RESUMO
Nuclear factor kappa B (NFκB) is a pathogenic factor in chronic lymphocytic leukemia (CLL) that is not addressed specifically by current therapies. NFκB is activated by inflammatory factors that stimulate toll-like receptors (TLRs) and receptors for interleukin-1 (IL-1) family members. IL-1 is considered a master regulator of inflammation, and IL-1 receptor signaling is inhibited by the IL-1 receptor antagonist anakinra. These considerations suggested that anakinra might have a role in the treatment of CLL. Consistent with this idea, anakinra inhibited spontaneous and TLR7-mediated activation of the canonical NFκB pathway in CLL cells in vitro. However, CLL cells exhibited only weak signaling responses to IL-1 itself, and anakinra was found to inhibit NFκB along with oxidative stress in an IL-1 receptor-independent manner. Anakinra was then administered with minimal toxicity to 11 previously untreated CLL patients in a phase I dose-escalation trial (NCT04691765). A stereotyped clinical response was observed in all patients. Anakinra lowered blood lymphocytes and lymph node sizes within the first month that were associated with downregulation of NFκB and oxidative stress in the leukemia cells. However, inhibition of NFκB was accompanied by upregulation of type 1 interferon (IFN) signaling, c-MYC-regulated genes and proteins, and loss of the initial clinical response. Anakinra increased IFN signaling and survival of CLL cells in vitro that were, respectively, phenocopied by mitochondrial antioxidants and reversed by IFN receptor blocking antibodies. These observations suggest that anakinra has activity in CLL and may be a useful adjunct for conventional therapies as long as compensatory IFN signaling is blocked at the same time.
Assuntos
Proteína Antagonista do Receptor de Interleucina 1 , Leucemia Linfocítica Crônica de Células B , NF-kappa B , Transdução de Sinais , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Interferons/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptores de Interleucina-1/metabolismo , Receptores de Interleucina-1/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Receptor 7 Toll-Like/metabolismo , Receptor 7 Toll-Like/antagonistas & inibidoresRESUMO
No disponible
Assuntos
Humanos , Feminino , Adolescente , Artrite Juvenil/complicações , Artrite Juvenil/tratamento farmacológico , Metotrexato/uso terapêutico , Cóccix , Cóccix/patologia , Corticosteroides/uso terapêutico , Receptores de Interleucina-1/antagonistas & inibidores , Quadril , Quadril/patologia , Pelve/patologia , Pelve , Cabeça do Fêmur/patologia , Cabeça do FêmurRESUMO
Injectable bone substitutes and techniques have been developed for use in minimally invasive procedures for bone augmentation. Objective : To develop a novel injectable thermo-sensitive alginate hydrogel (TSAH) as a scaffold to induce bone regeneration, using a minimally invasive tunnelling technique. Material and Methods : An injectable TSAH was prepared from a copolymer solution of 8.0 wt% Poly(N-isopropylacrylamide) (PNIPAAm) and 8.0 wt% AAlg-g-PNIPAAm. In vitro properties of the material, such as its microstructure and the sustained release of recombinant human bone morphogenetic protein-2 (rhBMP-2), were investigated. Then, with the subperiosteal tunnelling technique, this material, carrying rhBMP-2, was injected under the labial periosteum of the maxillary anterior alveolar ridge in a rabbit model. New bone formation was evaluated by means of X-ray, micro-computed tomography (micro-CT), fluorescence labelling, histological study, and immunohistochemistry study. Results : The material exhibited good injectability and thermo-irreversible properties. SEM showed an interconnected porous microstructure of the TSAH. The result of ALP activity indicated sustained delivery of BMP-2 from the TSAH from days 3 to 15. In a rabbit model, both TSAH and TSAH/rhBMP-2 induced alveolar ridge augmentation. The percentage of mineralised tissue in the TSAH/rhBMP-2 group (41.6±3.79%) was significantly higher than in the TSAH group (31.3±7.21%; p<0.05). The density of the regenerating tissue was higher in the TSAH/rhBMP-2 group than in the other groups (TSAH group, positive control, blank control; p<0.05). Conclusions : The TSAH provided convenient handling properties for clinical application. To some extent, TSAH could induce ridge augmentation and mineral deposition, which can be enhanced when combined with rhBMP-2 for a minimally invasive tunnelling injection. .
Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Lesões Encefálicas/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Receptores de Interleucina-1/antagonistas & inibidores , Lesões Encefálicas/imunologia , Lesões Encefálicas/patologia , Encéfalo/imunologia , Encéfalo/patologia , Citocinas/análise , Citocinas/imunologia , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Receptores de Interleucina-1/imunologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêuticoRESUMO
No disponible
Assuntos
Humanos , Feminino , Idoso , Síndrome de Schnitzler/tratamento farmacológico , Transtornos Mieloproliferativos/epidemiologia , Amiloidose/epidemiologia , Receptores de Interleucina-1/antagonistas & inibidoresRESUMO
En el tratamiento de los síndromes periódicos asociados a la criopirina (CAPS), clásicamente se han usado los antiinflamatorios no esteroideos, glucocorticoides y antihistamínicos, además de un sinfín de otras moléculas, con resultados poco alentadores. El conocimiento de su carácter genético y de su etiopatogenia relacionada con el inflamasoma y la producción de interleucina 1(IL1) ha permitido el desarrollo de nuevas terapias biológicas que consiguen no sólo mejorar la sintomatología y la calidad de vida de los pacientes, sino que logran el control de la inflamación subyacente. Las terapias anti_IL-1 han demostrado en los pacientes con CAPS tener una respuesta clínica espectacular, con normalización de los marcadores inflamatorios. Es posible que el uso de estas moléculas evite el desarrollo de complicaciones tardías derivadas de la inflamación crónica (AU)
Non-steroidal anti-inflammatories, corticoids and antihistamines, as well as a great many other molecules, have classically been used to control the symptoms of cryopyrin-associated periodic syndromes (CAPS), with very few encouraging results. Knowledge of its genetic character, and its aetiopathogenesis associated with inflammasome and the production of interlekin-1 (IL-1) has led to the development of new therapeutic weapons that have not just obtained improvements of the symptoms and quality of life of the patients, but also managed to control the underlying inflammation. Results show that anakinra, an IL-1 receptor antagonist molecule, improved the clinical symptoms and the inflammatory markers of patients with CAPS has motivated research with other molecules directed against IL-1: rilonacept and canakinumab. It is likely that the use of these molecules could prevent the development of the late complications associated with chronic inflammation (AU)
Assuntos
Humanos , Anti-Inflamatórios/uso terapêutico , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Antagonistas dos Receptores Histamínicos/uso terapêutico , Interleucina-1/antagonistas & inibidores , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/imunologia , Receptores de Interleucina-1/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Síndromes Periódicas Associadas à Criopirina/genética , Inflamassomos/antagonistas & inibidores , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Proteínas Recombinantes de Fusão/uso terapêuticoRESUMO
No disponible