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1.
Neurol Res Pract ; 6(1): 15, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38449051

RESUMO

INTRODUCTION: In Multiple Sclerosis (MS), patients´ characteristics and (bio)markers that reliably predict the individual disease prognosis at disease onset are lacking. Cohort studies allow a close follow-up of MS histories and a thorough phenotyping of patients. Therefore, a multicenter cohort study was initiated to implement a wide spectrum of data and (bio)markers in newly diagnosed patients. METHODS: ProVal-MS (Prospective study to validate a multidimensional decision score that predicts treatment outcome at 24 months in untreated patients with clinically isolated syndrome or early Relapsing-Remitting-MS) is a prospective cohort study in patients with clinically isolated syndrome (CIS) or Relapsing-Remitting (RR)-MS (McDonald 2017 criteria), diagnosed within the last two years, conducted at five academic centers in Southern Germany. The collection of clinical, laboratory, imaging, and paraclinical data as well as biosamples is harmonized across centers. The primary goal is to validate (discrimination and calibration) the previously published DIFUTURE MS-Treatment Decision score (MS-TDS). The score supports clinical decision-making regarding the options of early (within 6 months after study baseline) platform medication (Interferon beta, glatiramer acetate, dimethyl/diroximel fumarate, teriflunomide), or no immediate treatment (> 6 months after baseline) of patients with early RR-MS and CIS by predicting the probability of new or enlarging lesions in cerebral magnetic resonance images (MRIs) between 6 and 24 months. Further objectives are refining the MS-TDS score and providing data to identify new markers reflecting disease course and severity. The project also provides a technical evaluation of the ProVal-MS cohort within the IT-infrastructure of the DIFUTURE consortium (Data Integration for Future Medicine) and assesses the efficacy of the data sharing techniques developed. PERSPECTIVE: Clinical cohorts provide the infrastructure to discover and to validate relevant disease-specific findings. A successful validation of the MS-TDS will add a new clinical decision tool to the armamentarium of practicing MS neurologists from which newly diagnosed MS patients may take advantage. Trial registration ProVal-MS has been registered in the German Clinical Trials Register, `Deutsches Register Klinischer Studien` (DRKS)-ID: DRKS00014034, date of registration: 21 December 2018; https://drks.de/search/en/trial/DRKS00014034.

2.
Cell Death Dis ; 10(8): 571, 2019 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358732

RESUMO

Deregulated cell death pathways contribute to leukemogenesis and treatment failure in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Intrinsic apoptosis signaling is regulated by different proapoptotic and antiapoptotic molecules: proapoptotic BCL-2 homology domain 3 (BH3) proteins activate prodeath molecules leading to cellular death, while antiapoptotic molecules including B-cell lymphoma 2 (BCL-2) prevent activation of prodeath proteins and counter-regulate apoptosis induction. Inhibition of these antiapoptotic regulators has become a promising strategy for anticancer treatment, but variable anticancer activities in different malignancies indicate the need for upfront identification of responsive patients. Here, we investigated the activity of the BCL-2 inhibitor venetoclax (VEN, ABT-199) in B-cell precursor acute lymphoblastic leukemia and found heterogeneous sensitivities in BCP-ALL cell lines and in a series of patient-derived primografts. To identify parameters of sensitivity and resistance, we evaluated genetic aberrations, gene-expression profiles, expression levels of apoptosis regulators, and functional apoptosis parameters analyzed by mitochondrial profiling using recombinant BH3-like peptides. Importantly, ex vivo VEN sensitivity was most accurately associated with functional BCL-2 dependence detected by BH3 profiling. Modeling clinical application of VEN in a preclinical trial in a set of individual ALL primografts, we identified that leukemia-free survival of VEN treated mice was precisely determined by functional BCL-2 dependence. Moreover, the predictive value of ex vivo measured functional BCL-2 dependence for preclinical in vivo VEN response was confirmed in an independent set of primograft ALL including T- and high risk-ALL. Thus, integrative analysis of the apoptosis signaling indicating mitochondrial addiction to BCL-2 accurately predicts antileukemia activity of VEN, robustly identifies VEN-responsive patients, and provides information for stratification and clinical guidance in future clinical applications of VEN in patients with ALL.


Assuntos
Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Sulfonamidas/farmacologia , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Transdução de Sinais/efeitos dos fármacos
3.
PLoS One ; 14(5): e0216862, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31086407

RESUMO

Polytrauma (PT) is a life-threatening disease and a major global burden of injury. Mesenchymal stromal cells (MSC) might be a therapeutic option for PT patients due to their anti-inflammatory and regenerative potential. We hypothesised that the inflammatory response of MSC is similar after exposure to selected trauma-relevant factors to sera from PT patients (PTS). Therefore, we investigated the effects of a mixture of defined factors, supposed to play a role on MSC in the early phase of PT. Additionally, in a translational approach we investigated the effect of serum from PT patients on MSC in vitro. MSC were incubated with a PT cocktail in physiological (PTCL) and supra-physiological (PTCH) concentrations or PTS. The effect on gene expression and protein secretion of MSC was analysed by RNA sequencing, ELISA and Multiplex assays of cell culture supernatant. Stimulation of MSC with PTCH, PTCL or IL1B led to significant up- or downregulation of 470, 183 and 469 genes compared to unstimulated MSC at 6 h. The intersection of differentially expressed genes in these groups was very high (92% overlap with regard to the PTCL group; treated for 6 h). Cytokine secretion profile of MSC revealed that IL1B mimics the effect of a more complex PT cocktail as well. However, there was only a minor proportion of overlapping differentially expressed genes between the MSC group stimulated with early times of PTS and the MSC group stimulated with PTCH, PTCL and IL1B. In conclusion, the effect of sera from PT patients on MSC activation cannot be simulated by the chosen trauma-relevant factors. Furthermore, we conclude that while IL1B might be useful to prime MSC prior to therapeutic application, it might not be as useful for the in vitro study of functional properties of MSC in the context of PT.


Assuntos
Inflamação/imunologia , Células-Tronco Mesenquimais/imunologia , Traumatismo Múltiplo/imunologia , Adulto , Células Cultivadas , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Inflamação/sangue , Inflamação/complicações , Inflamação/patologia , Masculino , Células-Tronco Mesenquimais/patologia , Pessoa de Meia-Idade , Traumatismo Múltiplo/sangue , Traumatismo Múltiplo/complicações , Traumatismo Múltiplo/patologia , Adulto Jovem
4.
Biology (Basel) ; 6(4)2017 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-29258225

RESUMO

Biological pathways are thought to be robust against a variety of internal and external perturbations. Fail-safe mechanisms allow for compensation of perturbations to maintain the characteristic function of a pathway. Pathways can undergo changes during aging, which may lead to changes in their stability. Less stable or less robust pathways may be consequential to or increase the susceptibility of the development of diseases. Among others, NF- κ B signaling is a crucial pathway in the process of aging. The NF- κ B system is involved in the immune response and dealing with various internal and external stresses. Boolean networks as models of biological pathways allow for simulation of signaling behavior. They can help to identify which proposed mechanisms are biologically representative and which ones function but do not mirror physical processes-for instance, changes of signaling pathways during the aging process. Boolean networks can be inferred from time-series of gene expression data. This allows us to get insights into the changes of behavior of pathways such as NF- κ B signaling in aged organisms in comparison to young ones.

5.
Nature ; 503(7476): 392-6, 2013 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-24141946

RESUMO

Many organs with a high cell turnover (for example, skin, intestine and blood) are composed of short-lived cells that require continuous replenishment by somatic stem cells. Ageing results in the inability of these tissues to maintain homeostasis and it is believed that somatic stem-cell ageing is one underlying cause of tissue attrition with age or age-related diseases. Ageing of haematopoietic stem cells (HSCs) is associated with impaired haematopoiesis in the elderly. Despite a large amount of data describing the decline of HSC function on ageing, the molecular mechanisms of this process remain largely unknown, which precludes rational approaches to attenuate stem-cell ageing. Here we report an unexpected shift from canonical to non-canonical Wnt signalling in mice due to elevated expression of Wnt5a in aged HSCs, which causes stem-cell ageing. Wnt5a treatment of young HSCs induces ageing-associated stem-cell apolarity, reduction of regenerative capacity and an ageing-like myeloid-lymphoid differentiation skewing via activation of the small Rho GTPase Cdc42. Conversely, Wnt5a haploinsufficiency attenuates HSC ageing, whereas stem-cell-intrinsic reduction of Wnt5a expression results in functionally rejuvenated aged HSCs. Our data demonstrate a critical role for stem-cell-intrinsic non-canonical Wnt5a signalling in HSC ageing.


Assuntos
Senescência Celular , Células-Tronco Hematopoéticas/citologia , Via de Sinalização Wnt , Animais , Diferenciação Celular , Polaridade Celular , Feminino , Haploinsuficiência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Rejuvenescimento , Proteínas Wnt/deficiência , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Proteína Wnt-5a , Proteína cdc42 de Ligação ao GTP/metabolismo
6.
Cancer Cell ; 19(2): 206-17, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21295523

RESUMO

We investigated the engraftment properties and impact on patient outcome of 50 pediatric acute lymphoblastic leukemia (ALL) samples transplanted into NOD/SCID mice. Time to leukemia (TTL) was determined for each patient sample engrafted as weeks from transplant to overt leukemia. Short TTL was strongly associated with high risk for early relapse, identifying an independent prognostic factor. This high-risk phenotype is reflected by a gene signature that upon validation in an independent patient cohort (n = 197) identified a high-risk cluster of patients with early relapse. Furthermore, the signature points to independent pathways, including mTOR, involved in cell growth and apoptosis. The pathways identified can directly be targeted, thereby offering additional treatment approaches for these high-risk patients.


Assuntos
Perfilação da Expressão Gênica , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Animais , Apoptose/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Recidiva , Análise de Sobrevida , Transplante Heterólogo
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