RESUMEN
A phase 1b/2, three-month study of marstacimab, a human monoclonal antibody targeting tissue factor pathway inhibitor (TFPI), was conducted in participants with haemophilia A or B, with or without inhibitors. Participants assigned to four cohorts received escalating weekly doses based on inhibitor status (without inhibitors: 300 mg, a single 300-mg loading dose with subsequent 150-mg doses, or 450 mg; with inhibitors: 300 mg). Safety outcomes were treatment-emergent adverse events (TEAEs), injection site reactions, clinical and laboratory parameter changes. Efficacy was assessed by annualised bleeding rates (ABRs). Pharmacokinetics and pharmacodynamics (PD) were also evaluated. Among 26 treated participants [haemophilia A without inhibitor, n = 16 (61.5%); haemophilia A with inhibitor, n = 7 (26.9%); haemophilia B, n = 3 (11.5%)], 24 completed the study. Overall, 80.8% experienced TEAEs. ABR during treatment was significantly reduced versus an external on-demand control group (p < 0.0001) and versus pretreatment ABR (p < 0.0001), with significant reductions observed across all dose cohorts. Marstacimab exposure generally increased in a dose-related manner, with steady-state concentration reached by day 57. Changes in pharmacodynamic biomarkers occurred across all dose cohorts. Marstacimab was safe and well tolerated. Clinically meaningful reductions in ABR and treatment-related changes for all PD biomarkers indicated effective targeting of TFPI. (Clinicaltrials.gov identifier, NCT02974855).
Asunto(s)
Hemofilia A , Trastornos de los Cromosomas Sexuales , Humanos , Hemofilia A/tratamiento farmacológico , Hemofilia A/inducido químicamente , Anticuerpos Monoclonales Humanizados/efectos adversos , LipoproteínasRESUMEN
INTRODUCTION: Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of the extrinsic pathway that negatively regulates thrombin production during coagulation. Under haemophilic conditions, where the intrinsic coagulation pathway is impaired, inhibition of TFPI may improve clotting. AIM: We investigated the ex vivo effects of a human TFPI neutralizing antibody, marstacimab (previously PF-06741086), in coagulation assays including rotational thromboelastometry (ROTEM), thrombin generation assay (TGA) and the dilute prothrombin time (dPT) assay, performed in haemophilic whole blood and plasmas. We compared the effects of marstacimab to the effects of recombinant coagulation factors and investigated the reproducibility of marstacimab in restoring haemostasis by comparing its effect in whole blood collected from the same study participants on differing days. METHODS: Citrated whole blood and plasmas obtained from haemophilia participants were supplemented ex vivo with vehicle, marstacimab, recombinant FVIII (rFVIII) or recombinant factor IX (rFIX) and analysed in ROTEM, TGA and the dPT assay using low tissue factor concentrations to trigger coagulation. RESULTS: Marstacimab induced pro-coagulant responses in ROTEM parameters including reduction in clotting times and increases in angle. Similarly, participant plasmas supplemented with marstacimab exhibited improvements in TGA parameters, including reduced lag times, increased peak thrombin concentrations and reductions in dPT clotting time. Concentrations of marstacimab tested showed activity comparable to addition of rFVIII or rFIX and were reproducible. CONCLUSIONS: These studies show the ex vivo potency of marstacimab in restoring haemostasis in whole blood and plasmas from haemophilia participants and comparability to ex vivo reconstitution with recombination coagulation factors.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Coagulación Sanguínea/efectos de los fármacos , Hemofilia A/tratamiento farmacológico , Plasma/metabolismo , Tromboplastina/antagonistas & inhibidores , Anticuerpos Monoclonales Humanizados/farmacología , Femenino , Hemofilia A/patología , Humanos , MasculinoRESUMEN
BACKGROUND AND OBJECTIVES: There is an unmet medical need for additional treatment options for Parkinson's disease. This was a Phase I, double-blind clinical trial assessing safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of the novel dopamine D1 receptor partial agonist, PF-06669571, in subjects with idiopathic Parkinson's disease on a stable dose of L-DOPA. METHODS: Subjects received PF-06669571 (or matching placebo) titrated from 1 mg to 3 mg over 7 days. The primary pharmacodynamic endpoint was the change from baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III total motor score at the pharmacodynamic time of maximum change from baseline on day 7. RESULTS: Twenty subjects were randomized and 19 completed the study. Maximum plasma concentrations (Cmax) of PF-06669571 were reached 3.35 and 3.19 h post-dose on day 1 and day 7. Geometric mean Cmax and area under the plasma concentration-time profile from time 0 to 24 h post-dose on day 7 were 92.51 ng/mL and 1626 ng·h/mL, respectively. The primary pharmacodynamic endpoint did not meet the pre-specified criteria for significant improvement; however, the criteria were met in a sensitivity analysis excluding data from a L-DOPA outlier (L-DOPA dose of 2550 mg/d). The most common adverse events (AEs) were nausea (experienced by 2 subjects each in the PF-06669571 and placebo groups). There were no permanent discontinuations or dose reductions due to AEs. DISCUSSION: Multiple daily doses of PF-06669571 were safe and well tolerated with no notable safety concerns. The pharmacodynamic endpoint did not meet the pre-specified criteria for significant improvement. CLINICALTRIALS. GOV IDENTIFIER: NCT02565628.
Asunto(s)
Agonistas de Dopamina/administración & dosificación , Compuestos Orgánicos/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Agonistas de Dopamina/efectos adversos , Agonistas de Dopamina/farmacocinética , Agonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Levodopa/administración & dosificación , Masculino , Persona de Mediana Edad , Compuestos Orgánicos/efectos adversos , Compuestos Orgánicos/farmacocinética , Compuestos Orgánicos/farmacología , Receptores de Dopamina D1/agonistas , Factores de TiempoRESUMEN
As extensively used chemicals in a variety of consumer products, perfluoroalkyl substances (PFASs) are ubiquitous and could bring significant risk to human health. However, the effect of PFASs on metabolic syndrome (MetS) is not fully understood. In 2015, a preliminary cross-sectional study was undertaken. A total of 148 male subjects including 81 affected by MetS and 67 non-MetS participants as the reference were recruited from Physical Examination Center affiliated to Capital Medical University, China. Serum levels of perfluorohexane sulfonic acid (PFHxS), perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) were significantly higher in the subjects with MetS. Logistic regression results showed that concentration of PFNA in serum was associated with 10.9-fold [95% confidence interval (CI), 2.00-59.1] increased risk of MetS. Moreover, increased serum PFNA concentrations were associated with high blood pressure [both for systolic and diastolic blood pressure (SBP and DBP); odds ratio (OR) 7.52 (95%CI, 1.34-42.1) for SBP and 7.27 (95%CI, 1.17-45.1) for DBP], hypertriglyceridemia [13.2 (95%CI, 2.34-74.2)] and obesity [13.3 (95%CI, 2.38-74.4)], respectively. After adjustment by age in logistic regression models, serum levels of PFOA were associated with 29.4-fold (95%CI, 2.90-299.7) increased risk of MetS. Increased PFOA levels were also correlated with MetS [29.4 (95%CI, 2.9-299.7)], SBP [10.8 (95%CI, 1.31-90.0)], hypertriglyceridemia [16.6 (95%CI, 1.92-147.1)], and obesity [46.7 (95%CI, 4.47-487.7)] with adjustment for age. This study suggests bodily retention of PFASs and its association with MetS. Further clinical and animal studies are warranted to clarify the putative causal relationship.
Asunto(s)
Contaminantes Ambientales/sangre , Fluorocarburos/sangre , Síndrome Metabólico/sangre , Adulto , China , Estudios Transversales , Humanos , Hipertensión/sangre , Hipertrigliceridemia/sangre , MasculinoRESUMEN
Benzene is widely employed in the field of production, and its toxicity on biological systems has received increasing attention. Cell proliferation is a major life characteristic of living organisms. KLF15 and NOTCH1 are mature and classical genes in cell proliferation studies, particularly in the area of tumor investigation. The aim of this study was to investigate the effect and mechanism of VNN3 on cell proliferation induced by 1,4-benzoquinone (1,4-BQ), an important metabolite of benzene, and obtain a sensitive biomarker for the hazard screening and health care of benzene exposure. Normally growing AHH-1 cells were cultured in vitro and were incubated with different concentrations of 1,4-BQ (0, 10, 20, and 40 µM) for 24 h. A CCK-8 assay was used to assess the cell viability, whereas EdU was used to detect the cell proliferation of AHH-1 cells. The expression of VNN3, KLF15 and NOTCH1 was detected by real-time PCR. Moreover, a lentiviral model was constructed in AHH-1 cells to interfere with VNN3 expression. The results showed that 1,4-BQ clearly increased the expression of VNN3. Moreover, 1,4-BQ dose-dependently inhibited cell proliferation and caused increased KLF15 expression; in contrast, the NOTCH1 expression decreased in AHH-1 cells. Furthermore, following interference with the VNN3 expression, the cell proliferation inhibition and the expression of KLF15 and NOTCH1 were rescued. To further investigate the action of VNN3 in benzene hematotoxicity, we assessed it in benzene-exposed workers. The results showed that there was a remarkable correlation between the VNN3 expression and hemogram, which included RBC, NEUT and HGB. In addition, analysis of the KLF15 and NOTCH1 expression showed that the VNN3 expression was related to cell proliferation, which was consistent with the in vitro results. In conclusion, VNN3 influences cell proliferation induced by 1,4-BQ by regulating the expression of KLF15 and NOTCH1. VNN3 may represent a potential biomarker of benzene toxicity.
Asunto(s)
Benceno/toxicidad , Benzoquinonas/toxicidad , Proliferación Celular/efectos de los fármacos , Amidohidrolasas/metabolismo , Biomarcadores/metabolismo , Moléculas de Adhesión Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Proteínas Ligadas a GPI/metabolismo , Humanos , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
LncRNA has been considered to play a crucial role in the progression of several diseases by affecting cell proliferation. However, its role in benzene toxicity remains unclear. Our study showed that the expression of lncRNA-OBFC2A increased accompanied with the change of cell proliferation related-genes in benzene-exposed workers. In vitro experiments, 1,4-Benzoquinone dose-dependently inhibited cell proliferation and simultaneously caused the decrease of NOTCH1 expression and the increase of KLF15 in AHH-1 cell lines. Meanwhile, 1, 4-Benzoquinone obviously increased the expression of lncRNA-OBFC2A, which was consistent with our previous population results. Therefore, we propose that lncRNA-OBFC2A is involved in benzene toxicity by regulating cell proliferation. Further, we successfully constructed a lentivirus model of interfering the expression of lncRNA-OBFC2A. After interfering lncRNA-OBFC2A, the cell proliferation inhibition and the expression of NOTCH1 and KLF15 induced by 1, 4-Benzoquinone were reversed. Subsequently, RNA fluorescence in situ Hybridization assay showed that lncRNA-OBFC2A was located in cell nuclei. These results suggest that benzene and its metabolite decreases cell proliferation via LncRNA-OBFC2A-mediated anti-proliferation effect involving NOTCH1 and KLF15. LncRNA-OBFC2A can be a potential biomarker for benzene toxicity.
Asunto(s)
Benceno/envenenamiento , Factores de Transcripción de Tipo Kruppel/genética , Proteínas Nucleares/genética , ARN Largo no Codificante/genética , Receptor Notch1/genética , Benzoquinonas/envenenamiento , Biomarcadores/análisis , Estudios de Casos y Controles , Proliferación Celular/efectos de los fármacos , Humanos , Enfermedades Profesionales/sangre , Enfermedades Profesionales/inducido químicamente , Enfermedades Profesionales/genética , Enfermedades Profesionales/patología , Exposición Profesional , ARN Largo no Codificante/biosíntesis , TransfecciónRESUMEN
Exposure to benzene is inevitable, and concerns regarding the adverse health effects of benzene have been raised. Most investigators found that benzene exposure induced hematotoxicity. In this regard, Our study aimed to explore a novel potential biomarker of adverse health effects following benzene exposure and the toxic mechanisms of benzene metabolites in vitro. This study consisted of 314 benzene-exposed workers and 288 control workers, an air benzene concentration of who were 2.64 ± 1.60 mg/m3 and 0.05 ± 0.01 mg/m3, respectively. In this population-based study, miR-34a expression was elevated in benzene-exposed workers. The correlation of miR-34a with the airborne benzene concentration, S-phenylmercapturic acid (S-PMA) and trans, trans-muconic acid (t, t-MA), all of which reflect benzene exposure, was found. Correlation analysis indicated that miR-34a was associated with peripheral blood count, alanine transaminase (ALT) and oxidative stress. Furthermore, multivariate analysis demonstrated that miR-34a expression was strongly associated with white blood cell count (structure loadings = 0.952). In population-based study, miR-34a had the largest contribution to altered peripheral blood counts, which reflect benzene-induced hematotoxicity. The role of miR-34a in benzene toxicity was assessed using lentiviral vector transfection. Results revealed that 1,4-benzoquinone induced abnormal cell apoptosis and simultaneously upregulated miR-34a accompanied with decreased Bcl-2. Finally, inhibition of miR-34a elevated Bcl-2 and decreased 1,4-benzoquinone-induced apoptosis. In conclusion, miR-34a was observed to be involved in benzene-induced hematotoxicity by targeting Bcl-2 and could be regarded as a potential novel biomarker for benzene toxicity.
Asunto(s)
Benceno/toxicidad , Benzoquinonas/toxicidad , Genes bcl-2 , MicroARNs/metabolismo , Acetilcisteína/análogos & derivados , Acetilcisteína/toxicidad , Apoptosis/genética , Apoptosis/fisiología , Biomarcadores/metabolismo , Humanos , Ácido Sórbico/análogos & derivados , Ácido Sórbico/toxicidad , Regulación hacia ArribaRESUMEN
Benzene is an environmental and industrial chemical which is widely utilized in various applications. Our previous study showed that miR-133a expression was down-regulated in chronic benzene poisoning workers, but the mechanism of miR-133a in benzene-induced hematotoxicity remains unclear. In this population-based study, benzene-exposed group recruited workers whose concentration of air benzene was 3.50±1.60mg/m(3), and control workers who were exposed to 0.06±0.01mg/m(3) air benzene. By comparison, Caspase-9 and Caspase-3 was up-regulated while miR-133a expression decreased in benzene-exposed workers. Pearson correlation analysis showed that miR-133a was reversely correlated with pro-apoptotic gene Caspase-9 in population-based study. Moreover, multiple linear regressions indicated that miR-133a was positively associated with blood cells count. To explore the underlying mechanism of miR-133a in benzene-induced hematotoxicity, AO/EB staining and TEM ultrastructural analysis were conducted to verify the activation of apoptosis in Human Leukemic U937 Cells induced by benzene metabolites (1,4-Benzoquinone, 1,4-BQ), while the mechanism of miR-133a in 1,4-BQ-induced apoptosis was performed using lentivirus vectors transfection. The results demonstrated that 1,4-BQ evidently induced mitochondria-mediated apoptosis and increased pro-apoptotic genes (Caspase-9 and Caspase-3) expression in a dose-dependent manner. The mechanistic study showed 1,4-BQ decreased miR-133a expression and miR-133a over-expression attenuated 1, 4-BQ-caused upregulation of Caspase-9, Caspase-3 and apoptosis. In conclusion, our research suggested that benzene induced hematotoxicity by decreasing miR-133a and caspase-dependent apoptosis which might contribute to the underlying mechanism of miR-133a in benzene-induced hematotoxicity.
Asunto(s)
Apoptosis/efectos de los fármacos , Benceno/toxicidad , Caspasa 3/genética , Caspasa 9/genética , Benceno/metabolismo , Benzoquinonas/metabolismo , Benzoquinonas/toxicidad , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Biomarcadores Ambientales , Humanos , MicroARNs/metabolismo , Células U937 , Regulación hacia ArribaRESUMEN
Titanium dioxide (TiO2) nanoparticles (TNPs) are manufactured worldwide for a wide range of applications and the toxic effect of TNPs on biological systems is gaining attention. Autophagy is recognized as an emerging toxicity mechanism triggered by nanomaterials. MicroRNA 34a (miR34a) acts as a tumor suppressor gene by targeting many oncogenes, but how it affects autophagy induced by TNPs is not completely understood. Here, we observed the activation of TNP-induced autophagy through monodansylcadaverine staining and LC3-I/LC3-II conversion. Meanwhile, the transmission electron microscope ultrastructural analysis showed typical morphological characteristics in autophagy process. We detected the expression of miR34a and B-cell lymphoma/leukemia-2 (Bcl-2). In addition, the underlying mechanism of TNP-induced autophagy was performed using overexpression of miR34a by lentivirus vector transfection. Results showed that TNPs induced autophagy generation evidently. Typical morphological changes in the process of autophagy were observed by the transmission electron microscope ultrastructural analysis and LC3-I/LC3-II conversion increased significantly in TNP-treated cells. Meanwhile, TNPs induced the downregulation of miR34a and increased the expression of Bcl-2. Furthermore, overexpressed miR34a decreased the expression of Bcl-2 both in messenger RNA and protein level, following which the level of autophagy and cell death rate increased after the transfected cells were incubated with TNPs for 24 hours. These findings provide the first evidence that overexpressed miR34a enhanced TNP-induced autophagy and cell death through targeted downregulation of Bcl-2 in BEAS-2B cells.
Asunto(s)
Autofagia/efectos de los fármacos , MicroARNs/genética , Nanopartículas/toxicidad , Proteínas Proto-Oncogénicas c-bcl-2/genética , Titanio/toxicidad , Apoptosis/efectos de los fármacos , Bronquios/citología , Regulación hacia Abajo/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , MicroARNs/efectos de los fármacos , Microscopía Electrónica de Transmisión , Proteínas Asociadas a Microtúbulos/metabolismo , Nanopartículas/química , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , TransfecciónRESUMEN
Alterations in DNA methylation patterns play an essential role in disease process and are associated with cancer risk. To explore the toxic effect and early sensitive biomarker of the health effects of low-dose benzene exposure (LDBE), and investigate the correlation between DNA methylation and the toxic effect of LDBE, a cross-sectional study was conducted in a sample of 571 workers; 312 workers who were exposed to a 1.82 ± 1.16 mg m-3 air benzene concentration were assigned to the LDBE group, while 259 non-known benzene exposure (NBE) workers were assigned to the control group, with an air benzene concentration of 0.06 ± 0.01 mg m-3. Routine blood indexes, alanine transaminase (ALT), oxidative stress parameters and signal transducer and activator of transcription 3 (STAT3) methylation were detected. Compared with the NBE population, the STAT3 methylation level (P = 0.001), Platelets (PLTs) (P = 0.002) and 8-isoprostane-PGFs (8-iso-PGF2a) (P = 0.001) manifested a significant reduction, while ALT (P = 0.002) and 8-hydroxy-2 deoxyguanosine (8-OHdG) (P = 0.002) showed a significant rise in the LDBE population. In addition, a significant correlation was observed between STAT3 methylation and oxidative stress, namely 8-OhdG and 8-iso-PGF2a. Furthermore, a multivariate analysis showed that the STAT3 methylation (structure loadings = 0.909) was the most strongly correlated with the other set of variables, especially with white blood cells (WBCs) (structure loadings = 0.675). Taken together, STAT3 methylation may be the underlying mechanism involved in the early toxic effect of LDBE, therefore, STAT3 methylation can be a novel sensitive biomarker for the toxic effect of low-dose benzene exposure.
RESUMEN
PURPOSE: To measure pediatric program directors' (PDs') and trainees' perceptions of and expectations for the balance of service and education in their training programs. METHOD: In fall 2011, an electronic survey was sent to PDs and trainees at Boston Children's Hospital. Respondents described perceptions and expectations for service and education and rated the education and service inherent to 12 vignettes. Wilcoxon rank sum tests measured the agreement between PD and trainee perceptions and ratings of service and education assigned to each vignette. RESULTS: Responses were received from 28/39 PDs (78%) and 223/430 trainees (52%). Seventy-five (34%) trainees responded that their education had been compromised by excessive service obligations; only 1 (4%) PD agreed (P < .0001). Although 132 (59%) trainees reported that service obligations usually/sometimes predominated over clinical education, only 3 (11%) PDs agreed (P < .0001). One hundred trainees (45%) thought rotations never/rarely/sometimes provided a balance between education and clinical demands compared with 2 PDs (7%) (P < .0001). Both groups agreed that service can, without formal teaching, be considered educational. Trainees scored 6 vignettes as having greater educational value (P ≤ .01) and 10 as having lower service content (P ≤ .04) than PDs did. CONCLUSIONS: Trainees and medical educators hold mismatched impressions of their training programs' balance of service and education. Trainees are more likely to report an overabundance of service. These data may impact the interpretation of Accreditation Council for Graduate Medical Education survey results and should be incorporated into dialogue about future curricular design initiatives.
Asunto(s)
Educación de Postgrado en Medicina/organización & administración , Internado y Residencia/organización & administración , Pediatría/educación , Ejecutivos Médicos/organización & administración , Pautas de la Práctica en Medicina , Adulto , Anciano , Boston , Competencia Clínica , Estudios Transversales , Femenino , Hospitales Pediátricos , Humanos , Relaciones Interprofesionales , Masculino , Persona de Mediana Edad , Satisfacción Personal , Proyectos Piloto , Evaluación de Programas y Proyectos de Salud , Estadísticas no Paramétricas , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Pathogenic pain is a common sign of many diseases. The mechanism is unclear. Activating transcription factor 4 (ATF4) plays a critical role in cell activation. Brain-derived neurotrophic factor (BDNF) is an important molecule in pathogenic pain. This study aims to investigate the role of ATF4 in inducing BDNF release from microglial cells. In this study, mouse microglial cells were cultured. The levels of BDNF in the culture medium were determined by enzyme-linked immunosorbent assay. Overexpression of ATF4 in microglial cells was performed by gene transfection. The apoptosis of microglial cells was assessed by flow cytometry. The results showed that microglial cells expressed ATF4 and protease-activated receptor-2 (PAR2). BDNF was detectable in the culture medium of microglial cells, which was significantly increased in the ATF4-overexpressing microglial cells. The ATF4-overexpressing microglial cells showed a high frequency of apoptotic cells, which could be inhibited by exposure to the PAR2 agonist tryptase in the culture. The tryptase-treated ATF4-overexpressing microglial cells kept higher secretion of BDNF. We conclude that the activation of ATF4 can increase BDNF release from microglial cells.
Asunto(s)
Factor de Transcripción Activador 4/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Microglía/metabolismo , Factor de Transcripción Activador 4/genética , Animales , Apoptosis , Factor Neurotrófico Derivado del Encéfalo/genética , Línea Celular , Ratones , Microglía/fisiología , Receptor PAR-2/genética , Receptor PAR-2/metabolismoRESUMEN
BACKGROUND: The significance of pituitary stalk thickening (PST) on magnetic resonance imaging (MRI) is often unclear. We evaluated presenting symptoms, MRI findings, clinical course, and outcome predictors of patients with PST. PROCEDURE: We used a computerized search of the medical record from 1995 to 2008 to identify patients with PST without pituitary mass on MRI. Baseline and follow-up MRIs were reviewed in a blinded fashion. Relevant clinical data were abstracted. RESULTS: 69 patients with reported PST and adequate imaging for review were identified; 42 met study criteria. Median age at first abnormal MRI was 13.6 years (range: 0.8-19.7); 43% were male. Median follow-up was 3.4 years (range 0-12.8). Patients with diabetes insipidus (DI) were significantly more likely to have a neoplastic process than those without (P = 0.0008). Of 16 patients with DI, 8 (50%) had a neoplastic process, including germ cell tumor (n = 4), Langerhans cell histiocytosis (n = 3), and lymphoma (n = 1). Among patients with DI, 7 (44%) also developed anterior pituitary hormone dysfunction (APD), either at presentation or on pre-biopsy follow-up, including 6/8 patients with stalk neoplasm and only 1/8 patients with non-neoplastic PST (P = 0.04). Twenty-six patients presented without DI; none was found to have neoplasm of the stalk except one patient with craniopharyngioma. Progression of PST on follow-up imaging was significantly associated with a subsequent neoplastic diagnosis (P = 0.04). CONCLUSION: Patients with PST without DI are unlikely to have a neoplastic process. Among patients with DI, APD or progressive stalk increase over time are predictive of neoplasia.
Asunto(s)
Diabetes Insípida/complicaciones , Diabetes Insípida/diagnóstico por imagen , Registros Médicos , Neoplasias/diagnóstico por imagen , Enfermedades de la Hipófisis/complicaciones , Enfermedades de la Hipófisis/diagnóstico por imagen , Hipófisis/diagnóstico por imagen , Adolescente , Niño , Preescolar , Diabetes Insípida/epidemiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Neoplasias/epidemiología , Tamaño de los Órganos , Enfermedades de la Hipófisis/epidemiología , Valor Predictivo de las Pruebas , Radiografía , Estudios RetrospectivosRESUMEN
In mammals, most newly synthesized lumenal lysosomal proteins are delivered to the lysosome by the mannose 6-phosphate (Man6P) targeting pathway. Man6P -containing proteins can be affinity-purified and characterized using proteomic approaches, and such studies have led to the discovery of new lysosomal proteins and associated human disease genes. One limitation to this approach is that in most cell types the Man6P modification is rapidly removed by acid phosphatase 5 (ACP5) after proteins are targeted to the lysosome, and thus, some lysosomal proteins may escape detection. In this study, we have extended the analysis of the lysosomal proteome using high resolution/accuracy mass spectrometry to identify and quantify proteins in a combined analysis of control and ACP5-deficient mice. To identify Man6P glycoproteins with limited tissue distribution, we analyzed multiple tissues and used statistical approaches to identify proteins that are purified with high specificity. In addition to 68 known Man6P glycoproteins, 165 other murine proteins were identified that may contain Man6P and may thus represent novel lysosomal residents. For four of these lysosomal candidates, (lactoperoxidase, phospholipase D family member 3, ribonuclease 6, and serum amyloid P component), we demonstrate lysosomal residence based on the colocalization of fluorescent fusion proteins with a lysosomal marker.
Asunto(s)
Fosfatasa Ácida/metabolismo , Isoenzimas/metabolismo , Lisosomas/metabolismo , Manosafosfatos/metabolismo , Fosfatasa Ácida/genética , Animales , Isoenzimas/genética , Ratones , Ratones Noqueados , Proteoma , Espectrometría de Masas en Tándem/métodos , Fosfatasa Ácida TartratorresistenteRESUMEN
Chemotherapy dosing in hematopoietic cell therapy (HCT) conditioning regimens is based on patient weight. We hypothesized that potential underdosing or overdosing of patients with significant deviation of weight from normal might alter HCT outcomes, such as early mortality, overall or organ-specific toxicity, and/or relapse. We therefore conducted a retrospective analysis of 400 children between the ages of 2 and 18 years who underwent HCT for malignant or nonmalignant disease at Boston Children's Hospital over a 10-year period. Using the Centers for Disease Control and Prevention standard weight classification schema, we found no evidence to suggest a difference in survival or in time to engraftment or in relapse in patients with malignant disease. In the subgroups of patients either receiving autologous HCT or with underlying malignancy, combined overweight and obese patients had a higher rate of any organ, but not organ-specific, Grade 3-5 toxicity compared with the normal weight group. The study was not powered to detect a difference between underweight and normal weight patients. These data suggest that multiple outcome measures over the first year after HCT are unaffected by weight.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/mortalidad , Obesidad/mortalidad , Adolescente , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Neoplasias/mortalidad , Neoplasias/terapia , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante Autólogo , Trasplante HomólogoRESUMEN
Craniopharyngiomas are slow growing tumors of the sellar and parasellar region and may also involve the hypothalamus. Treatment involves maximal surgical excision or subtotal resection followed by focal radiation therapy. Late effects of treatment include endocrinopathies, cognitive deficits, behavioral changes, obesity and sleep dysfunction. We conducted a retrospective review of all patients with craniopharyngioma more than 2 years off treatment and who were evaluated in the neuro-oncology survivorship clinic between 2003 and 2007. Clinical data, extent of resection, treatment modalities, endocrine status, patient symptom report and sleep study results were collected to evaluate the presence of patient reported daytime sleepiness and sleep disturbance and to determine possible risk factors. 28 patients were identified (25 %) female. 19/28 self-reported daytime fatigue or sleep disturbance; this included 4/6 patients with gross total resection and 15/22 with subtotal resection. 16/22 patients treated with cranial irradiation reported sleep-related abnormalities, compared to 3/6 patients who did not receive radiation. All but one patient had pituitary dysfunction requiring hormonal replacement. Patients with more than ≥2 sleep related complaints had a higher BMI (44.6 vs. 32.6, p = 0.0192). 8 patients underwent formal sleep evaluation. 3 patients had documented central or obstructive sleep apnea. The mean arousal index was 11.0/h (normal <5). Two patients were treated with melatonin for sleep disturbance and 2 were treated with stimulants for excessive daytime sleepiness. A majority of patients with craniopharyngioma have self-reported daytime fatigue and/or sleep dysfunction after treatment. Extent of resection did not increase the likelihood of patient-reported daytime sleepiness and/sleep dysfunction; however, patients who received radiation more frequently reported daytime sleepiness and/or sleep dysfunction. Patients with a higher BMI were more likely to experience sleep disturbance. Formal sleep evaluations should be considered in all patients with craniopharyngioma.
Asunto(s)
Craneofaringioma/complicaciones , Trastornos del Sueño-Vigilia/etiología , Sobrevivientes , Adolescente , Adulto , Niño , Preescolar , Craneofaringioma/mortalidad , Craneofaringioma/terapia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Obesidad/complicaciones , Obesidad/mortalidad , Obesidad/terapia , Polisomnografía , Pronóstico , Estudios Retrospectivos , Trastornos del Sueño-Vigilia/mortalidad , Trastornos del Sueño-Vigilia/terapia , Tasa de Supervivencia , Adulto JovenRESUMEN
Hydrogen gas was reported to reduce reactive oxygen species and alleviate cerebral, myocardial and hepatic ischemia/reperfusion (I/R) injuries. This paper studied the effect of hydrogen-rich saline, which was easier for clinical application, on the intestinal I/R injury. Model of intestinal I/R injury was induced in male Sprague-Dawley rats. Physiological saline, hydrogen-rich saline or nitrogen-rich saline (5 ml/kg) was administered via intravenous infusion at 10 min before reperfusion, respectively. The intestine damage was detected microscopically and was assessed by Chiu score system after I/R injury. In addition, serum DAO activity, TNF-alpha, IL-1beta and IL-6 levels, tissue MDA, protein carbonyl and MPO activity were all increased significantly by I/R injury. Hydrogen-rich saline reduced these markers and relieved morphological intestinal injury, while no significant reduction was observed in the nitrogen-rich saline-treated animals. In conclusion, hydrogen-rich saline protected the small intestine against I/R injury, possibly by reduction of inflammation and oxidative stress.
Asunto(s)
Hidrógeno/administración & dosificación , Intestinos/irrigación sanguínea , Intestinos/lesiones , Daño por Reperfusión/prevención & control , Animales , Citocinas/sangre , Inflamación/prevención & control , Mediadores de Inflamación/sangre , Infusiones Intravenosas , Mucosa Intestinal/metabolismo , Intestinos/patología , Masculino , Malondialdehído/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/patología , Nitrógeno/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Peroxidasa/metabolismo , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Cloruro de Sodio/administración & dosificaciónRESUMEN
Most newly synthesized proteins destined for the lysosome reach this location via a specific intracellular pathway. In the Golgi, a phosphotransferase specifically labels lysosomal proteins with mannose 6-phosphate (Man-6-P). This modification is recognized by receptors that target the lysosomal proteins to the lysosome where, in most cell types, the Man-6-P recognition marker is rapidly removed. Despite extensive characterization of this pathway, the enzyme responsible for the removal of the targeting modification has remained elusive. In this study, we have identified this activity. Preliminary investigations using a cell-based bioassay were used to follow a dephosphorylation activity that was associated with the lysosomal fraction. This activity was high in the liver, where endogenous lysosomal proteins are efficiently dephosphorylated, but present at a much lower level in the brain, where the modification persists. This observation, combined with an analysis of the expression of lysosomal proteins in different tissues, led us to identify acid phosphatase 5 (ACP5) as a candidate for the enzyme that removes Man-6-P. Expression of ACP5 in N1E-115 neuroblastoma cells, which do not efficiently dephosphorylate lysosomal proteins, significantly decreased the steady state levels of Man6-P glycoproteins. Analysis of ACP5-deficient mice revealed that levels of Man-6-P glycoproteins were highly elevated in tissues that normally express ACP5, and this resulted from a failure to dephosphorylate lysosomal proteins. These results indicate a central role for ACP5 in removal of the Man-6-P recognition marker and open up new avenues to investigate the importance of this process in cell biology and medicine.