RESUMEN
In this observational study, we assessed treatment patterns and prognostic factors in patients with small cell lung cancer (SCLC) in a large state-mandated healthcare organization in Israel. Methods: All incident cases with histologically confirmed SCLC who initiated systemic anti-cancer treatment between 2011 and 2017 were identified. Treatment patterns and overall survival (OS) were evaluated for each line of therapy. Results: A total of 235 patients were identified (61% male, median age 64 years, 95% ever smokers, 64% had extensive stage). The first-line treatment was platinum-etoposide regimen for 98.7% of the cohort. The second and third-line regimen were given to 43% and 12% of patients, respectively. Mean OS for extensive and limited stage patients was 9.1 and 23.5 months respectively. In a multivariable model, increased risk for mortality was observed among patients with an ECOG performance status (PS) of 2 compared to a PS of 0-1 for the extensive stage patients (Hazard ratio (HR) = 1.63, 95% confidence ratios (CI): 1.00-2.65); and for males compared to females for the limited stage patients (HR = 2.17; 95% CI: 1.12-4.20). Regarding all 2nd line patients in a multivariable model incorporating relevant confounding factors, demonstrated a significantly better outcome with platinum-based regimens compared to topotecan. Median survival after initiation of 2nd line in platinum-sensitive patients was longer (p = 0.056) for those re-challenged with platinum-based regimen (n = 7): 6.8mo (6.1-not reported (NR)), compared with those switched to a different treatment (n = 27): 4.5 mo (2.6-6.6) for extensive stage patients, and a non-significant difference was also observed for limited stage patients. Conclusion: To our knowledge, this is one of the largest real-world studies of SCLC patients. OS for SCLC patients was similar to that reported in clinical trials. PS for extensive stage patients and sex for limited stage patients were significant correlates of prognosis. Re-challenge of the platinum-based doublet was associated with longer OS compared to switching treatment in extensive stage patients.
Asunto(s)
Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Selective serotonin reuptake inhibitors (SSRIs) show anti-inflammatory effects, suggesting a possible interaction with both Toll-like-receptor 4 (TLR4) responses and cholinergic signaling through as yet unclear molecular mechanism(s). Our results of structural modeling support the concept that the antidepressant fluoxetine physically interacts with the TLR4-myeloid differentiation factor-2 complex at the same site as bacterial lipopolysaccharide (LPS). We also demonstrate reduced LPS-induced pro-inflammatory interleukin-6 and tumor necrosis factor alpha in human peripheral blood mononuclear cells preincubated with fluoxetine. Furthermore, we show that fluoxetine intercepts the LPS-induced decreases in intracellular acetylcholinesterase (AChE-S) and that AChE-S interacts with the nuclear factor kappa B (NFκB)-activating intracellular receptor for activated C kinase 1 (RACK1). This interaction may prevent NFκB activation by residual RACK1 and its interacting protein kinase PKCßII. Our findings attribute the anti-inflammatory properties of SSRI to surface membrane interference with leukocyte TLR4 activation accompanied by intracellular limitation of pathogen-inducible changes in AChE-S, RACK1, and PKCßII.
Asunto(s)
Acetilcolinesterasa/metabolismo , Antiinflamatorios/farmacología , Fluoxetina/farmacología , Proteínas de Unión al GTP/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores de Superficie Celular/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Acetilcolinesterasa/química , Secuencia de Aminoácidos , Sitios de Unión , Proteínas Ligadas a GPI/química , Proteínas Ligadas a GPI/metabolismo , Proteínas de Unión al GTP/química , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolisacáridos/farmacología , Simulación del Acoplamiento Molecular , Datos de Secuencia Molecular , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Proteínas de Neoplasias/química , Unión Proteica , Proteína Quinasa C beta/metabolismo , Receptores de Cinasa C Activada , Receptores de Superficie Celular/química , Receptor Toll-Like 4/química , Receptor Toll-Like 4/metabolismoRESUMEN
Ischaemic stroke patients treated with Selective Serotonin Reuptake Inhibitors (SSRI) show improved motor, cognitive and executive functions, but the underlying mechanism(s) are incompletely understood. Here, we report that cerebral arterioles in the rat brain superfused with therapeutically effective doses of the SSRI fluoxetine showed consistent, dose-dependent vasodilatation (by 1.2 to 1.6-fold), suppressible by muscarinic and nitric oxide synthase (NOS) antagonists [atropine, NG-nitro-l-arginine methyl ester (l-NAME)] but resistant to nicotinic and serotoninergic antagonists (mecamylamine, methylsergide). Fluoxetine administered 10-30 min. following experimental vascular photo-thrombosis increased arterial diameter (1.3-1.6), inducing partial, but lasting reperfusion of the ischaemic brain. In brain endothelial b.End.3 cells, fluoxetine induced rapid muscarinic receptor-dependent increases in intracellular [Ca(2+) ] and promoted albumin- and eNOS-dependent nitric oxide (NO) production and HSP90 interaction. In vitro, fluoxetine suppressed recombinant human acetylcholinesterase (rhAChE) activity only in the presence of albumin. That fluoxetine induces vasodilatation of cerebral arterioles suggests co-promotion of endothelial muscarinic and nitric oxide signalling, facilitated by albumin-dependent inhibition of serum AChE.
Asunto(s)
Arteriolas/efectos de los fármacos , Corteza Cerebral/irrigación sanguínea , Fluoxetina/farmacología , Óxido Nítrico/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Vasodilatación/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Animales , Arteriolas/fisiología , Atropina/farmacología , Calcio/metabolismo , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Proteínas HSP90 de Choque Térmico/metabolismo , Masculino , Mecamilamina/farmacología , Metisergida/farmacología , Antagonistas Muscarínicos/provisión & distribución , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Muscarínicos/metabolismo , Reperfusión , Serotonina/metabolismo , Transducción de Señal/efectos de los fármacos , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Vasodilatación/fisiologíaRESUMEN
Exercise and inherited factors both affect recovery from stroke and head injury, but the underlying mechanisms and interconnections between them are yet unknown. Here, we report that similar cation channels mediate the protective effect of exercise and specific genetic background in a kainate injection model of cerebellar stroke. Microinjection to the cerebellum of the glutamatergic agonist, kainate, creates glutamatergic excito\xE2\x80\x90toxicity characteristic of focal stroke, head injury or alcoholism. Inherited protection and prior exercise were both accompanied by higher cerebellar expression levels of the Kir6.1 ATP-dependent potassium channel in adjacent Bergmann glia, and voltage-gated KVbeta2 and cyclic nucleotide-gated cation HCN1 channels in basket cells. Sedentary FVB/N and exercised C57BL/6 mice both expressed higher levels of these cation channels compared to sedentary C57BL/6 mice, and were both found to be less sensitive to glutamate toxicity. Moreover, blocking ATP-dependent potassium channels with Glibenclamide enhanced kainate-induced cell death in cerebellar slices from the resilient sedentary FVB/N mice. Furthermore, exercise increased the number of acetylcholinesterase-positive fibres in the molecular layer, reduced cerebellar cytokine levels and suppressed serum acetylcholinesterase activity, suggesting anti-inflammatory protection by enhanced cholinergic signalling. Our findings demonstrate for the first time that routine exercise and specific genetic backgrounds confer protection from cerebellar glutamatergic damages by similar molecular mechanisms, including elevated expression of cation channels. In addition, our findings highlight the involvement of the cholinergic anti-inflammatory pathway in insult-inducible cerebellar processes. These mechanisms are likely to play similar roles in other brain regions and injuries as well, opening new venues for targeted research efforts.
Asunto(s)
Cerebelo/metabolismo , Canales Catiónicos Regulados por Nucleótidos Cíclicos/metabolismo , Canales KATP/metabolismo , Canales de Potasio/metabolismo , Canales de Potasio de la Superfamilia Shaker/metabolismo , Accidente Cerebrovascular/metabolismo , Animales , Cerebelo/efectos de los fármacos , Cerebelo/fisiopatología , Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Agonistas de Aminoácidos Excitadores/toxicidad , Perfilación de la Expresión Génica , Glutamatos/metabolismo , Gliburida/farmacología , Humanos , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Inyecciones Intraventriculares , Canales KATP/antagonistas & inhibidores , Canales KATP/genética , Ácido Kaínico/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Condicionamiento Físico Animal , Canales de Potasio/genética , Receptores de Glutamato/genética , Receptores de Glutamato/metabolismo , Canales de Potasio de la Superfamilia Shaker/antagonistas & inhibidores , Canales de Potasio de la Superfamilia Shaker/genética , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/fisiopatología , Regulación hacia ArribaRESUMEN
BACKGROUND: The circulating cholinesterases acetyl- and butyrylcholinesterase may be suppressed and subsequently released from the brain in acute bacterial meningitis. METHODS: We report serum activities of acetylcholinesterase and butyrylcholinesterase in paired arterial and jugular venous samples from seven patients with acute bacterial meningitis and eight healthy controls. Paraoxonase 1, which protects these enzymes from oxidative inactivation, was also measured. FINDINGS AND CONCLUSION: Acetyl- and butyrylcholinesterase activities were lower in patients, independently of changes in paraoxonase 1. Arterial and jugular venous enzyme activities were similar both in patients and controls, suggesting that no cerebral release was present.
Asunto(s)
Acetilcolinesterasa/sangre , Butirilcolinesterasa/sangre , Meningitis Bacterianas/sangre , Enfermedad Aguda , Arildialquilfosfatasa/sangre , Biomarcadores/sangre , Estudios de Casos y Controles , Humanos , Meningitis Bacterianas/diagnóstico , PronósticoRESUMEN
To date there is no diagnostic biomarker for mild stroke, although elevation of inflammatory biomarkers has been reported at early stages. Previous studies implicated acetylcholinesterase (AChE) involvement in stroke, and circulating AChE activity reflects inflammatory response, since acetylcholine suppresses inflammation. Therefore, carriers of polymorphisms that modify cholinergic activity should be particularly susceptible to inflammatory damage. Our study sought diagnostic values of AChE and Cholinergic Status (CS, the total capacity for acetylcholine hydrolysis) in suspected stroke patients. For this purpose, serum cholinesterase activities, butyrylcholinesterase-K genotype and inflammatory biomarkers were determined in 264 ischemic stroke patients and matched controls during the acute phase. AChE activities were lower (P<0.001), and butyrylcholinesterase activities were higher in patients than in controls (P=0.004). When normalized to sampling time from stroke occurrence, both cholinergic parameters were correlated with multiple inflammatory biomarkers, including fibrinogen, interleukin-6 and C-reactive protein (r=0.713, r=0.607; r=0.421, r=0.341; r=0.276, r=0.255; respectively; all P values<0.001). Furthermore, very low AChE activities predicted subsequent nonsurvival (P=0.036). Also, carriers of the unstable butyrylcholinesterase-K variant were more abundant among patients than controls, and showed reduced activity (P<0.001). Importantly, a cholinergic score combining the two cholinesterase activities discriminated between 94.3% matched pairs of patients and controls, compared with only 75% for inflammatory measures. Our findings present the power of circulation cholinesterase measurements as useful early diagnostic tools for the occurrence of stroke. Importantly, these were considerably more distinctive than the inflammatory biomarkers, albeit closely associated with them, which may open new venues for stroke diagnosis and treatment.
Asunto(s)
Acetilcolinesterasa/sangre , Butirilcolinesterasa/sangre , Inflamación/sangre , Accidente Cerebrovascular/enzimología , Acetilcolina/sangre , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Butirilcolinesterasa/genética , Estudios de Casos y Controles , Biología Computacional , Análisis Discriminante , Femenino , Humanos , Mediadores de Inflamación/sangre , Masculino , Persona de Mediana Edad , Especificidad de Órganos , Valor Predictivo de las Pruebas , Factores de Riesgo , Accidente Cerebrovascular/sangreRESUMEN
Inflammatory cytokines and the cholinergic system have been implicated in the effects of stressors on mood and memory; however, the underlying mechanisms involved and the potential interrelationships between these pathways remain unclear. To address these questions, we administered neuropsychological tests to 33 generally healthy surgery patients who donated blood samples several days prior to undergoing moderate surgery (baseline), on the morning of the surgery (i.e., a psychological stressor), and one day after surgery. Eighteen control subjects were similarly tested. Serum levels of inflammatory cytokines, acetylcholinesterase (AChE) activity, and the stressor-inducible AChE-R variant were measured. An elevation in anxiety levels, an increase in depressed mood, and a decline in declarative memory were observed on the morning of the surgery, prior to any medical intervention, and were exacerbated one day after surgery. The surgical stressor-induced elevated IL-1 beta levels, which contributed to the increased depressed mood and to the post-surgery increase in AChE-R expression. The latter increase, which was also predicted by pre-surgery AChE-R and post-surgery mood disturbances, was associated with exacerbated memory impairments induced by surgery. In addition, elevated levels of AChE-R on the morning of the surgery predicted the post-surgery elevation in IL-6 levels, which was associated with amelioration of the memory impairments induced by surgery. Taken together, these findings suggest that exposure to a surgical stressor induces a reciprocal up-regulation of AChE-R and pro-inflammatory cytokines, which are involved in regulating the surgery-induced mood and memory disturbances.
Asunto(s)
Acetilcolinesterasa/metabolismo , Afecto , Citocinas/metabolismo , Memoria , Receptores de Superficie Celular/metabolismo , Transducción de Señal , Estrés Psicológico/psicología , Procedimientos Quirúrgicos Operativos/efectos adversos , Adulto , Anciano , Cognición , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Persona de Mediana Edad , Modelos Biológicos , Regulación hacia ArribaRESUMEN
BACKGROUND: Factors affecting acetylcholine-mediated neurotransmission have been proposed as possible explanations for physical and mental health symptoms among veterans of the 1990-1991 Gulf War. This study was designed to examine relationships of deployment to the Gulf, as well as symptoms after military service, with postdeployment activity of acetylcholinesterase (AChE) and related enzymes. METHODS: The patient population included 488 veterans, originally from Iowa at enlistment, who served in the US military during August 1990 to July 1991. Demographic, military, and clinical characteristics were obtained from a population-based cohort study (in 1995-1996) and from a nested case-control study (in 1999-2002). Stored serum samples (from the 1999-2002 assessment) were analyzed for activity of AChE and related enzymes. These two data sources were merged, and multiple linear regression models estimated the association of deployment, stress (anxiety) or mood disorders, and symptoms compatible with Gulf War veterans' illnesses (GWVIs), with enzyme activity. RESULTS: Seventy-four percent (n = 361) of veterans had been deployed to the Gulf. At the time of evaluation, 23% (n = 113) of participants reported anxiety and 15% (n = 71) reported mood disorders; 49% (n = 171 of 347 eligible veterans) had symptoms of GWVIs, and the median AChE activity was 839 units. AChE activity was similar for compared groups across all categories, including an adjusted difference of -27 units (p = .50) for deployed versus nondeployed veterans and 87 units (p = .13) for veterans with versus without symptoms of GWVIs. CONCLUSIONS: Neither deployment to the Gulf nor symptoms compatible with GWVIs are associated with long-term serum AChE activity.
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Acetilcolinesterasa/metabolismo , Guerra del Golfo , Personal Militar , Síndrome del Golfo Pérsico/enzimología , Trastornos de Estrés Traumático/enzimología , Veteranos , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Humor/enzimología , Síndrome del Golfo Pérsico/psicología , Estados UnidosRESUMEN
Cholinergic Status, the total soluble circulation capacity for acetylcholine hydrolysis, was tested for putative involvement in individual variabilities of the recruitment of immune cells in response to endotoxin challenge. Young (average age 26) and elderly (average age 70) volunteers injected with either Escherichia coli endotoxin or saline on two different occasions were first designated Enhancers and Suppressors if they showed increase or decrease, respectively, in plasma acetylcholinesterase (AChE) activity 1.5 h after endotoxin administration compared to saline. Enhancers showed significant co-increases in plasma butyrylcholinesterase (BChE) and paraoxonase (PON1) activities, accompanied by rapid recovery of lymphocyte counts. Young Enhancers alone showed pronounced post-exposure increases in the pro-inflammatory cytokine interleukin-6 (IL-6), and upregulation of the normally rare, stress-induced AChE-R variant, suggesting age-associated exhaustion of the cholinergic effects on recruiting innate immune reactions to endotoxin challenge. Importantly, IL-6 injected to young volunteers or administered in vitro to primary mononuclear blood cells caused upregulation of AChE, but not BChE or PON1, excluding it from being the sole cause for this extended response. Interestingly, Suppressors but not Enhancers showed improved post-exposure working memory performance, indicating that limited cholinergic reactions may be beneficial for cognition. Our findings establish Cholinergic Status modulations as early facilitators and predictors of individual variabilities in the peripheral response to infection.
Asunto(s)
Colina/metabolismo , Inflamación/metabolismo , Acetilcolinesterasa/genética , Acetilcolinesterasa/metabolismo , Enfermedad Aguda , Adulto , Anciano , Atención/efectos de los fármacos , Biomarcadores/metabolismo , Butirilcolinesterasa/metabolismo , Endotoxinas/farmacología , Humanos , Inmunidad Innata/efectos de los fármacos , Interleucina-6/administración & dosificación , Interleucina-6/farmacología , Masculino , Memoria/efectos de los fármacos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: Peripheral anionic site (PAS) blockade of acetylcholinesterase (AChE) notably affects neuronal activity and cyto-architecture, however, the mechanism(s) involved are incompletely understood. OBJECTIVE: We wished to specify the PAS extracellular effects on specific AChE mRNA splice variants, delineate the consequent cellular remodeling events, and explore the inhibitory effects on interchanging RACK1 interactions. METHODS: We exposed rat hippocampal cultured neurons to BW284C51, the peripheral anionic site inhibitor of AChE, and to the non-selective AChE active site inhibitor, physostigmine for studying the neuronal remodeling of AChE mRNA expression and trafficking. RESULTS: BW284C51 induced overexpression of both AChE splice variants, yet promoted neuritic translocation of the normally rare AChE-R, and retraction of AChE-S mRNA in an antisense-suppressible manner. BW284C51 further caused modest decreases in the expression of the scaffold protein RACK1 (receptor for activated protein kinase betaII), followed by drastic neurite retraction of both RACK1 and the AChE homologue neuroligin1, but not the tubulin-associated MAP2 protein. Accompanying BW284C51 effects involved decreases in the Fyn kinase and membrane insertion of the glutamate receptor NR2B variant and impaired glutamatergic activities of treated cells. Intriguingly, molecular modeling suggested that direct, non-catalytic competition with Fyn binding by the RACK1-interacting AChE-R variant may be involved. CONCLUSIONS: Our findings highlight complex neuronal AChE-R/RACK1 interactions and are compatible with the hypothesis that peripheral site AChE inhibitors induce RACK1-mediated neuronal remodeling, promoting suppressed glutamatergic neurotransmission.