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Ivancovsky et al. propose a novelty-seeking model linking curiosity to creativity. This commentary suggests integrating their work with a stage-based creativity model for additional insights. It also encourages readers to address knowledge gaps identified by the authors, including factors that trigger the pursuit of creative solutions. We aim to refine theory and direct future research to clarify the complex curiosity-creativity relationship.
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Creatividad , Conducta Exploratoria , Humanos , Conducta Exploratoria/fisiología , Modelos PsicológicosRESUMEN
The contemporary art world is conservatively estimated to be a $65 billion USD market that employs millions of human artists, sellers, and collectors globally. Recent attention paid to AI-made art in prestigious galleries, museums, and popular media has provoked debate around how these statistics will change. Unanswered questions fuel growing anxieties. Are AI-made and human-made art evaluated in the same ways? How will growing exposure to AI-made art impact evaluations of human creativity? Our research uses a psychological lens to explore these questions in the realm of visual art. We find that people devalue art labeled as AI-made across a variety of dimensions, even when they report it is indistinguishable from human-made art, and even when they believe it was produced collaboratively with a human. We also find that comparing images labeled as human-made to images labeled as AI-made increases perceptions of human creativity, an effect that can be leveraged to increase the value of human effort. Results are robust across six experiments (N = 2965) using a range of human-made and AI-made stimuli and incorporating representative samples of the US population. Finally, we highlight conditions that strengthen effects as well as dimensions where AI-devaluation effects are more pronounced.
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Arte , Creatividad , Humanos , MuseosRESUMEN
Enclothed cognition refers to the systematic influence that clothes can have on the wearer's feelings, thoughts, and behaviors through their symbolic meaning. It has attracted considerable academic and nonacademic interest, with the 2012 article that coined the phrase cited more than 600 times and covered in more than 160 news outlets. However, a recent high-powered replication failed to replicate one of the original effects. To determine whether the larger body of research on enclothed cognition possesses evidential value and replicable effects, we performed z-curve and meta-analyses using 105 effects from 40 studies across 24 articles (N = 3,789). Underscoring the marked improvement of psychological research practices in the mid-2010s, our results raise concerns about the replicability of early enclothed cognition studies but affirm the evidential value for effects published after 2015. These later studies support the core principle of enclothed cognition-what we wear influences how we think, feel, and act.
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Contributions of specific sleep stages to cognitive processes are increasingly understood. Non-REM sleep is particularly implicated in episodic memory consolidation, whilst REM sleep preferentially consolidates and regulates emotional information, and gives rise to creativity and insight. Dream content reflects these processes: non-REM dreams are more likely to picture episodic memories, whereas REM dreams are more emotional and bizarre. However, across-the-night differences in the memory sources of dream content, as opposed to sleep stage differences, are less well understood. In the present study, 68 participants were awoken from sleep in the early and late night and recorded their dreams and waking-life activities. Early-night dreams were more clearly relatable to (or continuous with) waking life than late-night dreams. Late-night dreams were more emotional-important, more time orientation varied, and more hyperassociative, than early-night dreams. These dream content differences may underlie the mental content that accompanies sleep processes like memory consolidation, emotion-processing, and creativity.
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Sueños , Sueño REM , Emociones , Humanos , Fases del Sueño , VigiliaRESUMEN
RNA-binding nuclear antigens are a major class of self-antigen to which immune tolerance is lost in rheumatic diseases. Serological tolerance to one such antigen, La/Sjögren's syndrome (SS)-B (La), is controlled by CD4(+) T cells. This study investigated peripheral tolerance to human La (hLa) by tracking the fate of hLa-specific CD4(+) T cells expressing the transgenic (Tg) 3B5.8 T cell receptor (TCR) after adoptive transfer into lymphocyte-replete recipient mice expressing hLa as a neo-self-antigen. After initial antigen-specific cell division, hLa-specific donor CD4(+) T cells expressed forkhead box protein 3 (FoxP3). Donor cells retrieved from hLa Tg recipients displayed impaired proliferation and secreted interleukin (IL)-10 in vitro in response to antigenic stimulation. Transfer of highly purified FoxP3-negative donor cells demonstrated that accumulation of hLa-specific regulatory T cells (Treg ) was due primarily to expansion of small numbers of donor Treg . Depletion of recipient plasmacytoid dendritic cells (pDC), but not B cells, severely hampered the accumulation of FoxP3(+) donor Treg in hLa Tg recipients. Recipient pDC expressed tolerogenic markers and higher levels of co-stimulatory and co-inhibitory molecules than B cells. Adoptive transfer of hLa peptide-loaded pDC into mice lacking expression of hLa recapitulated the accumulation of hLa-specific Treg . Blockade of the type 1 interferon (IFN) receptor in hLa Tg recipients of hLa-specific T cells impaired FoxP3(+) donor T cell accumulation. Therefore, peripheral expansion of Treg specific for an RNA-binding nuclear antigen is mediated by antigen-presenting pDC in a type 1 IFN-dependent manner. These results reveal a regulatory function of pDC in controlling autoreactivity to RNA-binding nuclear antigens.
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Autoantígenos/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Interferón Tipo I/metabolismo , Ribonucleoproteínas/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Epítopos de Linfocito T/inmunología , Factores de Transcripción Forkhead/metabolismo , Activación de Linfocitos/inmunología , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Ratones , Ratones Transgénicos , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/metabolismo , Antígeno SS-BRESUMEN
Accurate predictions of nuisance algae responses to algicide exposures are needed to guide management decisions. Copper sorption and responses of Lyngbya wollei (Farlow ex Gomont) Speziale and Dyck were measured in the laboratory and two areas in Lay Lake (AL, USA) to treatments of Captain(®) XTR (SePRO Corporation; chelated copper algicide) and a sequential treatment of GreenClean(®) Liquid (BioSafe Systems, LLC; peroxygen algicide) combined with Hydrothol(®) 191 (United Phosphorus, Inc.; endothall algicide) followed by Captain XTR. Measured filament viability in laboratory exposures predicted Captain XTR alone could control L. wollei in Lay Lake, with 2 mg Cu/g algae EC75. This produced a targeted field treatment of 9.7 kg Cu/ha which was divided into three applications of 0.3 mg Cu/L as Captain XTR in the treatment areas. Laboratory and field experiments indicated treatments of Captain XTR alone and the combination treatment resulted in comparable copper sorption and responses of L. wollei. Copper adsorbed greater to L. wollei in laboratory experiments than in the treated areas of Lay Lake with comparable exposures (2 mg Cu/g L. wollei). However, responses and infused copper were similar and correlated in laboratory experiments and treated areas of Lay Lake indicating infused copper is critical for governing toxicity. Laboratory exposures as mg Cu/g algae accurately predicted the necessary algicide exposure required to attain the critical burden of infused copper and elicit desired responses of L. wollei in treated areas of Lay Lake.
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Cobre/toxicidad , Cianobacterias/efectos de los fármacos , Floraciones de Algas Nocivas/efectos de los fármacos , Herbicidas/toxicidad , Lagos , Cobre/análisis , Ácidos Dicarboxílicos/farmacología , Herbicidas/análisis , North Carolina , Agua/químicaRESUMEN
Mesenchymal stem cells (MSCs) are of therapeutic interest to clinicians and researchers, as they have been shown to augment the osteogenic properties of bone grafts. MSCs are known to be prevalent in bone marrow, but are still limited in numbers. Hence, additional sources of MSCs are beneficial to increasing grafting potential. Aspirate material collected using the Reamer/Irrigator/Aspirator (RIA) device (Synthes; Paoli, PA) during reaming of the femoral shaft consists of three main components: bone fragments, liquid flow-through, and a fat layer. Currently, only the bone and liquid layers have been examined for osteoinductive elements, and the bone fragments are exclusively used as autologous bone graft. In the present study, a method to promote cellular outgrowth, tapping proliferative capacity from the previously discarded fatty layer of RIA aspirate, is described. Proliferating cells were successfully isolated from the bone and fatty layers of a consenting patient and found to be viable after liquid nitrogen storage. The osteogenic differentiation potential of the cells isolated from the fat and bone layers was assessed. Cells from both layers of the aspirate expressed statistically significant levels (p < 0.05) of the bone cell marker alkaline phosphatase compared to the control cells, suggesting differentiation along the osteoblastic pathway. Results from this pilot study indicate that the traditionally discarded fatty element of RIA aspirate may be a source of MSCs with bone-forming capabilities and the described isolation technique is effective. Combining the aspirate fatty and bony elements may enhance the clinical success of the RIA autograft.
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Tejido Adiposo/patología , Regeneración Ósea/fisiología , Trasplante Óseo , Fémur/patología , Tejido Adiposo/metabolismo , Adulto , Biopsia con Aguja , Trasplante Óseo/métodos , Calcio/metabolismo , Separación Celular , Células Cultivadas , Humanos , Masculino , Osteogénesis/fisiología , Proyectos PilotoRESUMEN
The aim of the present study was to investigate if prolonged status epilepticus (SE), secondary to a chemoconvulsant, can induce spontaneous recurrent seizures in dogs. Clinical records at two UK referral hospitals were searched for dogs that presented in SE secondary to intoxication. Dogs were only included in the study if there was clear historical evidence of intoxication and a prolonged SE. Clinical and follow-up information was retrieved and verified by using a combination of clinical records from the two hospitals and the referring veterinarian and by contacting the owners using a telephone questionnaire. Twenty dogs met the inclusion criteria: 17 presented for metaldehyde toxicity, one for moxidectin toxicity, one for theobromine toxicity and one for mycotoxin toxicity. Of these 20 dogs, three dogs had an SE duration between 0.5 and one hour, four dogs between one and 12 hours, 10 dogs between 12 and 24 hours and three dogs greater then 24 hours. Median follow-up time for the 20 dogs was 757 days (range 66 to 1663 days). No dog had any further seizures after its SE. The present study supports the view that dogs with a prolonged SE following intoxication with the aforementioned toxins might not need long-term treatment with antiepileptic drugs after the SE has been controlled.
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Acetaldehído/análogos & derivados , Enfermedades de los Perros/inducido químicamente , Moluscocidas/envenenamiento , Convulsiones/veterinaria , Estado Epiléptico/veterinaria , Acetaldehído/envenenamiento , Animales , Enfermedades de los Perros/epidemiología , Perros , Femenino , Insecticidas/envenenamiento , Macrólidos/envenenamiento , Masculino , Micotoxinas/envenenamiento , Factores de Riesgo , Convulsiones/inducido químicamente , Convulsiones/epidemiología , Estado Epiléptico/inducido químicamente , Estado Epiléptico/complicaciones , Estado Epiléptico/epidemiología , Reino Unido/epidemiologíaRESUMEN
Current scaffolds for the regeneration of anterior cruciate ligament injuries are unable to capture intricate mechanical and chemical gradients present in the natural ligament-bone interface. As a result, stress concentrations can develop at the scaffold-bone interface, leading to poor osseointegration. Hence, scaffolds that possess appropriate mechano-chemical gradients would help establish normal loading properties at the interface, while promoting scaffold integration with bone. With the long-term goal of investigating regeneration of the ligament-bone interface, this feasibility study aimed to fabricate a continuously graded mesh. Specifically, graded meshes were fabricated by co-electrospinning nanohydroxyapatite/polycaprolactone (nHAP-PCL) and poly(ester urethane) urea elastomer solutions from offset spinnerets. Next, mineral crystallites were selectively deposited on the nHAP-PCL fibers by treatment with a 5× simulated body fluid (5× SBF). X-ray diffraction and energy-dispersive spectroscopy indicated calcium-deficient hydroxyapatite-like mineral crystallites with an average Ca/P ratio of 1.48. Tensile testing demonstrated the presence of a mechanical gradient, which became more pronounced upon treatment with 5× SBF. Finally, biocompatibility of the graded meshes was verified using an MC3T3-E1 osteoprogenitor cell line. The study demonstrates that graded meshes, for potential application in interfacial tissue engineering, can be fabricated by co-electrospinning.
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Huesos , Ligamentos , Modelos Teóricos , Regeneración , Microscopía Electrónica de Rastreo , Difracción de Rayos XRESUMEN
PURPOSE: To compare the effects of pegylated interferon-alpha2b (P-IFN) and interferon-alpha2b (IFN) on quality of life (QoL) and toxicity in patients with multiple myeloma maintained on a steady dose of IFN. PATIENTS AND METHODS: Consenting, eligible myeloma patients on IFN maintenance therapy for at least 6 weeks were randomly (1:1) allocated to receive P-IFN for 3 months followed by IFN for 3 months, or to continue with IFN for 3 months followed by P-IFN for 3 months (cross-over design). Patients were assessed for toxicity and QoL. Dose of P-IFN was equivalent to IFN. RESULTS: The study enrolled 60 patients. At enrollment, 35 patients were in complete remission, 20 in partial remission and 5 were minimal responders. P-IFN was associated with significantly better global QoL score (mean difference 8.4; P = 0.0002). There was a significant improvement in functional scales--physical (P = 0.03), emotional (P = 0.04), social (P = 0.0008) with P-IFN. Fatigue (P = 0.0003), pain (P = 0.02) and appetite loss (P = 0.003) symptom scales were less in patients while on P-IFN. There were no statistically significant differences between treatment arms in QoL as measured by QLQ-MY24. CONCLUSION: These data suggest that patients on P-IFN have a better QoL. Dose escalation studies are warranted to investigate potential impact on survival.
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Antineoplásicos/efectos adversos , Interferón-alfa/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/psicología , Calidad de Vida , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Interferón alfa-2 , Masculino , Persona de Mediana Edad , Polietilenglicoles , Proteínas RecombinantesRESUMEN
The transcription factor NF-kappaB (nuclear factor kappaB) regulates critical cellular processes including the inflammatory response, apoptosis and the cell cycle. Over the past 20 years many of the components of the NF-kappaB signalling pathway have been elucidated along with their functions. Recent research in this field has focused on the dynamic regulation and network control of this system. With key roles in so many important cellular processes, it is critical that NF-kappaB signalling is tightly regulated. Recently, single-cell imaging and mathematical modelling have identified that the timing of cellular responses may play an important role in the regulation of this pathway. p65/RelA (RelA) has been shown to translocate between the nucleus and cytoplasm with varying oscillatory patterns in different cell lines leading to differences in transcriptional outputs from NF-kappaB-regulated genes. Variations in the timing or persistence of these movements may control the maintenance and differential expression of NF-kappaB-regulated genes.
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Proteínas I-kappa B/fisiología , FN-kappa B/fisiología , Células HeLa , Humanos , Cinética , Inhibidor NF-kappaB alfa , FN-kappa B/antagonistas & inhibidores , Oscilometría , Procesamiento Proteico-Postraduccional , Transducción de Señal , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
In vivo and in vitro studies suggest human growth hormone (hGH) receptors on bone marrow stem cells may be biologically active and could be exploited to promote haemopoetic recovery after intensive chemotherapy. Patients with haematological malignancies receiving intensive chemotherapy and requiring hospitalization were randomized in a double-blind, placebo-controlled single-centre trial. Patients were randomly assigned to receive either hGH 500 microg/day or placebo, for 6 weeks. There was no significant difference in patient characteristics at baseline between the placebo and treatment arms. Patients treated with hGH showed significantly faster recovery of platelets to 25 x 10(9)/l (median of 16 versus 19 days; P = 0.03) compared to the placebo-controlled arm (hazard ratio 1.47 favouring hGH, 95% confidence interval (CI), 1.03-2.08). Time to relapse did not differ significantly between arms. There was no change in the anthropometric parameters at the start and end of hGH/placebo therapy. The study drug was well tolerated. Treatment with hGH in physiological doses improves platelet recovery, but is not associated with a lower relapse rate or improved anthropometric parameters in patients receiving intensive chemotherapy.
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Enfermedades Hematológicas/tratamiento farmacológico , Hematopoyesis/efectos de los fármacos , Hormona de Crecimiento Humana/uso terapéutico , Leucemia/terapia , Recuento de Leucocitos , Mieloma Múltiple/terapia , Recuento de Plaquetas , Adolescente , Adulto , Anciano , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Leucemia/patología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Estadificación de Neoplasias , Placebos , Recurrencia , Irradiación Corporal TotalRESUMEN
In all, 451 myeloma patients, 51% previously untreated, underwent elective single autotransplantation after 200 mg/m(2) melphalan between 1985 and 2001 at the Royal Marsden Hospital. The therapy sequence was: Induction (vincristine, doxorubicin, methylprednisolone+/-cyclophosphamide), marrow or filgrastim-mobilized blood stem cell harvest, autograft, and interferon-alpha2b maintenance. A total of 27 (6%) died of transplant-related toxicity, all within 3 months. Complete or near-complete remission was seen in 59% with an overall response rate of 91%. Subsequent disease progression was seen in 285, and 17 died of unrelated causes. In all, 206 patients were alive at the last follow-up, 6 months to 17.7 years post-transplant (median 65 months); 122 without disease progression at 6 months to 17.7 years (median 58 months). The median overall (OS) and event-free (EFS) survivals were 5.9 and 2.4 years, with 10-year OS and EFS probabilities of 31.4 and 16.5%, respectively. In Cox analysis, it was seen that significantly longer OS occurred for patients who had beta-2-microglobulin <3.5 mg/l (P<0.0001), age <60 years (P=0.001) and albumin > or =35 g/l (P=0.009). EFS was also longer if beta-2-microglobulin was <3.5 mg/l (P=0.0056) and patients were <60 years of age (P=0.033). We conclude that with a single planned autograft, patients with myeloma have an excellent outcome.
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Trasplante de Células Madre Hematopoyéticas/métodos , Melfalán/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Movilización de Célula Madre Hematopoyética , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Leucaféresis , Masculino , Persona de Mediana Edad , Probabilidad , Pronóstico , Inducción de Remisión/métodos , Análisis de Supervivencia , Trasplante Autólogo , Resultado del TratamientoRESUMEN
Signaling by the transcription factor nuclear factor kappa B (NF-kappaB) involves its release from inhibitor kappa B (IkappaB) in the cytosol, followed by translocation into the nucleus. NF-kappaB regulation of IkappaBalpha transcription represents a delayed negative feedback loop that drives oscillations in NF-kappaB translocation. Single-cell time-lapse imaging and computational modeling of NF-kappaB (RelA) localization showed asynchronous oscillations following cell stimulation that decreased in frequency with increased IkappaBalpha transcription. Transcription of target genes depended on oscillation persistence, involving cycles of RelA phosphorylation and dephosphorylation. The functional consequences of NF-kappaB signaling may thus depend on number, period, and amplitude of oscillations.
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Regulación de la Expresión Génica , FN-kappa B/metabolismo , Transducción de Señal , Transporte Activo de Núcleo Celular , Línea Celular Tumoral , Núcleo Celular/metabolismo , Simulación por Computador , Citoplasma/metabolismo , Etopósido/farmacología , Retroalimentación Fisiológica , Células HeLa , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Modelos Biológicos , Inhibidor NF-kappaB alfa , Fosforilación , Proteínas Recombinantes de Fusión/metabolismo , Factor de Transcripción ReIA , Transcripción Genética , Transfección , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
The role of autologous stem cell transplantation in adult patients with acute myeloid leukaemia (AML) in first remission is unclear, yet it has become standard treatment for myeloma and this paper explores whether the source of transplanted stem cells may explain this paradox. In total, 57 patients from the Royal Marsden Hospital who received an unpurged bone marrow transplant (ABMT) were matched with 114 patients from the EBMT registry who had undergone peripheral blood stem cell transplantation (PBSCT). Patients were matched for karyotype, FAB type, remission-autograft interval and age. In the PBSCT group, haematopoietic recovery was significantly faster and nonrelapse mortality at 4 years was significantly lower (13 vs 1%, P=0.04). The relapse rate and overall survival at 4 years (20 vs 31% and 77 vs 63%) were also better with PBSCT, although the differences were not statistically significant. Autografting should be reassessed in a randomised trial for first remission AML patients using peripheral blood as a source of stem cells rather than bone marrow.
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Trasplante de Médula Ósea/estadística & datos numéricos , Leucemia Mieloide/terapia , Trasplante de Células Madre de Sangre Periférica/estadística & datos numéricos , Enfermedad Aguda , Hematopoyesis , Humanos , Cariotipificación , Análisis por Apareamiento , Probabilidad , Recurrencia , Sistema de Registros , Inducción de Remisión , Tasa de Supervivencia , Factores de Tiempo , Trasplante AutólogoRESUMEN
Expression of the gonadotropin genes has been shown to be modulated by pharmacological or physiological activators of both the protein kinase C (PKC) and the cAMP second messenger signaling pathways. Over the past few years, a substantial amount of progress has been made in the identification and characterization of the transcription factors and cognate cis-elements which mediate the PKC response in the LH beta-subunit (LHbeta) gene. In contrast, little is known regarding the molecular mechanisms which mediate cAMP-mediated regulation of this gene. Using pituitary cell lines, we now demonstrate that rat LHbeta gene promoter activity is stimulated following activation of the cAMP system by the adenylate cyclase activating agent, forskolin, or by the peptide, pituitary adenylate cyclase-activating peptide. The forskolin response was eliminated with mutation of a previously identified 3' cis-acting element for the early growth response protein-1 (Egr-1) when evaluated in the context of region -207/+5 of the LHbeta gene. Activation of the cAMP system increased Egr-1 gene promoter activity, Egr-1 protein levels and Egr-1 binding to the LHbeta gene promoter, supporting the role of this transcription factor in mediating the cAMP response. Analysis of a longer LHbeta promoter construct (-797/+5) revealed additional contribution by upstream Sp1 DNA-regulatory regions. Of interest, forskolin-induced stimulation of LHbeta gene promoter activity was observed to increase synergistically with introduction of the transcription factor, steroidogenic factor-1 (SF-1). Although SF-1 is a critical mediator of the cAMP response in other genes, mutation of the SF-1 DNA-binding sites in the rat LHbeta gene did not alter the forskolin response nor did forskolin increase SF-1 protein levels in a gonadotrope cell line. In a further set of experiments, it was determined that forskolin-responsiveness was maintained following mutation of the previously defined homeobox-binding element at position -100. We conclude that both Egr-1 and Sp1 contribute to cAMP-dependent transcription of the rat LHbeta gene promoter. While SF-1 does not act independently to mediate the cAMP/PKA response, SF-1 is important for magnification of this response.
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AMP Cíclico/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas Inmediatas-Precoces/metabolismo , Hormona Luteinizante de Subunidad beta/metabolismo , Proteínas Quinasas/metabolismo , Factores de Transcripción/metabolismo , Adenilil Ciclasas/metabolismo , Animales , Células Cultivadas , Colforsina/farmacología , Proteína 1 de la Respuesta de Crecimiento Precoz , Ensayo de Cambio de Movilidad Electroforética , Activación Enzimática/efectos de los fármacos , Regulación de la Expresión Génica , Proteínas de Homeodominio , Ratones , Hipófisis/metabolismo , Regiones Promotoras Genéticas/genética , Proteína Quinasa C/metabolismo , Ratas , Receptores Citoplasmáticos y Nucleares , Factor Esteroidogénico 1RESUMEN
The gene coding for alcohol acetyltransferase ( ATF2), which catalyzes the esterification of isoamyl alcohol and acetyl coenzyme A (acetyl-CoA), was cloned from Saccharomyces cerevisiae and expressed in Escherichia coli. This genetically engineered strain of E. coli produced the ester isoamyl acetate when isoamyl alcohol was added externally to the cell culture medium. Various competing pathways at the acetyl-CoA node were inactivated to increase the intracellular acetyl-CoA pool and divert more carbon flux to the ester synthesis pathway. Several strains with deletions in the ackA-pta and/or ldh pathways and bearing the ATF2 on a high-copy-number plasmid were constructed and studied. Compared to the wild-type, ackA-pta and nuo mutants produced higher amounts of ester and an ackA-pta-ldh-nuo mutant lower amounts. Isoamyl acetate production correlated well with intracellular coenzyme A (CoA) and acetyl-CoA levels. The ackA-pta-nuo mutant had the highest intracellular CoA/acetyl-CoA level and hence produced the highest amount of ester (1.75 mM) during the growth phase under oxic conditions and during the production phase under anoxic conditions.
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Acetiltransferasas/genética , Acetiltransferasas/metabolismo , Escherichia coli/enzimología , Escherichia coli/genética , Pentanoles/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Acetato Quinasa/genética , Acetato Quinasa/metabolismo , Biotransformación , Clonación Molecular , Escherichia coli/crecimiento & desarrollo , Eliminación de Gen , Expresión Génica , Genes Bacterianos , Genes Fúngicos , L-Lactato Deshidrogenasa/genética , L-Lactato Deshidrogenasa/metabolismo , Mutación , Fosfato Acetiltransferasa/genética , Fosfato Acetiltransferasa/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
Thalidomide was used to treat acute (n=21) or chronic (n=59) graft-vs-host disease (GVHD) in 80 haematopoietic stem cell allograft recipients after failure to respond to the combination of cyclosporine and corticosteroids with or without other agents. The median time to onset of acute GVHD was 11 days, and thalidomide was started at a median of 48 days post transplant. In addition to corticosteroids and cyclosporine, 13 patients had also received other agents before thalidomide. None of the patients responded and all died of acute GVHD. For chronic GVHD (limited in 13, extensive in 46), thalidomide was started at a median of 385 days post transplant. In addition to corticosteroids and cyclosporine, 34 patients received azathioprine concomitantly. In all patients, thalidomide was added to the ongoing immunosuppressive regimen. The median duration of therapy with thalidomide was 60 days (range, 11-1210; <2 weeks in 11). In total, 13 patients (22%) had complete response, eight (14%) partial response and 38 (64%) no response. Response rates were comparable for limited (39%) and extensive (33%) chronic GVHD. At a median of 53 months, 19 patients are alive, 13 without evidence of chronic GVHD. Survival was significantly better in patients who responded to thalidomide. The principal causes of death were progressive chronic GVHD (n=29) and relapsed leukaemia (n=7). In conclusion, thalidomide has no activity in acute GVHD, but has some activity in chronic GVHD in combination with other agents.
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Enfermedad Injerto contra Huésped/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Talidomida/uso terapéutico , Enfermedad Aguda , Adolescente , Corticoesteroides/uso terapéutico , Adulto , Niño , Preescolar , Enfermedad Crónica , Ciclosporina/uso terapéutico , Femenino , Enfermedad Injerto contra Huésped/mortalidad , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Análisis de Supervivencia , Trasplante HomólogoRESUMEN
We have shown that primary therapy with non-myeloablative (140 mg/m(2)) high-dose melphalan (HDM) without hematopoietic support results in high response rates in untreated myeloma and very long-term survival of some patients. This study was designed to see if sufficient CD34 (+) cells can be harvested at presentation in newly diagnosed patients to administer myeloablative HDM (200 mg/m(2); HDM200) with autograft as primary therapy. This may improve outcome by rapid achievement of complete remission (CR) and possible avoidance of late myelodysplasia as a consequence of non-transplant induction chemotherapy. Thirty untreated patients received 1 g/m(2) methylprednisolone daily (days 1-6) and 12-16 micro g/kg G-CSF daily (days 3-6), and underwent leukapheresis on days 6 and 7. The median CD34(+) cell yield was 1.31 x10(6)/kg (range, 0.23-5.63), and was > or =1 x10(6)/kg in 73%. Cell yields were significantly lower than in 82 historical controls apheresed after completion of induction chemotherapy (median 2.16 x 10(6)/kg), and improved in patients who were apheresed again after induction chemotherapy. Three patients received primary therapy with HDM200 and autograft using these cells and attained CR. We conclude that it is possible to harvest stem cells in three-quarters of untreated myeloma patients. Increasing the number of apheresis procedures is needed to improve the number of CD34(+) cells collected.
Asunto(s)
Leucaféresis , Mieloma Múltiple/terapia , Trasplante de Células Madre de Sangre Periférica/métodos , Adulto , Anciano , Antígenos CD34 , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Recuento de Células , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Movilización de Célula Madre Hematopoyética , Humanos , Masculino , Melfalán/administración & dosificación , Metilprednisolona/administración & dosificación , Persona de Mediana Edad , Trasplante Autólogo/métodos , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
Of the 61 newly diagnosed patients with Bence-Jones (BJ) myeloma presenting to our centre between May 1986 and December 1997, 53 received sequential therapy (ST) comprising infusional chemotherapy (IC) followed by high-dose therapy and autotransplantation with interferon-alpha2b maintenance. The outcome was compared with 153 IgG and 39 IgA similarly treated myeloma patients. Response to IC and high-dose was comparable between the three subtypes but a significantly higher proportion of patients with BJ myeloma failed to receive high-dose compared to IgG (P = 0.003) and IgA (P = 0.04) myeloma. Median overall survival (OS) of patients with BJ myeloma (2.8 years) and event-free survival (EFS, 1.2 years) was significantly shorter than for patients with IgG myeloma (4.5 years, P = 0.03 and 2.1 years, P = 0.03, respectively). However, among those patients who achieved complete remission there was no difference in OS and EFS between IgG and BJ myeloma. In distinction to IgG myeloma where age and beta2M were significant, Cox analysis on presentation features identified performance status and urine total protein as having significant impact on OS. We conclude that achieving CR is an important treatment aim in patients with BJ myeloma, conferring a similar outlook on survival as in patients with the IgG subtype, and there is a need to consider different subtype-specific staging systems when evaluating the results of published or ongoing therapeutic trials.