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1.
Nature ; 553(7686): 96-100, 2018 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-29258294

RESUMEN

Cellular senescence is a stress-responsive cell-cycle arrest program that terminates the further expansion of (pre-)malignant cells. Key signalling components of the senescence machinery, such as p16INK4a, p21CIP1 and p53, as well as trimethylation of lysine 9 at histone H3 (H3K9me3), also operate as critical regulators of stem-cell functions (which are collectively termed 'stemness'). In cancer cells, a gain of stemness may have profound implications for tumour aggressiveness and clinical outcome. Here we investigated whether chemotherapy-induced senescence could change stem-cell-related properties of malignant cells. Gene expression and functional analyses comparing senescent and non-senescent B-cell lymphomas from Eµ-Myc transgenic mice revealed substantial upregulation of an adult tissue stem-cell signature, activated Wnt signalling, and distinct stem-cell markers in senescence. Using genetically switchable models of senescence targeting H3K9me3 or p53 to mimic spontaneous escape from the arrested condition, we found that cells released from senescence re-entered the cell cycle with strongly enhanced and Wnt-dependent clonogenic growth potential compared to virtually identical populations that had been equally exposed to chemotherapy but had never been senescent. In vivo, these previously senescent cells presented with a much higher tumour initiation potential. Notably, the temporary enforcement of senescence in p53-regulatable models of acute lymphoblastic leukaemia and acute myeloid leukaemia was found to reprogram non-stem bulk leukaemia cells into self-renewing, leukaemia-initiating stem cells. Our data, which are further supported by consistent results in human cancer cell lines and primary samples of human haematological malignancies, reveal that senescence-associated stemness is an unexpected, cell-autonomous feature that exerts its detrimental, highly aggressive growth potential upon escape from cell-cycle blockade, and is enriched in relapse tumours. These findings have profound implications for cancer therapy, and provide new mechanistic insights into the plasticity of cancer cells.


Asunto(s)
Reprogramación Celular , Senescencia Celular , Linfoma de Células B/patología , Células Madre Neoplásicas/patología , Animales , Biomarcadores/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Reprogramación Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Senescencia Celular/genética , Células Clonales/efectos de los fármacos , Células Clonales/patología , Femenino , Humanos , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/genética , Masculino , Ratones , Ratones Transgénicos , Células Madre Neoplásicas/efectos de los fármacos , Fenotipo , Vía de Señalización Wnt/efectos de los fármacos
2.
BMC Neurol ; 20(1): 75, 2020 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-32126977

RESUMEN

BACKGROUND: Neuroprotection and promotion of remyelination represent important therapeutic gaps in multiple sclerosis (MS). Acute optic neuritis (ON) is a frequent MS manifestation. Based on the presence and properties of sphingosine-1-phosphate receptors (S1PR) on astrocytes and oligodendrocytes, we hypothesized that remyelination can be enhanced by treatment with fingolimod, a S1PR modulator currently licensed for relapsing-remitting MS. METHODS: MOVING was an investigator-driven, rater-blind, randomized clinical trial. Patients with acute unilateral ON, occurring as a clinically isolated syndrome or MS relapse, were randomized to 6 months of treatment with 0.5 mg oral fingolimod or subcutaneous IFN-ß 1b 250 µg every other day. The change in multifocal visual evoked potential (mfVEP) latency of the qualifying eye was examined as the primary (month 6 vs. baseline) and secondary (months 3, 6 and 12 vs. baseline) outcome. In addition, full field visual evoked potentials, visual acuity, optical coherence tomography as well as clinical relapses and measures of disability, cerebral MRI, and self-reported visual quality of life were obtained for follow-up. The study was halted due to insufficient recruitment (n = 15), and available results are reported. RESULTS: Per protocol analysis of the primary endpoint revealed a significantly larger reduction of mfVEP latency at 6 months compared to baseline with fingolimod treatment (n = 5; median decrease, 15.7 ms) than with IFN-ß 1b treatment (n = 4; median increase, 8.15 ms) (p <  0.001 for interaction). Statistical significance was maintained in the secondary endpoint analysis. Descriptive results are reported for other endpoints. CONCLUSION: Preliminary results of the MOVING trial argue in support of a beneficial effect of fingolimod on optic nerve remyelination when compared to IFN-ß treatment. Interpretation is limited by the small number of complete observations, an unexpected deterioration of the control group and a difference in baseline mfVEP latencies. The findings need to be confirmed in larger studies. TRIAL REGISTRATION: The trial was registered as EUDRA-CT 2011-004787-30 on October 26, 2012 and as NCT01647880 on July 24, 2012.


Asunto(s)
Clorhidrato de Fingolimod/uso terapéutico , Inmunosupresores/uso terapéutico , Neuritis Óptica/tratamiento farmacológico , Adulto , Potenciales Evocados Visuales/efectos de los fármacos , Femenino , Humanos , Interferon beta-1b/uso terapéutico , Masculino , Persona de Mediana Edad
3.
Nature ; 501(7467): 421-5, 2013 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-23945590

RESUMEN

Activated oncogenes and anticancer chemotherapy induce cellular senescence, a terminal growth arrest of viable cells characterized by S-phase entry-blocking histone 3 lysine 9 trimethylation (H3K9me3). Although therapy-induced senescence (TIS) improves long-term outcomes, potentially harmful properties of senescent tumour cells make their quantitative elimination a therapeutic priority. Here we use the Eµ-myc transgenic mouse lymphoma model in which TIS depends on the H3K9 histone methyltransferase Suv39h1 to show the mechanism and therapeutic exploitation of senescence-related metabolic reprogramming in vitro and in vivo. After senescence-inducing chemotherapy, TIS-competent lymphomas but not TIS-incompetent Suv39h1(-) lymphomas show increased glucose utilization and much higher ATP production. We demonstrate that this is linked to massive proteotoxic stress, which is a consequence of the senescence-associated secretory phenotype (SASP) described previously. SASP-producing TIS cells exhibited endoplasmic reticulum stress, an unfolded protein response (UPR), and increased ubiquitination, thereby targeting toxic proteins for autophagy in an acutely energy-consuming fashion. Accordingly, TIS lymphomas, unlike senescence models that lack a strong SASP response, were more sensitive to blocking glucose utilization or autophagy, which led to their selective elimination through caspase-12- and caspase-3-mediated endoplasmic-reticulum-related apoptosis. Consequently, pharmacological targeting of these metabolic demands on TIS induction in vivo prompted tumour regression and improved treatment outcomes further. These findings unveil the hypercatabolic nature of TIS that is therapeutically exploitable by synthetic lethal metabolic targeting.


Asunto(s)
Autofagia , Senescencia Celular , Glucosa/metabolismo , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/metabolismo , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Caspasa 12/metabolismo , Caspasa 3/metabolismo , Senescencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico , Femenino , Linfoma de Células B/genética , Linfoma de Células B/patología , Masculino , Ratones , Ratones Transgénicos , Proteolisis , Estrés Fisiológico , Tasa de Supervivencia
4.
Genes Dev ; 25(20): 2137-46, 2011 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-21979374

RESUMEN

In malignancies, enhanced nuclear factor-κB (NF-κB) activity is largely viewed as an oncogenic property that also confers resistance to chemotherapy. Recently, NF-κB has been postulated to participate in a senescence-associated and possibly senescence-reinforcing cytokine response, thereby suggesting a tumor-restraining role for NF-κB. Using a mouse lymphoma model and analyzing transcriptome and clinical data from lymphoma patients, we show here that therapy-induced senescence presents with and depends on active NF-κB signaling, whereas NF-κB simultaneously promotes resistance to apoptosis. Further characterization and genetic engineering of primary mouse lymphomas according to distinct NF-κB-related oncogenic networks reminiscent of diffuse large B-cell lymphoma (DLBCL) subtypes guided us to identify Bcl2-overexpressing germinal center B-cell-like (GCB) DLBCL as a clinically relevant subgroup with significantly superior outcome when NF-κB is hyperactive. Our data illustrate the power of cross-species investigations to functionally test genetic mechanisms in transgenic mouse tumors that recapitulate distinct features of the corresponding human entity, and to ultimately use the mouse model-derived genetic information to redefine novel, clinically relevant patient subcohorts.


Asunto(s)
Antineoplásicos/farmacología , Senescencia Celular/efectos de los fármacos , Senescencia Celular/fisiología , FN-kappa B/metabolismo , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma no Hodgkin/metabolismo , Ratones , Ratones Endogámicos C57BL , Transducción de Señal
5.
J Neurol Neurosurg Psychiatry ; 89(4): 330-338, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29248894

RESUMEN

OBJECTIVE: To investigate whether oral administration of a standardised frankincense extract (SFE) is safe and reduces disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: We performed an investigator-initiated, bicentric phase IIa, open-label, baseline-to-treatment pilot study with an oral SFE in patients with RRMS (NCT01450124). After a 4-month baseline observation phase, patients were treated for 8 months with an option to extend treatment for up to 36 months. The primary outcome measures were the number and volume of contrast-enhancing lesions (CEL) measured in MRI during the 4-month treatment period compared with the 4-month baseline period. Eighty patients were screened at two centres, 38 patients were included in the trial, 28 completed the 8-month treatment period and 18 of these participated in the extension period. RESULTS: The SFE significantly reduced the median number of monthly CELs from 1.00 (IQR 0.75-3.38) to 0.50 (IQR 0.00-1.13; difference -0.625, 95% CI -1.25 to -0.50; P<0.0001) at months 5-8. We observed significantly less brain atrophy as assessed by parenchymal brain volume change (P=0.0081). Adverse events were generally mild (57.7%) or moderate (38.6%) and comprised mainly gastrointestinal symptoms and minor infections. Mechanistic studies showed a significant increase in regulatory CD4+ T cell markers and a significant decrease in interleukin-17A-producing CD8+ T cells indicating a distinct mechanism of action of the study drug. INTERPRETATION: The oral SFE was safe, tolerated well and exhibited beneficial effects on RRMS disease activity warranting further investigation in a controlled phase IIb or III trial. CLINICAL TRIAL REGISTRATION: NCT01450124; Results.


Asunto(s)
Olíbano/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Administración Oral , Adulto , Atrofia , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Proyectos Piloto , Extractos Vegetales/uso terapéutico , Resultado del Tratamiento
6.
Mult Scler ; 23(7): 963-972, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27679460

RESUMEN

BACKGROUND: Previous studies have postulated an association between dentate nucleus T1 hyperintensity and multiple sclerosis (MS)-related progressive neurodegeneration. Therefore, MS patients have been excluded from most studies investigating brain deposition of gadolinium-based contrast agents (GBCAs). OBJECTIVE: To study the hypothesis that dentate nucleus T1 hyperintensity in MS patients is associated with GBCA administration. METHODS: In a cohort of 97 MS patients, the dentate-to-pons signal intensity ratio (DPSIR) was calculated for 265 consecutive T1-weighted magnetic resonance (MR) scans (including sessions with and without the administration of GBCA). Patients exclusively received either gadopentetate dimeglumine (Gd-DTPA, linear) or gadobutrol (Gd-BT-DO3A, macrocyclic). RESULTS: In patients receiving Gd-DTPA, DPSIR increased significantly between the first and the last scan (+0.009, p < 0.001), and following magnetic resonance imaging (MRI) with Gd-DTPA administration as compared to following an MRI without Gd-DTPA administration (+0.005 vs -0.001; p = 0.022). Additionally, there was a positive linear relationship between the number of Gd-DTPA administrations and the increase in DPSIR ( p = 0.017). No DPSIR increase was observed after Gd-BT-DO3A administration. CONCLUSION: Dentate nucleus T1 hyperintensity in MS patients is associated with Gd-DTPA (but not Gd-BT-DO3A) administration, suggesting an alternative explanation for the association of T1 hyperintensity with disease duration and severity.


Asunto(s)
Núcleos Cerebelosos/diagnóstico por imagen , Medios de Contraste/metabolismo , Gadolinio DTPA/metabolismo , Esclerosis Múltiple Crónica Progresiva/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Compuestos Organometálicos/metabolismo , Adulto , Núcleos Cerebelosos/metabolismo , Medios de Contraste/administración & dosificación , Bases de Datos Factuales , Femenino , Gadolinio DTPA/administración & dosificación , Humanos , Modelos Lineales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/metabolismo , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Compuestos Organometálicos/administración & dosificación , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Distribución Tisular
7.
J Neurol Neurosurg Psychiatry ; 87(12): 1287-1295, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28103199

RESUMEN

BACKGROUND: Susac syndrome is characterised by the triad of encephalopathy with or without focal neurological signs, branch retinal artery occlusions and hearing loss. Establishment of the diagnosis is often delayed because the triad is complete only in a minority of patients at disease onset. This leads to a critical delay in the initiation of appropriate treatment. Our objective was to establish criteria for diagnosis of either definite or probable Susac syndrome. METHOD: The establishment of diagnostic criteria was based on the following three steps: (1) Definition of a reference group of 32 patients with an unambiguous diagnosis of Susac syndrome as assessed by all interdisciplinary experts of the European Susac Consortium (EuSaC) team (EuSaC cohort); (2) selection of diagnostic criteria, based on common clinical and paraclinical findings in the EuSaC cohort and on a review of the literature; and (3) validation of the proposed criteria in the previously published cohort of all Susac cases reported until 2012. RESULTS: Integrating the clinical presentation and paraclinical findings, we propose formal criteria and recommend a diagnostic workup to facilitate the diagnosis of Susac syndrome. More than 90% of the cases in the literature fulfilled the proposed criteria for probable or definite Susac syndrome. We surmise that more patients could have been diagnosed with the recommended diagnostic workup. CONCLUSIONS: We propose diagnostic criteria for Susac syndrome that may help both experts and physicians not familiar with Susac syndrome to make a correct diagnosis and to prevent delayed treatment initiation.


Asunto(s)
Síndrome de Susac/diagnóstico , Adolescente , Adulto , Estudios de Cohortes , Diagnóstico Tardío , Diagnóstico Diferencial , Intervención Médica Temprana , Femenino , Adhesión a Directriz , Humanos , Comunicación Interdisciplinaria , Colaboración Intersectorial , Masculino , Persona de Mediana Edad , Valores de Referencia , Síndrome de Susac/terapia , Adulto Joven
8.
Eur J Neurol ; 23(1): 62-7, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26220765

RESUMEN

BACKGROUND AND PURPOSE: Low 25-hydroxyvitamin D [25(OH)D] levels correlate with higher disease activity in patients with multiple sclerosis (MS). However, it is not clear whether low 25(OH)D levels directly contribute to increased disease activity or merely represent a consequence of reduced endogenous vitamin D synthesis in more disabled MS patients. Furthermore, recent data suggest that bioavailable vitamin D, which also integrates the levels of vitamin D binding proteins and albumin, could be a biologically more relevant parameter than 25(OH)D. METHODS: Measured de-seasonalized 25(OH)D3 and vitamin D binding protein and calculated bioavailable and free vitamin D were compared in the baseline serum samples of 76 patients with clinically isolated syndrome enrolled in a longitudinal observational study and in 76 age- and sex-matched healthy controls (HC). RESULTS: 25(OH)D3 levels were lower in patients with clinically isolated syndrome (P = 0.002) than in HC, and more patients (8/76, 10.5%) than HC (1/76, 1.3%) had 25(OH)D3 levels <25 nmol/l (P = 0.03). In contrast, levels of 25(OH)D2, vitamin D binding protein and calculated levels of free and bioavailable vitamin D did not differ between the two groups. CONCLUSIONS: Lower 25(OH)D3 levels already in the earliest phase of disease and in clinically hardly affected patients suggest that low 25(OH)D3 levels are rather a risk factor for than a consequence of MS. Nevertheless, because bioavailable vitamin D levels did not differ between the two groups, the mechanism underlying the association of 25(OH)D3 and MS does not appear to be related to reduced bioavailability of vitamin D.


Asunto(s)
Calcifediol/sangre , Ergocalciferoles/sangre , Esclerosis Múltiple/sangre , Vitamina D/análogos & derivados , Adulto , Disponibilidad Biológica , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Factores de Riesgo , Vitamina D/sangre , Adulto Joven
9.
Retina ; 36(2): 366-74, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26200513

RESUMEN

PURPOSE: To describe retinal lesion development in Susac syndrome during acute, postacute, and late phases of the disease. METHODS: Cross-sectional study of four patients with Susac syndrome and longitudinal short-interval case study of one additional patient. Retinal changes were analyzed with high-resolution spectral domain optical coherence tomography and retinal fluorescein angiography. RESULTS: Retinal Susac syndrome lesions comprise four different lesion sections, which can be distinguished in acute and postacute phases of the disease: a primary section at the site of branch retinal artery occlusion, which spans more layers than supplied by the affected vessel; hypoxic sections from superficial and deep capillary networks; and an axonal damage section with degenerating axons from perished ganglion cells in the main and hypoxic sections. In the later stages, main and hypoxic lesion sections can no longer be distinguished, and both show degeneration from outer plexiform to retinal nerve fiber layers. CONCLUSION: The dynamics of lesion development and morphologically distinct lesion sections suggest more complex mechanisms of lesion evolution beyond an isolated endothelial immune reaction and subsequent hypoxic tissue damage. The characteristic lesion morphology assists in differentiating the diagnosis of acute visual loss in neuroinflammatory disease. Specificity of the identified changes has to be determined in future studies also including patients with other retinal vascular diseases.


Asunto(s)
Arteria Retiniana/patología , Enfermedades de la Retina/diagnóstico , Síndrome de Susac/diagnóstico , Enfermedad Aguda , Anciano , Enfermedad Crónica , Estudios Transversales , Femenino , Angiografía con Fluoresceína , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Enfermedades de la Retina/fisiopatología , Síndrome de Susac/fisiopatología , Tomografía de Coherencia Óptica , Agudeza Visual
10.
Eur Radiol ; 25(1): 122-31, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25129119

RESUMEN

OBJECTIVE: To investigate posterior visual pathway damage in multiple sclerosis using ultrahigh-field magnetic resonance imaging (MRI) at 7 Tesla (7 T), and to determine its correlation with visual disability and retinal fibre layer (RNFL) damage detectable by optic coherence tomography (OCT). METHODS: We studied 7 T MRI, OCT, functional acuity contrast testing (FACT), and visually evoked potentials (VEP, n = 16) in 30 patients (including 26 relapsing-remitting MS and four clinically isolated syndrome patients) and 12 healthy controls to quantify RNFL thickness, optic radiation lesion volume, and optic radiation thickness. RESULTS: Optic radiation lesion volume was associated with thinning of the optic radiation (p < 0.001), delayed VEP (p = 0.031), and visual disability indicated by FACT (p = 0.020). Furthermore, we observed an inverse correlation between optic radiation lesion volume and RNFL thickness (p < 0.001), including patients without previous optic neuritis (p < 0.001). CONCLUSIONS: Anterior visual pathway damage, but also (subclinical) optic radiation integrity loss detectable by 7 T MRI are common findings in MS that are mutually affected. Given the association between optic radiation damage, visual impairment, and increased VEP latency in this exploratory study of a limited sample size, clinicians should be aware of acute lesions within the optic radiation in patients with (bilateral) visual disturbances. KEY POINTS: • Focal destruction of the optic radiation is detectable by 7 T MRI. • Focal optic radiation damage is common in MS. • Optic radiation damage is associated with RNFL thinning, detectable by OCT. • Optic radiation damage is associated with delayed VEP and visual dysfunction. • RNFL thickness in non-optic neuritis eyes correlates with optic radiation demyelination.


Asunto(s)
Esclerosis Múltiple Recurrente-Remitente/patología , Neuritis Óptica/patología , Trastornos de la Visión/etiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Potenciales Evocados Visuales , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fibras Nerviosas/patología , Músculos Oculomotores/patología , Proyectos Piloto , Estudios Prospectivos , Enfermedades de la Retina/patología , Tomografía de Coherencia Óptica , Trastornos de la Visión/patología , Adulto Joven
11.
J Neuroinflammation ; 11: 46, 2014 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-24606999

RESUMEN

BACKGROUND: Susac syndrome (SuS) is a rare disorder thought to be caused by autoimmune-mediated occlusions of microvessels in the brain, retina and inner ear leading to central nervous system (CNS) dysfunction, visual disturbances due to branch retinal artery occlusions (BRAO), and hearing deficits. Recently, a role for anti-endothelial cell antibodies (AECA) in SuS has been proposed. OBJECTIVES: To report the clinical and paraclinical findings in the largest single series of patients so far and to investigate the frequency, titers, and clinical relevance of AECA in SuS. PATIENTS AND METHODS: A total of 107 serum samples from 20 patients with definite SuS, 5 with abortive forms of SuS (all with BRAO), and 70 controls were tested for AECA by immunohistochemistry employing primate brain tissue sections. RESULTS: IgG-AECA >1:100 were detected in 25% (5/20) of patients with definite SuS and in 4.3% (3/70) of the controls. Median titers were significantly higher in SuS (1:3200, range 1:100 to 1:17500) than in controls (1:100, range 1:10 to 1:320); IgG-AECA titers >1:320 were exclusively present in patients with SuS; three controls had very low titers (1:10). Follow-up samples (n = 4) from a seropositive SuS patient obtained over a period of 29 months remained positive at high titers. In all seropositive cases, AECA belonged to the complement-activating IgG1 subclass. All but one of the IgG-AECA-positive samples were positive also for IgA-AECA and 45% for IgM-AECA. SuS took a severe and relapsing course in most patients and was associated with bilateral visual and hearing impairment, a broad panel of neurological and neuropsychological symptoms, and brain atrophy in the majority of cases. Seropositive and seronegative patients did not differ with regard to any of the clinical or paraclinical parameters analyzed. CONCLUSIONS: SuS took a severe and protracted course in the present cohort, resulting in significant impairment. Our finding of high-titer IgG1 and IgM AECA in some patients suggest that humoral autoimmunity targeting the microvasculature may play a role in the pathogenesis of SuS, at least in a subset of patients. Further studies are warranted to define the exact target structures of AECA in SuS.


Asunto(s)
Autoanticuerpos/sangre , Síndrome de Susac/sangre , Síndrome de Susac/diagnóstico , Adolescente , Adulto , Anciano , Trastornos del Conocimiento/etiología , Enfermedades del Tejido Conjuntivo/sangre , Trastornos de la Audición/etiología , Humanos , Inmunoglobulina G/sangre , Cooperación Internacional , Recuento de Leucocitos , Vasculitis por Lupus del Sistema Nervioso Central/sangre , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Pruebas Serológicas , Síndrome de Susac/complicaciones , Trastornos de la Visión/etiología , Adulto Joven
12.
Mult Scler ; 20(14): 1866-71, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24781284

RESUMEN

Potential differences between primary progressive (PP) and relapsing-remitting (RR) multiple sclerosis (MS) have been controversially discussed. In this study, we compared lesion morphology and distribution in patients with PPMS and RRMS (nine in each group) using 7 T MRI. We found that gray and white matter lesions in PPMS and RRMS patients did not differ in their respective morphological characteristics (e.g., perivascular p = 0.863, hypointense rim p = 0.796, cortical lesion count p = 0.436). Although limited by a small sample size, our study results suggest that PPMS and RRMS, despite differences in disease course and clinical characteristics, exhibit identical lesion morphology under ultrahigh field MRI.


Asunto(s)
Corteza Cerebral/patología , Sustancia Gris/patología , Esclerosis Múltiple Crónica Progresiva/patología , Esclerosis Múltiple Recurrente-Remitente/patología , Sustancia Blanca/patología , Adulto , Encéfalo/patología , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad
13.
Mult Scler ; 20(3): 295-303, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23836875

RESUMEN

BACKGROUND: MicroRNAs (miRNAs) are short, noncoding RNAs with gene regulatory functions whose expression profiles may serve as disease biomarkers. OBJECTIVE: The objective of this study was to perform a comprehensive analysis of miRNA expression profiles in blood of patients with a clinically isolated syndrome (CIS) or relapsing-remitting multiple sclerosis (RRMS) including next-generation sequencing (NGS). METHODS: miRNA expression was analyzed in whole blood samples from treatment-naïve patients with CIS (n = 25) or RRMS (n = 25) and 50 healthy controls by NGS, microarray analysis, and quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: In patients with CIS/RRMS, NGS and microarray analysis identified 38 and eight significantly deregulated miRNAs, respectively. Three of these miRNAs were found to be significantly up- (hsa-miR-16-2-3p) or downregulated (hsa-miR-20a-5p, hsa-miR-7-1-3p) by both methods. Another five of the miRNAs significantly deregulated in the NGS screen showed the same direction of regulation in the microarray analysis. qRT-PCR confirmed the direction of regulation for all eight and was significant for three miRNAs. CONCLUSIONS: This study identifies a set of miRNAs deregulated in CIS/RRMS and reconfirms the previously reported underexpression of hsa-miR-20a-5p in MS. hsa-miR-20a-5p and the other validated miRNAs may represent promising candidates for future evaluation as biomarkers for MS and could be of relevance in the pathophysiology of this disease.


Asunto(s)
Enfermedades Desmielinizantes/genética , MicroARNs/genética , Esclerosis Múltiple Recurrente-Remitente/genética , Biología Computacional , Regulación hacia Abajo , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos
14.
Neuropsychobiology ; 69(2): 112-9, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24643119

RESUMEN

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive, safe and efficacious technique for treating various neuropsychiatric disorders, but its underlying mechanisms are poorly understood. A newly developed H-coil allows the stimulation of deeper brain regions. This study is the first to investigate the effects of deep high-frequency rTMS on brain-derived neurotrophic factor (BDNF) serum concentrations in healthy volunteers. We aimed to evaluate the short-term effect of deep rTMS on BDNF serum concentrations. METHODS: This was a double-blind, randomized deep high-frequency rTMS study using an H-coil on a cohort of 13 healthy volunteers (NCT01106365). The following stimulation protocols were applied: 18-Hz stimulation of the left dorsolateral prefrontal cortex (PFC), 5-Hz stimulation of the primary motor cortex (MC) and sham stimulation in random order. Blood samples were obtained before, 30 min after and 60 min after each treatment. RESULTS: The BDNF serum concentration decreased significantly after MC and PFC stimulation, but not after sham stimulation. Furthermore, BDNF serum level changes were associated with changes in individual alertness. CONCLUSION: Although BDNF serum concentrations do not necessarily correlate with BDNF levels in the cerebrospinal fluid or the brain, these results indicate an acute biological effect of deep rTMS on BDNF release, and demonstrate that this change correlates with alertness.


Asunto(s)
Nivel de Alerta/fisiología , Factor Neurotrófico Derivado del Encéfalo/sangre , Corteza Motora/fisiología , Corteza Prefrontal/fisiología , Estimulación Magnética Transcraneal , Adulto , Análisis Químico de la Sangre , Estudios de Cohortes , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tiempo de Reacción , Factores de Tiempo , Estimulación Magnética Transcraneal/métodos , Adulto Joven
15.
BMC Neurol ; 14: 31, 2014 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-24555757

RESUMEN

BACKGROUND: Although common and often disabling in multiple sclerosis (MS), visual dysfunction is currently not adequately accounted for in both clinical routine and MS trials. Sloan low contrast letter acuity (SLCLA) is a standardised chart-based measure of visual function particular at low contrast and has been suggested as additional visual component to the Multiple Sclerosis Functional Composite (MSFC). Here, we evaluate the relations between SLCLA, retinal integrity, MSFC, and quality of life (QoL) in MS patients. METHODS: Cross-sectional analysis of retinal nerve fibre layer (RNFL) thickness, MSFC, SLCLA (2.5% and 1.25% contrast levels), visual evoked potentials, and QoL (Short Form (SF) 36, National Eye Institute Visual Functioning Questionnaire (NEIVFQ)) using baseline data of 92 MS patients from an ongoing prospective longitudinal trial. Relations between RNFL thickness or P100 latency and SLCLA were analysed using generalised estimating equations (GEE) accounting for intra-individual inter-eye dependencies and corrected for age, gender, and history of optic neuritis. Pearson's correlations were used to assess relations between SLCLA, MSFC, and QoL. RESULTS: SLCLA reflected RNFL thickness (p = 0.021) and P100 latency (p = 0.004) and predicted vision-related QoL, reflected by the NEIVFQ39 subscores "general vision" and "near activities" (p < 0.008 for both). SLCLA did not predict general QoL reflected by SF36. Implementing SLCLA into MSFC, thus creating a four-dimensional MSFC4, captured aspects of disability reflected by the NEIVFQ39 subscores "general vision" (r = 0.42, p < 0.0001) and "near activity" (r = 0.3, p = 0.014) which were not captured by standard MSFC3. CONCLUSIONS: SLCLA at 2.5% and 1.25% contrast levels correlates with retinal morphology and P100 latency and predicts some aspects of vision-related QoL in MS. More importantly, using a prospective cross-sectional approach we provide evidence that extending the MSFC by SLCLA as an additional visual component increases the performance of MSFC to capture MS-related disability. Longitudinal data on the relation between SLCLA, MSFC, and QoL will be available in the near future.


Asunto(s)
Sensibilidad de Contraste/fisiología , Esclerosis Múltiple/fisiopatología , Esclerosis Múltiple/psicología , Calidad de Vida/psicología , Agudeza Visual/fisiología , Adulto , Estudios de Cohortes , Estudios Transversales , Potenciales Evocados Visuales/fisiología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico
16.
Eur Neurol ; 71(1-2): 89-92, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24335148

RESUMEN

BACKGROUND: Susac syndrome is a rare disease characterized by the triad of encephalopathy, branch retinal artery occlusion, and sensorineural hearing loss mainly affecting young women. The finding of antibodies against the endothelium in the sera of these patients has supported the hypothesis of an autoimmune endotheliopathy of the brain, inner ear and retina. Because of the rarity of the disease, treatment is based on the knowledge of case reports and small case series. Medical therapy consists of glucocorticoids, immunosuppressants, acetyl salicylic acid, and immunomodulatory agents such as intravenous immunoglobulin. METHODS: We present the case histories of 2 young women with Susac syndrome presenting with several episodes of encephalopathy, branch retinal artery occlusions, and hearing loss that were treated with different immunosuppressive drugs, glucocorticoids and intravenous immunoglobulin. In the course of the disease, the treatment was successfully switched to subcutaneous immunoglobulin without any further relapse in both patients. CONCLUSION: We conclude that the application of subcutaneous immunoglobulin is easy to learn, helps to reduce in-hospital costs and enables a more flexible everyday life. The treatment with subcutaneous immunoglobulin helps to reduce immunosuppressants and appears to prevent relapses.


Asunto(s)
Inmunoglobulinas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Síndrome de Susac/terapia , Femenino , Humanos , Inmunoglobulinas/administración & dosificación , Factores Inmunológicos/administración & dosificación , Bombas de Infusión Implantables , Infusiones Subcutáneas , Autoadministración , Síndrome de Susac/diagnóstico , Resultado del Tratamiento , Adulto Joven
17.
Neurol Neuroimmunol Neuroinflamm ; 11(3): e200209, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38364193

RESUMEN

Susac syndrome (SuS) is an orphan microangiopathic disease characterized by a triad of encephalopathy, visual disturbances due to branch retinal artery occlusions, and sensorineuronal hearing loss. Our previous systematic review on all cases of SuS reported until 2012 allowed for a better understanding of clinical presentation and diagnostic findings. Based on these data, we suggested diagnostic criteria in 2016 to allow early diagnosis and treatment of SuS. In view of the accumulation of new SuS cases reported in the last 10 years and improved diagnostic tools, we here aimed at updating the demographic and clinical features of SuS and to review the updated ancillary tests being used for SuS diagnosis. Therefore, based on the 2016 criteria, we systematically collected and evaluated data on SuS published from January 2013 to March 2022.


Asunto(s)
Síndrome de Susac , Síndrome de Susac/diagnóstico , Humanos
18.
Cancer Discov ; 14(3): 492-507, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38197697

RESUMEN

DNA amplifications in cancer do not only harbor oncogenes. We sought to determine whether passenger coamplifications could create collateral therapeutic vulnerabilities. Through an analysis of >3,000 cancer genomes followed by the interrogation of CRISPR-Cas9 loss-of-function screens across >700 cancer cell lines, we determined that passenger coamplifications are accompanied by distinct dependency profiles. In a proof-of-principle study, we demonstrate that the coamplification of the bona fide passenger gene DEAD-Box Helicase 1 (DDX1) creates an increased dependency on the mTOR pathway. Interaction proteomics identified tricarboxylic acid (TCA) cycle components as previously unrecognized DDX1 interaction partners. Live-cell metabolomics highlighted that this interaction could impair TCA activity, which in turn resulted in enhanced mTORC1 activity. Consequently, genetic and pharmacologic disruption of mTORC1 resulted in pronounced cell death in vitro and in vivo. Thus, structurally linked coamplification of a passenger gene and an oncogene can result in collateral vulnerabilities. SIGNIFICANCE: We demonstrate that coamplification of passenger genes, which were largely neglected in cancer biology in the past, can create distinct cancer dependencies. Because passenger coamplifications are frequent in cancer, this principle has the potential to expand target discovery in oncology. This article is featured in Selected Articles from This Issue, p. 384.


Asunto(s)
Neoplasias , Oncogenes , Humanos , Neoplasias/genética , Oncología Médica , Muerte Celular , Diana Mecanicista del Complejo 1 de la Rapamicina/genética
19.
Mult Scler ; 19(3): 316-25, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22736752

RESUMEN

BACKGROUND: Damage to venules in multiple sclerosis was first described decades ago. Today, ultrahigh magnetic field strength T2*-weighted magnetic resonance imaging (MRI) techniques depict very small cerebral veins in vivo with great anatomical detail. OBJECTIVE: We aimed to investigate alterations of periventricular small blood vessel appearance in relation to T2 lesion count and distribution in multiple sclerosis and clinically isolated syndrome in comparison with healthy control subjects at 7 Tesla MRI. METHODS: We investigated 38 patients (including 16 with early multiple sclerosis and seven with clinically isolated syndrome) and 22 matched healthy controls at 7 Tesla. The protocol included T2*-weighted Fast Low Angle Shot, and T2-weighted Turbo Inversion Recovery Magnitude sequences. We quantified periventricular venous density by a novel region-of-interest-based algorithm, expressing the ratio of 'veins per region-of-interest' as well as of 'periventricular vascular area'. RESULTS: Our study revealed significantly decreased venous density in multiple sclerosis patients compared with healthy controls. Venous alterations were already detectable in clinically isolated syndrome and early multiple sclerosis, although to a smaller extent. Venous density correlated inversely with periventricular and whole-brain T2 lesion count. Furthermore, we found no indication for cerebral venous congestion in multiple sclerosis. CONCLUSION: High spatially resolving anatomical T2*-weighted MRI revealed vascular alterations in early stages of multiple sclerosis, presumably as a part of widespread haemodynamic and metabolic alterations.


Asunto(s)
Venas Cerebrales/patología , Ventrículos Cerebrales/patología , Imagen por Resonancia Magnética/métodos , Esclerosis Múltiple/patología , Adulto , Anciano , Ventrículos Cerebrales/irrigación sanguínea , Enfermedades Desmielinizantes/patología , Femenino , Humanos , Imagen por Resonancia Magnética/instrumentación , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/fisiopatología , Índice de Severidad de la Enfermedad , Adulto Joven
20.
Mult Scler ; 19(4): 443-50, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22936335

RESUMEN

BACKGROUND: Retinal nerve fibre layer (RNFL) thinning is associated with brain atrophy in multiple sclerosis (MS). An influence of optic neuritis is well documented but sparsely investigated. Recently, the retinal ganglion cell layer (GCL) has been shown to provide superior information regarding visual function and retinal neurodegeneration as compared with RNFL. OBJECTIVE: To investigate the association of white and grey matter brain volume with peripapillary RNFL and macular GCL in MS patients with and without a history of optic neuritis. METHODS: 63 patients with relapsing-remitting MS were included in a two-centre cross-sectional prospective study. All patients underwent retinal examination with spectral domain optical coherence tomography and 1.5 T MRI for determination of normalized brain volume (NBV), white matter volume (NWMV) and grey matter volume (NGMV). RESULTS: Both RNFL and GCL were associated with NBV, NWMV and NGMV in eyes without previous optic neuritis. This association is disrupted in the case of NGMV following optic neuritis. CONCLUSIONS: Both RNFL and GCL as parameters of neuro-axonal damage are comparably linked to whole brain as well as white and grey matter atrophy. An event of optic neuritis interferes with this relation, adding further damage to the optic nerve and disrupting especially an association with grey matter.


Asunto(s)
Encéfalo/patología , Esclerosis Múltiple Recurrente-Remitente/patología , Neuritis Óptica/patología , Células Ganglionares de la Retina/patología , Adulto , Estudios Transversales , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Fibras Nerviosas Mielínicas/patología , Neuritis Óptica/complicaciones , Neuronas Retinianas/patología , Tomografía de Coherencia Óptica , Adulto Joven
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