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1.
Target Oncol ; 18(3): 327-358, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37074594

RESUMEN

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are the preferred regimen for patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced or metastatic breast cancer. However, the optimal treatment sequencing for CDK4/6i with other available therapeutic options is unclear. We conducted a targeted literature review to identify the current evidence on CDK4/6i treatment patterns in patients with breast cancer. The search was initially conducted in October 2021 and subsequently updated in October 2022. Biomedical databases and gray literature were searched, and bibliographies of included reviews were screened for relevant studies. The search identified ten reviews published since 2021 and 87 clinical trials or observational studies published since 2015. The included reviews discussed CDK4/6i usage with or without endocrine therapy (ET) in first-line and second-line treatment for patients with HR+/HER2- advanced or metastatic breast cancer, followed by ET, chemotherapy, or targeted therapy with ET. Clinical studies reported similar treatment sequences consisting of ET, chemotherapy, or targeted therapy with ET prior to CDK4/6i with ET, followed by ET monotherapy, chemotherapy, targeted therapy with ET, or continued CDK4/6i with ET. Current evidence suggests CDK4/6i are effective for HR+/HER2- advanced or metastatic breast cancer in earlier lines of therapy. Efficacy of CDK4/6i as measured by progression-free survival and overall survival was similar within a line of therapy regardless of the type of prior therapy. Survival on different post-CDK4/6i treatments was also similar within the same line of therapy. Additional research is needed to investigate the optimal place in therapy of CDK4/6i and the sequencing of treatments following progression on CDK4/6i.


Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Quinasa 4 Dependiente de la Ciclina , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Supervivencia sin Progresión , Quinasa 6 Dependiente de la Ciclina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Receptor ErbB-2/metabolismo
2.
Mult Scler Relat Disord ; 66: 104031, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35841716

RESUMEN

BACKGROUND: Ofatumumab is a subcutaneously administered anti-CD20 monoclonal antibody (MoAb) therapy that has been evaluated in two identically designed randomized controlled trials (RCTs), ASCLEPIOS I (NCT02792218) and ASCLEPIOS II (NCT02792231), in patients with relapsing multiple sclerosis (RMS). Ocrelizumab is another anti-CD20 MoAb therapy, administered intravenously, that has been evaluated in two identically designed RCTs, OPERA I (NCT01247324) and OPERA II (NCT01412333) in RMS. Given the absence of published RCTs with head-to-head comparisons between these MoAbs, this study assessed the indirect comparative efficacy of ofatumumab and ocrelizumab. METHODS: Given the availability of individual patient data for ASCLEPIOS I/II and summary-level data for OPERA I/II, simulated treatment comparisons were used to assess the comparative efficacy of ofatumumab versus ocrelizumab while adjusting for differences in baseline characteristics between trials. Comparative efficacy was estimated for the proportion of patients with 3- and 6-month confirmed disability progression (CDP) and for annualized relapse rate (ARR). Exploratory analyses were conducted for the outcome of no evidence of disease activity based on three parameters (NEDA-3) and magnetic resonance imaging (MRI) outcomes (proportion of patients with gadolinium-enhancing T1 lesions and brain volume change). RESULTS: Although comparative results were not significant for 3-month CDP (hazard ratio [HR]: 0.90 [95% confidence interval [CI]: 0.57-1.42]) or 6-month CDP (HR: 0.84 [95% CI: 0.47-1.49]), ofatumumab showed a significant improvement in ARR (rate ratio: 0.60 [95% CI: 0.43-0.84]) compared with ocrelizumab. Significantly favorable results were also associated with ofatumumab for NEDA-3 and MRI outcomes. CONCLUSION: Ofatumumab was associated with more favorable efficacy results compared with ocrelizumab for clinical, NEDA-3, and MRI outcomes.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Esclerosis Múltiple Recurrente-Remitente , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Gadolinio/uso terapéutico , Factores Inmunológicos/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto
3.
J Comp Eff Res ; 10(6): 495-507, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33620251

RESUMEN

Background: The Association of British Neurologists (ABN) 2015 guidelines suggested classifying multiple sclerosis therapies according to their average relapse reduction. We sought to classify newer therapies (cladribine, ocrelizumab, ofatumumab, ozanimod) based on these guidelines. Materials & methods: Therapies were classified by using direct comparative trial results as per ABN guidelines and generating classification probabilities for each therapy based on comparisons versus placebo in a network meta-analysis for annualized relapse rate. Results: For both approaches, cladribine and ofatumumab were classified as high efficacy. Ocrelizumab and ozanimod (1.0 mg) were classified as moderate or high efficacy depending on the approach used. Conclusion: Cladribine and ofatumumab have an efficacy comparable with therapies classified in the ABN guidelines as high efficacy.


Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Cladribina/uso terapéutico , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Metaanálisis en Red , Recurrencia
4.
J Comp Eff Res ; 9(18): 1255-1274, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33090003

RESUMEN

Aim: To compare the efficacy of ofatumumab to other disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS). Materials & methods: A network meta-analysis was conducted to determine the relative effect of ofatumumab on annualized relapse rate and confirmed disability progression at 3 months and 6 months. Results: For each outcome, ofatumumab was as effective as other highly efficacious monoclonal antibody DMTs (i.e., alemtuzumab, natalizumab and ocrelizumab). Conclusion: Ofatumumab offers beneficial outcomes for RMS by reducing relapse and disability progression risk.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Investigación sobre la Eficacia Comparativa , Humanos , Metaanálisis en Red , Recurrencia
5.
Nat Commun ; 11(1): 5304, 2020 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-33082323

RESUMEN

A missense mutation, S85C, in the MATR3 gene is a genetic cause for amyotrophic lateral sclerosis (ALS). It is unclear how the S85C mutation affects MATR3 function and contributes to disease. Here, we develop a mouse model that harbors the S85C mutation in the endogenous Matr3 locus using the CRISPR/Cas9 system. MATR3 S85C knock-in mice recapitulate behavioral and neuropathological features of early-stage ALS including motor impairment, muscle atrophy, neuromuscular junction defects, Purkinje cell degeneration and neuroinflammation in the cerebellum and spinal cord. Our neuropathology data reveals a loss of MATR3 S85C protein in the cell bodies of Purkinje cells and motor neurons, suggesting that a decrease in functional MATR3 levels or loss of MATR3 function contributes to neuronal defects. Our findings demonstrate that the MATR3 S85C mouse model mimics aspects of early-stage ALS and would be a promising tool for future basic and preclinical research.


Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Neuronas Motoras/metabolismo , Proteínas Asociadas a Matriz Nuclear/genética , Proteínas Asociadas a Matriz Nuclear/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Esclerosis Amiotrófica Lateral/genética , Animales , Modelos Animales de Enfermedad , Femenino , Técnicas de Sustitución del Gen , Humanos , Mutación con Pérdida de Función , Masculino , Ratones , Mutación Missense , Células de Purkinje/metabolismo
6.
FEBS Lett ; 594(17): 2800-2818, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32515490

RESUMEN

Mutations in the nuclear matrix protein Matrin 3 (MATR3) have been identified in amyotrophic lateral sclerosis and myopathy. To investigate the mechanisms underlying MATR3 mutations in neuromuscular diseases and efficiently screen for modifiers of MATR3 toxicity, we generated transgenic MATR3 flies. Our findings indicate that expression of wild-type or mutant MATR3 in motor neurons reduces climbing ability and lifespan of flies, while their expression in indirect flight muscles (IFM) results in abnormal wing positioning and muscle degeneration. In both motor neurons and IFM, mutant MATR3 expression results in more severe phenotypes than wild-type MATR3, demonstrating that the disease-linked mutations confer pathogenicity. We conducted a targeted candidate screen for modifiers of the MATR3 abnormal wing phenotype and identified multiple enhancers involved in axonal transport. Knockdown of these genes enhanced protein levels and insolubility of mutant MATR3. These results suggest that accumulation of mutant MATR3 contributes to toxicity and implicate axonal transport dysfunction in disease pathogenesis.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Transporte Axonal/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Neuronas Motoras/metabolismo , Enfermedades Musculares/genética , Proteínas Asociadas a Matriz Nuclear/genética , Proteínas de Unión al ARN/genética , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Animales , Animales Modificados Genéticamente , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Proteínas de Drosophila/antagonistas & inhibidores , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Epistasis Genética , Vuelo Animal/fisiología , Expresión Génica , Humanos , Longevidad/genética , Neuronas Motoras/patología , Músculos/metabolismo , Músculos/patología , Enfermedades Musculares/metabolismo , Enfermedades Musculares/patología , Proteínas Asociadas a Matriz Nuclear/metabolismo , Fenotipo , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Proteínas de Unión al ARN/metabolismo , Transgenes , Alas de Animales/metabolismo , Alas de Animales/patología
7.
Nat Neurosci ; 22(4): 556-564, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30911184

RESUMEN

Heterozygous loss-of-function mutations in SHANK2 are associated with autism spectrum disorder (ASD). We generated cortical neurons from induced pluripotent stem cells derived from neurotypic and ASD-affected donors. We developed sparse coculture for connectivity assays where SHANK2 and control neurons were differentially labeled and sparsely seeded together on a lawn of unlabeled control neurons. We observed increases in dendrite length, dendrite complexity, synapse number, and frequency of spontaneous excitatory postsynaptic currents. These findings were phenocopied in gene-edited homozygous SHANK2 knockout cells and rescued by gene correction of an ASD SHANK2 mutation. Dendrite length increases were exacerbated by IGF1, TG003, or BDNF, and suppressed by DHPG treatment. The transcriptome in isogenic SHANK2 neurons was perturbed in synapse, plasticity, and neuronal morphogenesis gene sets and ASD gene modules, and activity-dependent dendrite extension was impaired. Our findings provide evidence for hyperconnectivity and altered transcriptome in SHANK2 neurons derived from ASD subjects.


Asunto(s)
Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/patología , Dendritas/patología , Proteínas del Tejido Nervioso/genética , Neuronas/patología , Trastorno del Espectro Autista/metabolismo , Técnicas de Cocultivo , Dendritas/metabolismo , Potenciales Postsinápticos Excitadores , Técnicas de Inactivación de Genes , Haploinsuficiencia , Humanos , Células Madre Pluripotentes Inducidas , Masculino , Plasticidad Neuronal , Neuronas/metabolismo , Transcriptoma
8.
Mol Cells ; 41(9): 818-829, 2018 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-30157547

RESUMEN

Significant research efforts are ongoing to elucidate the complex molecular mechanisms underlying amyotrophic lateral sclerosis (ALS), which may in turn pinpoint potential therapeutic targets for treatment. The ALS research field has evolved with recent discoveries of numerous genetic mutations in ALS patients, many of which are in genes encoding RNA binding proteins (RBPs), including TDP-43, FUS, ATXN2, TAF15, EWSR1, hnRNPA1, hnRNPA2/B1, MATR3 and TIA1. Accumulating evidence from studies on these ALS-linked RBPs suggests that dysregulation of RNA metabolism, cytoplasmic mislocalization of RBPs, dysfunction in stress granule dynamics of RBPs and increased propensity of mutant RBPs to aggregate may lead to ALS pathogenesis. Here, we review current knowledge of the biological function of these RBPs and the contributions of ALS-linked mutations to disease pathogenesis.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Animales , Animales Modificados Genéticamente , Gránulos Citoplasmáticos/metabolismo , Humanos , Modelos Animales , Mutación , Neuronas/metabolismo , ARN/metabolismo
10.
Cell Rep ; 17(3): 720-734, 2016 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-27732849

RESUMEN

A progressive increase in MECP2 protein levels is a crucial and precisely regulated event during neurodevelopment, but the underlying mechanism is unclear. We report that MECP2 is regulated post-transcriptionally during in vitro differentiation of human embryonic stem cells (hESCs) into cortical neurons. Using reporters to identify functional RNA sequences in the MECP2 3' UTR and genetic manipulations to explore the role of interacting factors on endogenous MECP2, we discover combinatorial mechanisms that regulate RNA stability and translation. The RNA-binding protein PUM1 and pluripotent-specific microRNAs destabilize the long MECP2 3' UTR in hESCs. Hence, the 3' UTR appears to lengthen during differentiation as the long isoform becomes stable in neurons. Meanwhile, translation of MECP2 is repressed by TIA1 in hESCs until HuC predominates in neurons, resulting in a switch to translational enhancement. Ultimately, 3' UTR-directed translational fine-tuning differentially modulates MECP2 protein in the two cell types to levels appropriate for normal neurodevelopment.


Asunto(s)
Regulación de la Expresión Génica , Proteína 2 de Unión a Metil-CpG/genética , MicroARNs/metabolismo , Neuronas/metabolismo , Proteínas de Unión al ARN/metabolismo , Transcripción Genética , Regiones no Traducidas 3'/genética , Elementos Ricos en Adenilato y Uridilato/genética , Secuencia de Bases , Linaje de la Célula , Proliferación Celular , Secuencia Conservada/genética , Células Madre Embrionarias Humanas/citología , Células Madre Embrionarias Humanas/metabolismo , Humanos , Proteína 2 de Unión a Metil-CpG/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Prosencéfalo/embriología , Unión Proteica/genética , Biosíntesis de Proteínas , Estabilidad del ARN/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo
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