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1.
Ann Oncol ; 33(9): 916-928, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35690221

RESUMEN

BACKGROUND: Anti-CD19 chimeric antigen receptor T-cell immunotherapy (CAR-T) is now a standard treatment of relapsed or refractory B-cell non-Hodgkin lymphomas; however, a significant portion of patients do not respond to CAR-T and/or experience toxicities. Lymphodepleting chemotherapy is a critical component of CAR-T that enhances CAR-T-cell engraftment, expansion, cytotoxicity, and persistence. We hypothesized that the lymphodepletion regimen might affect the safety and efficacy of CAR-T. PATIENTS AND METHODS: We compared the safety and efficacy of lymphodepletion using either fludarabine/cyclophosphamide (n = 42) or bendamustine (n = 90) before tisagenlecleucel in two cohorts of patients with relapsed or refractory large B-cell lymphomas treated consecutively at three academic institutions in the United States (University of Pennsylvania, n = 90; Oregon Health & Science University, n = 35) and Europe (University of Vienna, n = 7). Response was assessed using the Lugano 2014 criteria and toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and, when possible, the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. RESULTS: Fludarabine/cyclophosphamide led to more profound lymphocytopenia after tisagenlecleucel infusion compared with bendamustine, although the efficacy of tisagenlecleucel was similar between the two groups. We observed significant differences, however, in the frequency and severity of adverse events. In particular, patients treated with bendamustine had lower rates of cytokine release syndrome and neurotoxicity. In addition, higher rates of hematological toxicities were observed in patients receiving fludarabine/cyclophosphamide. Bendamustine-treated patients had higher nadir neutrophil counts, hemoglobin levels, and platelet counts, as well as a shorter time to blood count recovery, and received fewer platelet and red cell transfusions. Fewer episodes of infection, neutropenic fever, and post-infusion hospitalization were observed in the bendamustine cohort compared with patients receiving fludarabine/cyclophosphamide. CONCLUSIONS: Bendamustine for lymphodepletion before tisagenlecleucel has efficacy similar to fludarabine/cyclophosphamide with reduced toxicities, including cytokine release syndrome, neurotoxicity, infectious and hematological toxicities, as well as reduced hospital utilization.


Asunto(s)
Clorhidrato de Bendamustina , Inmunoterapia Adoptiva , Depleción Linfocítica , Linfoma de Células B Grandes Difuso , Receptores de Antígenos de Linfocitos T , Clorhidrato de Bendamustina/efectos adversos , Clorhidrato de Bendamustina/uso terapéutico , Ciclofosfamida/uso terapéutico , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Humanos , Inmunoterapia Adoptiva/métodos , Depleción Linfocítica/métodos , Linfoma de Células B Grandes Difuso/terapia , Receptores de Antígenos de Linfocitos T/uso terapéutico
2.
Phys Rev Lett ; 124(14): 143602, 2020 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-32338967

RESUMEN

We investigate the dynamics of a Bose-Einstein condensate interacting with two noninterfering and counterpropagating modes of a ring resonator. Superfluid, supersolid, and dynamic phases are identified experimentally and theoretically. The supersolid phase is obtained for sufficiently equal pump strengths for the two modes. In this regime we observe the emergence of a steady state with crystalline order, which spontaneously breaks the continuous translational symmetry of the system. The supersolidity of this state is demonstrated by the conservation of global phase coherence at the superfluid to supersolid phase transition. Above a critical pump asymmetry the system evolves into a dynamic runaway instability commonly known as collective atomic recoil lasing. We present a phase diagram and characterize the individual phases by comparing theoretical predictions with experimental observations.

3.
BMC Cancer ; 20(1): 16, 2020 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-31906955

RESUMEN

BACKGROUND: Improved, multimodal treatment strategies have been shown to increase cure rates in cancer patients. Those who survive cancer as a child, adolescent or young adult (CAYA), are at a higher risk for therapy-, or disease-related, late or long-term effects. The CARE for CAYA-Program has been developed to comprehensively assess any potential future problems, to offer need-based preventative interventions and thus to improve long-term outcomes in this particularly vulnerable population. METHODS: The trial is designed as an adaptive trial with an annual comprehensive assessment followed by needs stratified, modular interventions, currently including physical activity, nutrition and psycho-oncology, all aimed at improving the lifestyle and/or the psychosocial situation of the patients. Patients, aged 15-39 years old, with a prior cancer diagnosis, who have completed tumour therapy and are in follow-up care, and who are tumour free, will be included. At baseline (and subsequently on an annual basis) the current medical and psychosocial situation and lifestyle of the participants will be assessed using a survey compiled of various validated questionnaires (e.g. EORTC QLQ C30, NCCN distress thermometer, PHQ-4, BSA, nutrition protocol) and objective parameters (e.g. BMI, WHR, co-morbidities like hyperlipidaemia, hypertension, diabetes), followed by basic care (psychological and lifestyle consultation). Depending on their needs, CAYAs will be allocated to preventative interventions in the above-mentioned modules over a 12-month period. After 1 year, the assessment will be repeated, and further interventions may be applied as needed. During the initial trial phase, the efficacy of this approach will be compared to standard care (waiting list with intervention in the following year) in a randomized study. During this phase, 530 CAYAs will be included and 320 eligible CAYAs who are willing to participate in the interventions will be randomly allocated to an intervention. Overall, 1500 CAYAs will be included and assessed. The programme is financed by the innovation fund of the German Federal Joint Committee and will be conducted at 14 German sites. Recruitment began in January 2018. DISCUSSION: CAYAs are at high risk for long-term sequelae. Providing structured interventions to improve lifestyle and psychological situation may counteract against these risk factors. The programme serves to establish uniform regular comprehensive assessments and need-based interventions to improve long-term outcome in CAYA survivors. TRIAL REGISTRATION: Registered at the German Clinical Trial Register (ID: DRKS00012504, registration date: 19th January 2018).


Asunto(s)
Cuidados Posteriores/métodos , Supervivientes de Cáncer/psicología , Adolescente , Adulto , Cuidados Posteriores/organización & administración , Niño , Depresión/psicología , Depresión/terapia , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/complicaciones , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Ejercicio Físico/fisiología , Femenino , Humanos , Estilo de Vida , Masculino , Neoplasias/complicaciones , Neoplasias/psicología , Evaluación Nutricional , Medicina Preventiva/métodos , Medicina Preventiva/organización & administración , Factores de Riesgo , Encuestas y Cuestionarios , Factores de Tiempo , Adulto Joven
4.
Ann Oncol ; 30(10): 1613-1621, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31504118

RESUMEN

BACKGROUND: Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity. PATIENTS AND METHODS: This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1-3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy. RESULTS: A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107). CONCLUSION: Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits. CLINICAL TRAIL NUMBER: NCT02499770.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Células Mieloides/efectos de los fármacos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/secundario , Carboplatino/administración & dosificación , Cisplatino/administración & dosificación , Método Doble Ciego , Etopósido/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Pronóstico , Pirimidinas/administración & dosificación , Pirroles/administración & dosificación , Carcinoma Pulmonar de Células Pequeñas/enzimología , Carcinoma Pulmonar de Células Pequeñas/patología , Tasa de Supervivencia , Distribución Tisular
5.
Herz ; 44(1): 16-21, 2019 Feb.
Artículo en Alemán | MEDLINE | ID: mdl-30627740

RESUMEN

The current guidelines of the European Society of Cardiology have up-dated and confirmed the role of a primary percutaneous coronary intervention (PCI) as the preferred reperfusion therapy in patients with acute coronary syndrome and ST-elevation. The establishment of regional network structures for implementation of this reperfusion strategy is recommended and described. Primary PCI should preferably be carried out via the transradial route and should include the implantation of modern drug-eluting stents. In most cases of coronary multivessel disease, primary PCI should be limited to the treatment of the infarcted artery. Routine mechanical thrombus aspiration during primary PCI is no longer recommended. Recommendations for a specific anti-thrombotic and secondary prophylactic medication after primary PCI are highlighted.


Asunto(s)
Síndrome Coronario Agudo , Enfermedad de la Arteria Coronaria , Stents Liberadores de Fármacos , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST , Síndrome Coronario Agudo/complicaciones , Síndrome Coronario Agudo/terapia , Humanos , Infarto del Miocardio con Elevación del ST/complicaciones , Infarto del Miocardio con Elevación del ST/terapia , Resultado del Tratamiento
6.
Phys Rev Lett ; 121(22): 223601, 2018 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-30547603

RESUMEN

We experimentally investigate the dynamic instability of Bose-Einstein condensates in an optical ring resonator that is asymmetrically pumped in both directions. We find that, beyond a critical resonator-pump detuning, the system becomes stable regardless of the pump strength. Phase diagrams and quenching curves are presented and described by numerical simulations. We discuss a physical explanation based on a geometric interpretation of the underlying nonlinear equations of motion.

7.
Phys Rev Lett ; 121(17): 173602, 2018 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-30411934

RESUMEN

We experimentally investigate the formation of subradiant atomic momentum states in Bose-Einstein condensates inside a recoil resolving optical ring resonator according to the theoretical proposal of Cola, Bigerni, and Piovella. The atoms are pumped from the side with laser light that contains two frequency components. They resonantly drive cavity assisted Raman transitions between three discreet atomic momentum states. Within a few hundred microseconds, the system evolves into a stationary subradiant state. In this state, the condensate develops two density gratings suitable to diffract the two frequency components of the pump field into the resonator. Both components destructively interfere such that scattering is efficiently suppressed. A series of subradiant states for various amplitude ratios of the two pump components between 0 and 2.1 have been observed. The results are well explained with a three state quantum model in mean field approximation.

8.
Ann Oncol ; 28(5): 1050-1056, 2017 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-28453705

RESUMEN

Background: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results: A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions: In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Adenina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Supervivencia sin Enfermedad , Esquema de Medicación , Humanos , Estimación de Kaplan-Meier , Leucemia Linfocítica Crónica de Células B/mortalidad , Persona de Mediana Edad , Piperidinas , Modelos de Riesgos Proporcionales , Purinas/administración & dosificación , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Quinazolinonas/administración & dosificación , Estudios Retrospectivos , Sulfonamidas/administración & dosificación , Resultado del Tratamiento , Adulto Joven
9.
Ann Oncol ; 28(7): 1436-1447, 2017 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-28379322

RESUMEN

In recent years, the number of approved and investigational agents that can be safely administered for the treatment of lymphoma patients for a prolonged period of time has substantially increased. Many of these novel agents are evaluated in early-phase clinical trials in patients with a wide range of malignancies, including solid tumors and lymphoma. Furthermore, with the advances in genome sequencing, new "basket" clinical trial designs have emerged that select patients based on the presence of specific genetic alterations across different types of solid tumors and lymphoma. The standard response criteria currently in use for lymphoma are the Lugano Criteria which are based on [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography or bidimensional tumor measurements on computerized tomography scans. These differ from the RECIST criteria used in solid tumors, which use unidimensional measurements. The RECIL group hypothesized that single-dimension measurement could be used to assess response to therapy in lymphoma patients, producing results similar to the standard criteria. We tested this hypothesis by analyzing 47 828 imaging measurements from 2983 individual adult and pediatric lymphoma patients enrolled on 10 multicenter clinical trials and developed new lymphoma response criteria (RECIL 2017). We demonstrate that assessment of tumor burden in lymphoma clinical trials can use the sum of longest diameters of a maximum of three target lesions. Furthermore, we introduced a new provisional category of a minor response. We also clarified response assessment in patients receiving novel immune therapy and targeted agents that generate unique imaging situations.


Asunto(s)
Antineoplásicos/uso terapéutico , Linfoma no Hodgkin/diagnóstico por imagen , Linfoma no Hodgkin/tratamiento farmacológico , Tomografía de Emisión de Positrones/normas , Criterios de Evaluación de Respuesta en Tumores Sólidos , Tomografía Computarizada por Rayos X/normas , Antineoplásicos/efectos adversos , Consenso , Medios de Contraste/administración & dosificación , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Determinación de Punto Final , Fluorodesoxiglucosa F18/administración & dosificación , Humanos , Linfoma no Hodgkin/mortalidad , Linfoma no Hodgkin/patología , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Factores de Tiempo , Resultado del Tratamiento , Carga Tumoral
10.
Indoor Air ; 27(2): 345-353, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27120709

RESUMEN

Air-conditioning systems harbor microorganisms, potentially spreading them to indoor environments. While air and surfaces in air-conditioning systems are periodically sampled as potential sources of indoor microbes, little is known about the dynamics of cooling coil-associated communities and their effect on the downstream airflow. Here, we conducted a 4-week time series sampling to characterize the succession of an air-conditioning duct and cooling coil after cleaning. Using an universal primer pair targeting hypervariable regions of the 16S/18S ribosomal RNA, we observed a community succession for the condensed water, with the most abundant airborne taxon Agaricomycetes fungi dominating the initial phase and Sphingomonas bacteria becoming the most prevalent taxa toward the end of the experiment. Duplicate air samples collected upstream and downstream of the coil suggest that the system does not act as ecological filter or source/sink for specific microbial taxa during the duration of the experiment.


Asunto(s)
Aire Acondicionado/instrumentación , Microbiología del Aire , Contaminación del Aire Interior/análisis , Clima Tropical , Ecosistema , Monitoreo del Ambiente/métodos , Hongos/crecimiento & desarrollo , ARN Ribosómico 16S/análisis , Sphingomonas/crecimiento & desarrollo
11.
Gesundheitswesen ; 79(7): 535-541, 2017 Jul.
Artículo en Alemán | MEDLINE | ID: mdl-27144710

RESUMEN

Background In Germany, 35% of all children are considered to have a "migration background", and in the state of North-Rhine-Westfalia 43%. Frequently, one or both parents of a patient with a migration background have limited German language proficiency. Communication barriers due to a language difference can have a negative impact on quality of care, patient safety and costs of care. In this study, we investigate how children's hospitals are prepared to meet the challenges associated with language barriers. Methods We surveyed all children's hospitals in the state of North-Rhine-Westfalia, Germany. The questionnaire was based on the "Standards for Culturally and Linguistically Appropriate Services in Health and Health Care (CLAS)" and was adapted to circumstances in Germany. Results Thirty-eight hospitals participated (51%) in this survey. Language barriers occurred frequently (75% of respondents mentioned language difficulties in more than 10% of the patient population). 82% of respondents rated their hospital to be "less than well prepared" to overcome language barriers. In the majority of hospitals (62%), the need for an interpreter was determined on a case-to-case basis and not according to any set protocol. In most cases bilingual staff was used for interpreting. However, only 38% of respondents found a list of available bilingual staff to be a sufficient resource. 42% of respondents did not know the monthly costs for professional interpreting services. In the remaining cases, costs were less than € 500/month. Conclusion To overcome language barriers, hospitals rely on local resources. The majority of respondents did not find them to be appropriate and sufficient. The development of quality standards and the provision of financial resources are necessary to mobilize this potential for improvement. Therefore, other disciplines and sectors of healthcare need to be analyzed in order to provide the evidence for a constructive discussion with decision makers in policy and health insurance.


Asunto(s)
Barreras de Comunicación , Hospitales Pediátricos , Pacientes Internos , Niño , Alemania , Humanos , Lenguaje , Proyectos Piloto
12.
Biochim Biophys Acta ; 1851(5): 641-56, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25677822

RESUMEN

A pronounced heterogeneity between hepatocytes in subcellular structure and enzyme activities was discovered more than 50years ago and initiated the idea of metabolic zonation. In the last decades zonation patterns of liver metabolism were extensively investigated for carbohydrate, nitrogen and lipid metabolism. The present review focuses on zonation patterns of the latter. We review recent findings regarding the zonation of fatty acid uptake and oxidation, ketogenesis, triglyceride synthesis and secretion, de novo lipogenesis, as well as bile acid and cholesterol metabolism. In doing so, we expose knowledge gaps and discuss contradictory experimental results, for example on the zonation pattern of fatty acid oxidation and de novo lipogenesis. Thus, possible rewarding directions of further research are identified. Furthermore, recent findings about the regulation of metabolic zonation are summarized, especially regarding the role of hormones, nerve innervation, morphogens, gender differences and the influence of the circadian clock. In the last part of the review, a short collection of models considering hepatic lipid metabolism is provided. We conclude that modeling, despite its proven benefit for understanding of hepatic carbohydrate and ammonia metabolisms, has so far been largely disregarded in the study of lipid metabolism; therefore some possible fields of modeling interest are presented.


Asunto(s)
Ácidos Grasos/metabolismo , Hepatocitos/metabolismo , Metabolismo de los Lípidos , Hígado/metabolismo , Modelos Biológicos , Animales , Hepatocitos/enzimología , Humanos , Hígado/citología , Hígado/enzimología
13.
Ann Oncol ; 27(7): 1226-34, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27052651

RESUMEN

Lenalidomide is an oral immunomodulatory drug with significant activity in indolent B-cell and mantle cell lymphomas. Lenalidomide has a manageable safety profile whether administered as a single agent or in combination with rituximab. The combination of lenalidomide with rituximab, known as the 'R(2)' regimen, enhances efficacy over what has been shown with monotherapy and has demonstrated activity in patients considered resistant to rituximab. Tolerability of these regimens has been consistent among studies. Asymptomatic neutropenia is the most common grade 3/4 adverse event, typically managed by dose interruption, followed by dose reduction once neutrophils have recovered. Nonhematologic toxicities (e.g. fatigue) are generally low-grade, manageable with concomitant treatment, and/or lenalidomide dose modification. More frequent with R(2), immune-related symptoms such as rash and tumor flare are important to recognize as lenalidomide-associated treatment effects in patients with lymphoma who require supportive care and potential dose modifications. Severe tumor flare reactions with painful lymphadenopathy are not typically observed outside of chronic lymphocytic leukemia/small lymphocytic lymphoma. Venous thromboembolism is uncommon in lymphomas, though prophylaxis is recommended. The general safety profile, differences between lenalidomide monotherapy and R(2) treatment, and optimal strategies for managing adverse events are discussed here.


Asunto(s)
Linfoma de Células B/tratamiento farmacológico , Linfoma de Células del Manto/tratamiento farmacológico , Rituximab/administración & dosificación , Talidomida/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Linfocitos B/efectos de los fármacos , Linfocitos B/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Humanos , Lenalidomida , Linfoma de Células B/patología , Linfoma de Células del Manto/patología , Rituximab/efectos adversos , Talidomida/administración & dosificación , Talidomida/efectos adversos , Resultado del Tratamiento
14.
Mol Psychiatry ; 20(9): 1120-31, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25869807

RESUMEN

Neuropsychiatric developmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia, are typically characterized by alterations in social behavior and have been linked to aberrant dendritic spine and synapse development. Here we show, using genetically engineered mice, that the Cdc42 GTPase-activating multiadaptor protein, NOMA-GAP, regulates autism-like social behavior in the mouse, as well as dendritic spine and synapse development. Surprisingly, we were unable to restore spine morphology or autism-associated social behavior in NOMA-GAP-deficient animals by Cre-mediated deletion of Cdc42 alone. Spine morphology can be restored in vivo by re-expression of wild-type NOMA-GAP or a mutant of NOMA-GAP that lacks the RhoGAP domain, suggesting that other signaling functions are involved. Indeed, we show that NOMA-GAP directly interacts with several MAGUK (membrane-associated guanylate kinase) proteins, and that this modulates NOMA-GAP activity toward Cdc42. Moreover, we demonstrate that NOMA-GAP is a major regulator of PSD-95 in the neocortex. Loss of NOMA-GAP leads to strong upregulation of serine 295 phosphorylation of PSD-95 and moreover to its subcellular mislocalization. This is associated with marked loss of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and defective synaptic transmission, thereby providing a molecular basis for autism-like social behavior in the absence of NOMA-GAP.


Asunto(s)
Trastorno del Espectro Autista/metabolismo , Conducta Animal/fisiología , Proteínas Activadoras de GTPasa/metabolismo , Conducta Social , Sinapsis/fisiología , Animales , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/patología , Células Cultivadas , Espinas Dendríticas/metabolismo , Modelos Animales de Enfermedad , Femenino , Proteínas Activadoras de GTPasa/genética , Guanilato-Quinasas/metabolismo , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neocórtex/metabolismo , Receptores AMPA/metabolismo , Transducción de Señal , Sinapsis/metabolismo
15.
Biochim Biophys Acta ; 1841(1): 62-9, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23999488

RESUMEN

A hallmark of the nonalcoholic fatty liver disease is the accumulation of lipids. We developed a mathematical model of the hepatic lipid dynamics to simulate the fate of fatty acids in hepatocytes. Our model involves fatty acid uptake, lipid oxidation, and lipid export. It takes into account that storage of triacylglycerol within hepatocytes leads to cell enlargement reducing the sinusoids radius and impairing hepatic microcirculation. Thus oxygen supply is reduced, which impairs lipid oxidation. The analysis of our model revealed a bistable behavior (two stable steady states) of the system, in agreement with histological observations showing distinct areas of lipid accumulation in lobules. The first (healthy) state is characterized by intact lipid oxidation and a low amount of stored lipids. The second state in our model may correspond to the steatotic cell; it is marked by a high amount of stored lipids and a reduced lipid oxidation caused by impaired oxygen supply. Our model stresses the role of insufficient oxygen supply for the development of steatosis. We discuss implications of our results in regard to the experimental design aimed at exploring lipid metabolism reactions under steatotic conditions. Moreover, the model helps to understand the reversibility of lipid accumulation and predicts the reversible switch to show hysteresis. The system can switch from the steatotic state back to the healthy state by reduction of fatty acid uptake below the threshold at which steatosis started. The reversibility corresponds to the observation that caloric restriction can reduce the lipid content in the liver.


Asunto(s)
Hígado Graso/metabolismo , Hepatocitos/metabolismo , Metabolismo de los Lípidos , Hígado/metabolismo , Modelos Biológicos , Animales , Ácidos Grasos/metabolismo , Hígado Graso/patología , Hepatocitos/patología , Humanos , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico , Oxidación-Reducción , Triglicéridos/metabolismo
16.
Am J Transplant ; 15(10): 2665-73, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25988622

RESUMEN

We examined the associations of Epstein-Barr virus (EBV) status with characteristics and outcomes of posttransplantation lymphoproliferative disorder (PTLD) by studying 176 adult solid organ transplant recipients diagnosed with PTLD between 1990 and 2013 (58 [33%] EBV-negative; 118 [67%] EBV-positive). The proportion of EBV-negative cases increased over time from 10% (1990-1995) to 48% (2008-2013) (p < 0.001). EBV-negative PTLD had distinct characteristics (monomorphic histology, longer latency) though high-risk features (advanced stage, older age, high lactate dehydrogenase, central nervous system involvement) were not more common compared to EBV-positive PTLD. In multivariable analysis, EBV negativity was not significantly associated with worse response to initial therapy (adjusted odds ratio, 0.84; p = 0.75). The likelihood of achieving a complete remission (CR) was not significantly different for EBV-negative versus EBV-positive PTLD including when therapy was reduction of immunosuppression alone (35% vs. 43%, respectively, p = 0.60) or rituximab (43% vs. 47%, p = 1.0). EBV negativity was also not associated with worse overall survival (adjusted hazard ratio, 0.91; p = 0.71). Our findings indicate that EBV status is not prognostic or predictive of treatment response in adults with PTLD. The high proportion of EBV-negative disease diagnosed in recent years highlights the need for new strategies for prevention and management of EBV-negative PTLD.


Asunto(s)
Infecciones por Virus de Epstein-Barr/complicaciones , Trastornos Linfoproliferativos/virología , Trasplante de Órganos , Complicaciones Posoperatorias/virología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios Transversales , Infecciones por Virus de Epstein-Barr/diagnóstico , Femenino , Humanos , Lactante , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/mortalidad , Trastornos Linfoproliferativos/terapia , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/terapia , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento , Adulto Joven
17.
Z Rheumatol ; 74(10): 854-6, 858-60, 862, 2015 Dec.
Artículo en Alemán | MEDLINE | ID: mdl-26589203

RESUMEN

Primary angiitis of the central nervous system (PACNS) is a rare disorder. However, it is often considered in the differential diagnosis of vascular or inflammatory CNS diseases. Diagnosis is challenging, as specific biomarkers are lacking and the clinical presentation can be variable. A definitive diagnosis can only be established by biopsy of the inflammatory changes in the vascular wall. Alternatively, the diagnosis of PACNS can also be based on the synopsis of clinical, radiological, and laboratory findings. Different subtypes of PACNS have been described in recent years, depending on the size of the affected vessels or histopathological patterns. Based on selective literature research in the database PubMed on the subject of CNS vasculitis, this article reviews the diagnostic characteristics and differential diagnosis of the condition. We suggest a diagnostic algorithm customized to the size of the affected vessels. Lastly, therapeutic options and the outcome of PACNS are briefly outlined.


Asunto(s)
Algoritmos , Vasculitis del Sistema Nervioso Central/sangre , Vasculitis del Sistema Nervioso Central/diagnóstico , Diagnóstico Diferencial , Diagnóstico por Imagen/métodos , Humanos , Examen Físico
18.
Rev Med Suisse ; 10(451): 2222-5, 2014 Nov 19.
Artículo en Francés | MEDLINE | ID: mdl-25603570

RESUMEN

The development of Migrant Friendly Hospitals is an important first step towards eliminating health care disparities in Switzerland and an important reminder to health policy makers and practitioners across the health care system of their responsibility to provide non-discriminatory quality health care to all patients.


Asunto(s)
Diversidad Cultural , Accesibilidad a los Servicios de Salud/organización & administración , Emigrantes e Inmigrantes , Necesidades y Demandas de Servicios de Salud , Disparidades en Atención de Salud/organización & administración , Humanos , Suiza
19.
Environ Int ; 186: 108587, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38579450

RESUMEN

Air pollution is a key global environmental problem raising human health concern. It is essential to comprehensively assess the long-term characteristics of air pollution and the resultant health impacts. We first assessed the global trends of fine particulate matter (PM2.5) during 1980-2020 using a monthly global PM2.5 reanalysis dataset, and evaluated their association with three types of climate variability including El Niño-Southern Oscillation, Indian Ocean Dipole and North Atlantic Oscillation. We then estimated PM2.5-attributable premature deaths using integrated exposure-response functions. Results show a significant increasing trend of ambient PM2.5 during 1980-2020 due to increases in anthropogenic emissions. Ambient PM2.5 caused a total of âˆ¼ 135 million premature deaths globally during the four decades. Occurrence of air pollution episodes was strongly associated with climate variability, which were associated with up to 14 % increase in annual global PM2.5-attributable premature deaths.


Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Salud Global , Material Particulado , Material Particulado/análisis , Contaminación del Aire/estadística & datos numéricos , Humanos , Contaminantes Atmosféricos/análisis , Cambio Climático , Exposición a Riesgos Ambientales/estadística & datos numéricos , Clima , Mortalidad Prematura
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