RESUMEN
The molecular basis of interleukin (IL)-17A in driving psoriasis pathogenesis is not fully elucidated yet. To investigate the underlying mechanisms and biomarkers associated with IL-17A and the role in psoriasis pathogenesis, over 30 serum proteins were evaluated in a study assessing the effectiveness and safety of secukinumab, where treatment was directly switched from cyclosporin A to secukinumab. Serum ß-defensin 2 (BD-2) levels rapidly and robustly reduced following secukinumab treatment. BD-2 levels were well-correlated with Psoriasis Area and Severity Index (PASI) score; changes in BD-2 levels preceded change in PASI score. Serum BD-2, an easily measurable protein, can possibly be used as a suitable surrogate biomarker to monitor responses to IL-17A-targeted therapies for psoriasis in clinical practice.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Psoriasis/tratamiento farmacológico , beta-Defensinas/sangre , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Biomarcadores/sangre , Femenino , Humanos , Interleucina-17/antagonistas & inhibidores , Interleucina-17/inmunología , Masculino , Psoriasis/sangre , Psoriasis/diagnóstico , Psoriasis/inmunología , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Carcinogenesis is caused by genome instability, one of the major causes of which is double-strand DNA breaks (DSBs). Interestingly, infection by particular species of bacteria can induce DSBs in host cells. For example, several reports suggest an association between periodontal disease and oral cancer. Aggregatibacter actinomycetemcomitans, a common periodontal pathogen, causes DSBs in the host cell. Pulsed-field gel electrophoresis (PFGE) is often used to identify DSBs in host cells. However, as established during investigation of A. actinomycetemcomitans infection, it is often difficult to determine whether broken DNA fragments are indeed from human chromosomes or whether they are bacterial in origin using PFGE-based methods. Because the method involves the coculture of human cells with bacteria, both bacterial and human DNA fragments may be present in the broken DNA fraction. To address this problem, we have developed a method to detect only human chromosomal DNA upon PFGE analysis. Human chromosomes were prelabeled with halogenated deoxyuridine (e.g., BrdU and IdU) before being fractionated by PFGE and visualized by immunoblotting. As proof of concept, we successfully used this method to investigate the mechanism of DSB formation in host chromosomes following infection with genotoxic bacterial species.
Asunto(s)
Aggregatibacter actinomycetemcomitans , Cromosomas Humanos/metabolismo , Roturas del ADN de Doble Cadena , Electroforesis en Gel de Campo Pulsado , Infecciones por Pasteurellaceae/metabolismo , Línea Celular , Cromosomas Humanos/química , Humanos , Infecciones por Pasteurellaceae/patologíaRESUMEN
A global, randomized, double-blind placebo-controlled study was conducted to confirm that BYM338 (bimagrumab), an anti-activin type II receptor antibody, improves motor function in patients with sporadic inclusion body myositis after 52 weeks' treatment consisting of intravenous administration every 4 weeks at doses of 10, 3, and 1â mg/kg. In a Japanese sub-population (20 patients in total, 5 per dose group), no significant differences in the change from baseline of the 6-minute walking distance at Week 52 (primary endpoint) were observed between the placebo group and each BYM338 dose group. Furthermore, the lean body mass as an indicator of skeletal muscle mass increased in all BYM338 groups compared with the placebo group and the effects were dose-dependent. Overall, the Japanese sub-population showed similar trends as observed in the entire population (251 patients in total).
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Miositis por Cuerpos de Inclusión/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Actividad Motora , Miositis por Cuerpos de Inclusión/fisiopatología , Resultado del TratamientoRESUMEN
OBJECTIVES: The aim of this study was to obtain real-world clinical data on the safety and efficacy of ranibizumab treatment for myopic choroidal neovascularization (CNV) due to pathologic myopia. METHODS: This was a prospective, observational, post-marketing surveillance study in ranibizumab-naive Japanese patients with myopic CNV. Patients who initiated ranibizumab treatment were registered and prospectively observed over 12 months. Safety endpoints were the incidence of ocular and non-ocular adverse drug reactions (ADRs) and serious adverse events (SAEs). The efficacy endpoint included the average change in best-corrected visual acuity (BCVA) in logarithm of the minimal angle of resolution (logMAR) units (logMAR BCVA) from baseline to the last observation. RESULTS: Three hundred and eighteen patients were included in the safety analysis population. Of these 79.9% were female and the mean age was 65.5 years. The incidences of SAEs and ADRs were 0.6 and 0.3%, respectively. A total of 268 patients (84.0%) completed the 12-month study period. The mean (±SD) and median number of ranibizumab injections were 2.0 ± 1.5 and 1.0 during the 12-month study period, respectively. The number of ranibizumab injections received was one in 52.2% of patients and less than or equal to three in 89.2%. The mean change in logMAR BCVA from baseline to month 12 was -0.193, and the mean logMAR BCVA improved from 0.517 to 0.319 between baseline and month 12. CONCLUSIONS: This study showed that ranibizumab is generally well tolerated, and that a minimum number of injections were necessary to produce a therapeutic effect in Japanese myopic CNV patients in a real-world setting.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Neovascularización Coroidal/tratamiento farmacológico , Miopía Degenerativa/complicaciones , Ranibizumab/uso terapéutico , Adulto , Anciano , Neovascularización Coroidal/etiología , Neovascularización Coroidal/fisiopatología , Femenino , Humanos , Inyecciones Intravítreas , Japón , Masculino , Persona de Mediana Edad , Miopía Degenerativa/tratamiento farmacológico , Miopía Degenerativa/fisiopatología , Estudios Prospectivos , Agudeza Visual/fisiologíaRESUMEN
Periodontal disease, an inflammatory disease, is caused by infection with periodontal pathogens. Long-term periodontal disease increases the risk of oral carcinogenesis. Similar to other peptic cancers, oral carcinogenesis also requires multiple genome instabilities; however, the risk factors related to the accumulation of genome instabilities are poorly understood. Here, we suggested that specific periodontal pathogens may increase the risk of genome instability. Accordingly, we screened several periodontal pathogens based on the ability to induce DNA double-strand breaks (DSBs) in host cells. We found that Aggregatibacter actinomycetemcomitans Y4 infection induced DSB formation in host cells. To assess whether DSB formation induced by infection with A. actinomycetemcomitans occurred through apoptotic chromosome fragmentation, cells were treated with a caspase inhibitor, Z-VAD-FMK. DSB accumulation induced by infection with A. actinomycetemcomitans was observed, even in the presence of Z-VAD-FMK, suggesting that this breakage occurred independently of apoptosis. These results suggested that some periodontal pathogens can increase the risk of genome instabilities in host cells and subsequently increase the risk of carcinogenesis.
Asunto(s)
Aggregatibacter actinomycetemcomitans/fisiología , Carcinoma de Células Escamosas/genética , Roturas del ADN de Doble Cadena , Inestabilidad Genómica , Infecciones por Pasteurellaceae/microbiología , Neoplasias de la Lengua/genética , Apoptosis , Carcinoma de Células Escamosas/microbiología , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Células HeLa , Humanos , Infecciones por Pasteurellaceae/patología , Neoplasias de la Lengua/microbiología , Neoplasias de la Lengua/patologíaRESUMEN
There are limited data on the safety and efficacy of switching to secukinumab from cyclosporine A (CyA) in patients with psoriasis. The purpose of the present study was to assess the efficacy and safety of secukinumab for 16 weeks after direct switching from CyA in patients with moderate-to-severe psoriasis. In this multicenter, open-label, phase IV study, 34 patients with moderate-to-severe psoriasis and inadequate response to CyA received secukinumab 300 mg s.c. at baseline and weeks 1, 2, 3, 4, 8 and 12. The primary end-point was ≥75% improvement from baseline in Psoriasis Area and Severity Index score (PASI 75) at week 16. The efficacy of secukinumab treatment was evaluated up to week 16, and adverse events (AE) were monitored during the study. The primary end-point of the PASI 75 response at week 16 was achieved by 82.4% (n = 28) of patients receiving secukinumab. Early improvements were observed with secukinumab, with PASI 50 response of 41.2% at week 2 and PASI 75 response of 44.1% at week 4. AE were observed in 70.6% (n = 24) of patients, and there were no serious AE or deaths reported in the entire study period. Secukinumab showed a favorable safety profile consistent with previous data with no new or unexpected safety signals. The results of the present study show that secukinumab is effective in patients with psoriasis enabling a smooth and safe direct switch from CyA to biological therapy.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Ciclosporina/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Sustitución de Medicamentos/métodos , Interleucina-17/antagonistas & inhibidores , Psoriasis/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados , Terapia Biológica/efectos adversos , Terapia Biológica/métodos , Sustitución de Medicamentos/efectos adversos , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
A DNA double-strand break (DSB) is one of the most cytotoxic DNA lesions because unrepaired DSBs cause chromosomal aberrations and cell death. Although many physiological DSBs occur at DNA replication sites, the molecular mechanisms underlying this remain poorly understood. There was therefore a need to develop a highly specific method to detect DSB fragments containing DNA replication sites. Here we investigated whether pulsed-field gel electrophoresis (PFGE) combined with visualization of DNA replication sites by immunoblotting using halogenized deoxyuridines, such as BrdU and IdU, was sufficient for this detection. Our methodology enabled us to reproduce previously reported data. In addition, this methodology was also applied to the detection of bacterial infection-induced DSBs on human chromosomal DNA. Based on our findings, we propose that this strategy combining PFGE with immunoblot analysis will be applicable to studies analyzing the mechanistic details of DNA repair, the DNA damage response and the activity of DNA-damaging agents.
Asunto(s)
Roturas del ADN de Doble Cadena/efectos de los fármacos , Replicación del ADN/genética , ADN/aislamiento & purificación , Electroforesis en Gel de Campo Pulsado , Bromodesoxiuridina/farmacología , Cromosomas/genética , ADN/genética , Daño del ADN/genética , Reparación del ADN/genética , Replicación del ADN/efectos de los fármacos , HumanosRESUMEN
BACKGROUND: No study to date has evaluated the efficacy and safety of everolimus with reduced-exposure cyclosporine in Japanese de-novo renal transplant (RTx) patients. METHODS: This 12-month, multicenter, open-label study randomized (1:1) 122 Japanese de-novo RTx patients to either an everolimus regimen (1.5 mg/day starting dose (target trough: 3 to 8 ng/ml) + reduced-dose cyclosporine) or a mycophenolate mofetil (MMF) regimen (2 g/day + standard dose cyclosporine). All patients received basiliximab and corticosteroids. Key endpoints at month 12 were composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up) and renal function (estimated glomerular filtration rate; Modification of Diet in Renal Disease-4). RESULTS: Clear cyclosporine exposure reduction was achieved in the everolimus group throughout the study (52% reduction at month 12). Month 12 efficacy failure rates showed everolimus 1.5 mg to be non-inferior to MMF (11.5% vs. 11.5%). The median estimated glomerular filtration rate at month 12 was 58.00 ml/minute/1.73 m2 in the everolimus group versus 55.25 ml/minute/1.73 m2 in the MMF group (P = 0.063). Overall, the incidence of adverse events was comparable between the groups with some differences in line with the known safety profile of the treatments. The everolimus group had a higher incidence of wound healing events and edema, whereas a higher rate of cytomegalovirus infections was reported in the MMF group. CONCLUSIONS: This study confirmed the efficacy of everolimus 1.5 mg/day (target trough: 3 to 8 ng/ml) in Japanese RTx patients for preventing acute rejection, while allowing for substantial cyclosporine sparing. Renal function and safety findings were comparable with previous reports from other RTx populations. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT00658320.