence of dry cough during the double-masked period, as rated by the patient at each visit using a validated symptom assessment questionnaire. A secondary end point was the frequency of dry cough, as measured at each visit using a visual analogue scale (VAS). The incidence of dry cough was significantly higher in the lisinopril group than in the losartan and placebo groups (87.5% vs 36.7% and 31.4%, respectively) at the end of the double-masked treatment period; there was no statistically significant difference between the losartan and placebo groups. Mean VAS scores showed that patients treated with lisinopril rated themselves as having a significantly higher frequency of cough than did patients treated with losartan or placebo (4.0 vs 1.2 and 1.5, respectively). Again, the difference between the losartan and placebo groups was not statistically significant. All treatments were otherwise well tolerated, and no serious clinical or laboratory adverse events were reported during the double-masked phase of the study. These results demonstrate that the incidence, severity, and frequency of dry cough in patients with a history of ACE inhibitor-induced dry cough are significantly lower in those treated with losartan than in those treated with lisinopril and are similar to the incidence, severity, and frequency of dry cough in those receiving placebo.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Tosse/induzido quimicamente , Hipertensão/tratamento farmacológico , Losartan/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
It is known that equilibrium thermodynamics can be deduced from a constrained Fisher information extemizing process. We show here that, more generally, both nonequilibrium and equilibrium thermodynamics can be obtained from such a Fisher treatment. Equilibrium thermodynamics corresponds to the ground-state solution, and nonequilibrium thermodynamics corresponds to excited-state solutions, of a Schrödinger wave equation (SWE). That equation appears as an output of the constrained variational process that extremizes Fisher information. Both equilibrium and nonequilibrium situations can thereby be tackled by one formalism that clearly exhibits the fact that thermodynamics and quantum mechanics can both be expressed in terms of a formal SWE, out of a common informational basis. As an application, we discuss viscosity in dilute gases.
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As recently shown, a constrained Fisher-information extremizing (CFIE) process is able to deal with both equilibrium and nonequilibrium thermodynamic processes, thus being able to reproduce results deduced by a recourse to Boltzmann's transport equation (BTE). Here, we discuss the propagation of sound waves in a dilute gas and compare the ensuing CFIE solutions with those obtained by a recourse to Grad's approach to the BTE. The final molecular distribution function arrived at is the same following two alternative routes, either (i) the BTE via the Grad approach or (ii) the constrained Fisher treatment that does not require the use of the BTE. The way the necessary a priori information is used in these two instances, is however, quite different.
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We describe an optical interconnection method based on self-pumped phase-conjugate mirrors in which each connection weight is distributed among many angularly and spatially multiplexed gratings. This approach greatly reduces cross talk caused by the conical Bragg degeneracy associated with a single grating and permits the entire input plane to be used. Applications to optical neural networks are described.
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This introduction briefly defines the scope of the feature in this 10 May 1990 issue on optical computing.
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We discuss an optical interconnection method for neural networks based on mutually pumped phase conjugation in a photorefractive crystal. Cross talk due to Bragg degeneracies is reduced by storing each connection weight in a continuum of angularly and spatially multiplexed volume gratings.
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An optical system, which divides two arrays in real time, has been conceived and demonstrated for the first time to our knowledge. The pixel-by-pixel division, performed with analog signals, treats two incoherently illuminated arrays in parallel. The configuration used is a feedback arrangement with the data introduced in the loop through two optical image converters (liquid-crystal light valves in our experiments). Analysis of the circuit and experimental results are presented.
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Some basic effects of population genetics are derived governing the occurrences of alleles A(i)and genotypes A(i)A(j)among its members. A principle of extreme physical information (EPI) is used. These effects are (1) the equation of genetic change, (2) Fisher's theorem of partial change, (3) a new uncertainty principle, and (4) the monotonic decrease of Fisher information with time, indicating increased disorder for the population. General conditions of population change are allowed: fitness coefficients w(ij)generally changing with time [except in effect (2)], population randomly or non-randomly mating, and a general number of loci present within each chromosome. EPI is a practical tool for deriving probability laws. It is an outgrowth of a physical process that occurs during any act of measurement. Here the measurement is the random observation of a genotype A(i)A(j). This observation is to be used to estimate the time of the observation, called "evolutionary time". The measurement activity incurs errors in the estimated observation time and fitness value of the observed genotype. By the Cramer-Rao inequality, the product of the two uncertainties must exceed unity [effect (3)]. The Fisher information I in data space is postulated to originate in the space of the genotype where it had some generally larger value J. The EPI principle extremizes the loss of information (I--J) with I=1/2 J. The solution gives rise to effects (1) and (2). Finally, it is shown that effect (4) holds when the population approaches an equilibrium state, e.g. for time values greater than a threshold if fitness coefficients w(ij)are constant. EPI provides a common framework for deriving physical laws and laws of population genetics. The new effects (3) and (4) are confirmed through computer simulation.
Assuntos
Simulação por Computador , Genética Populacional , Modelos Genéticos , Animais , Frequência do Gene , GenótipoRESUMO
This feature of Applied Optics: Information Processing on optical computing comprises thirty papers. Most of the papers evolved from papers presented at the Fifth Topical Meeting on Optical Computing held in March 1993 in Palm Springs, California.
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We present experimental results from an all-optical associative memory that combines holography and phase conjugation. The device has the capability to recall a complete image when merely a portion of the stored image is input to the system. Multiple superimposed two-dimensional images with gray scale can be stored and recalled. In addition, we have demonstrated the system's invariance to translation of the input images.
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We describe a shift-invariant all-optical holographic associative memory implemented using phase conjugate mirrors and Fourier transform holograms. A key feature of our system is the large storage capacity obtained through the use of nonlinearities in the correlation domain. The use of angularly multiplexed plane wave reference beams allows access to the correlation domain where nonlinearities in the phase conjugate mirrors can be used to reduce greatly crosstalk and correlation noise.
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It is shown that the Legendre-transform structure of thermodynamics can be replicated without any change if one replaces the entropy S by Fisher's information measure I. Also, the important thermodynamic property of concavity is shown to be obeyed by I. By this use of the Fisher information measure we develop a thermodynamics that seems to be able to treat equilibrium and nonequilibrium situations in a manner entirely similar to the conventional one.
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Parallel logarithmic filtering of multiplicatively combined image signals is achieved in real time. A liquid-crystal light valve (LCLV) is combined with a specially designed halftone screen that matches the LCLV characteristics to produce an overall logarithmic transformation. Experimental results are shown.
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The principal features of the liquid-crystal molecular orientation within the variable-grating-mode liquid-crystal device have been determined as a function of the applied voltage across the cell by measurement of the polarization properties of light diffracted by the liquid-crystal birefringent phase grating.
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Chest pain and submaximal exercise testing were prospectively assessed over a 6-month period, for detecting the evolution of restenosis in patients undergoing percutaneous coronary angioplasty, following either acute myocardial infarction or treatment of an anginal syndrome. Seventy-eight patients with one-vessel coronary artery disease underwent a modified treadmill exercise test at the 1-week, 3-month and 6-month follow-up after angioplasty, when a final angiogram was also performed. Forty-four patients (group A) were examined after myocardial infarction; in 34 patients (group B) angioplasty was done for incapacitating angina. Both groups showed similar results with low sensitivity and relatively moderate specificity of both chest pain and exercise tests; this was also the case for the time of restenosis to occur. It is thus concluded that the parameters examined are somewhat limited markers of restenosis following coronary angioplasty.
Assuntos
Angina Pectoris/terapia , Angioplastia Coronária com Balão , Eletrocardiografia , Teste de Esforço , Infarto do Miocárdio/terapia , Adulto , Idoso , Angina Pectoris/diagnóstico , Angina Pectoris/fisiopatologia , Angiografia Coronária , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/fisiopatologia , Recidiva , Função Ventricular Esquerda/fisiologiaRESUMO
Expression of the 210-kD bcr/abl fusion oncoprotein can cause a chronic myelogenous leukemia (CML)-like disease in mice receiving bone marrow cells transduced by bcr/abl-encoding retroviruses. However, previous methods failed to yield this disease at a frequency sufficient enough to allow for its use in the study of CML pathogenesis. To overcome this limitation, we have developed an efficient and reproducible method for inducing a CML-like disease in mice receiving P210 bcr/abl-transduced bone marrow cells. All mice receiving P210 bcr/abl-transduced bone marrow cells succumb to a myeloproliferative disease between 3 and 5 weeks after bone marrow transplantation. The myeloproliferative disease recapitulates many of the hallmarks of human CML and is characterized by high white blood cell counts and extensive extramedullary hematopoiesis in the spleen, liver, bone marrow, and lungs. Use of a retroviral vector coexpressing P210 bcr/abl and green fluorescent protein shows that the vast majority of bcr/abl-expressing cells are myeloid. Analysis of the proviral integration pattern shows that, in some mice, the myeloproliferative disease is clonal. In multiple mice, the CML-like disease has been transplantable, inducing a similar myeloproliferative syndrome within 1 month of transfer to sublethally irradiated syngeneic recipients. The disease in many of these mice has progressed to the development of acute lymphoma/leukemia resembling blast crisis. These results demonstrate that murine CML recapitulates important features of human CML. As such, it should be an excellent model for addressing specific issues relating to the pathogenesis and treatment of this disease.