Assuntos
Escherichia coli , Salmonella enterica , Escherichia coli/genética , Escherichia coli/metabolismo , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/metabolismo , Salmonella enterica/genética , Salmonella enterica/metabolismo , Proteínas de Membrana Transportadoras/genética , Resistência a Medicamentos , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Testes de Sensibilidade Microbiana , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteínas da Membrana Bacteriana Externa/metabolismoRESUMO
On March 28th, 2022, asciminib hydrochloride (Scemblix® Tablets 20â |mg/40â |mg), the world's first tyrosine kinase inhibitor (TKI) specifically targeting the ABL myristoyl pocket (STAMP inhibitor), was approved for chronic myeloid leukemia (CML) resistant or intolerant to prior therapy. Asciminib specifically binds to the myristoyl pocket, an allosteric site of BCR::ABL1, and inhibits the ABL1 family molecules. In vitro and in vivo pharmacology studies demonstrated cell growth inhibition and antitumor effects of asciminib. The international phase I study for patients with chronic or accelerated phase CML investigated the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) of asciminib monotherapy. However, the MTD was not reached, so and RDE was determined based on tolerability, safety, pharmacokinetics (PK) and preliminary efficacy data obtained by the time of the study. RDE was determined to be 40â |mg twice daily in chronic or accelerated phase CML without T315I mutation, and 200â |mg twice daily in chronic or accelerated phase CML with T315I mutation. The international phase III study for patients with chronic phase CML who were previously treated with ≥2 TKIs and resistant or intolerant to the recent treatment demonstrated the superiority of asciminib over bosutinib in achieving the primary endpoint of a major molecular response (MMR) at week 24. Regarding safety, the most common treatment-related adverse event in asciminib arm was thrombocytopenia, and others included neutropenia. Asciminib is expected to be a new treatment option for CML patients who have limited choices due to resistance or intolerance to previous therapies.
Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêuticoRESUMO
The 5th Asia Partnership Conference of Regenerative Medicine (APACRM) was held online on April 7, 2022 to promote regulatory harmonization of regenerative medicine products throughout Asia. The recognition of domestic regulatory guidelines within each country and region and the underpinning rationales are important initial steps toward the harmonization of regulations. The 5th APACRM featured open dialog regarding non-clinical, quality and environmental impact assessment settings for cell and gene therapy products through presentations from the industry and panel discussions with regulatory agencies. The latest updates on regenerative medicine fields in each country and region were also introduced. This paper summarizes the proceedings of the 5th APACRM for public dissemination to foster future discussion.
Assuntos
Meio Ambiente , Medicina Regenerativa , Ásia , Terapia Genética/efeitos adversosRESUMO
Fatty acids salts exert bactericidal and bacteriostatic effects that inhibit bacterial growth and survival. However, bacteria can overcome these effects and adapt to their environment. Bacterial efflux systems are associated with resistance to different toxic compounds. Here, several bacterial efflux systems were examined to determine their influence on fatty acid salt resistance in Escherichia coli. Both acrAB and tolC E. coli deletion strains were susceptible to fatty acid salts, while plasmids carrying acrAB, acrEF, mdtABC, or emrAB conferred drug resistance to the ΔacrAB mutant, which indicated complementary roles for these multidrug efflux pumps. Our data exemplify the importance of bacterial efflux systems in E. coli resistance to fatty acid salts.
RESUMO
Fatty acids salts exhibit bacteriostatic and bactericidal effects to inhibit bacterial growth and survival. Bacteria adapt to their environment to overcome these antibacterial effects through undefined mechanisms. In Gram-negative bacteria, drug efflux systems are associated with resistance to various substances. Studies have identified multiple drug efflux systems in Salmonella enterica. The aim of this study was to investigate whether drug efflux systems contribute to fatty acid salts resistance in S. enterica. We used deletion and overexpressing strains of S. enterica for drug efflux transporters. Susceptibility to fatty acid salts was determined by measuring minimum inhibitory concentrations and performing growth assays. Our findings revealed that acrAB, acrEF, emrAB and tolC in S. enterica contribute resistance to fatty acid salts. Furthermore, EmrAB, which is known to function with TolC, contributes to the fatty acid salts resistance of S. enterica in a TolC-independent manner. This study revealed that drug efflux systems confer fatty acid satls resistance to S. enterica. Notably, although EmrAB is normally associated with antimicrobial resistance in a TolC-dependent manner, it was found to be involved in fatty acid salts resistance in a TolC-independent manner, indicating that the utilization of TolC by EmrAB is substrate dependent in S. enterica.
Assuntos
Salmonella enterica , Sais , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana Múltipla , Ácidos Graxos/farmacologia , Proteínas de Membrana Transportadoras/genética , Testes de Sensibilidade Microbiana , Salmonella enterica/genética , Salmonella enterica/metabolismo , Salmonella typhimurium , Sais/farmacologiaRESUMO
The 4th Asia Partnership Conference of Regenerative Medicine (APACRM) was held online on April 15, 2021, to promote regulatory harmonization of regenerative medicine products throughout Asia. Recognizing domestic regulatory guidelines within each country and region, and their underpinning rationales, is an important initial step toward a convergence of regulations. The 4th APACRM consisted of an open dialog with regulatory agencies regarding nonclinical and quality settings for cell therapy products (CTPs) through industry presentations and panel discussions with regulatory agencies. The latest updates on regenerative medicine fields in each country and region, and specific regulatory schematics in Japan, were also introduced. The objective of this paper is to summarize the proceedings of the 4th APACRM for public dissemination and to foster further discussion in the future.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Medicina Regenerativa , Ásia , JapãoRESUMO
Onasemnogene abeparvovec (Zolgensma®; formerly AVXS-101) is a one-time gene therapy designed to address the genetic root cause of spinal muscular atrophy (SMA) by replacing the function of the missing or nonworking SMN1 gene via an adeno-associated AAV9 viral vector. On March 19, 2020, the Japanese Ministry of Health, Labor and Welfare approved onasemnogene abeparvovec for the treatment of SMA patients <2 years of age, including presymptomatic patients with a genetic diagnosis. Patients must be negative for elevated anti-AAV9 antibodies. Onasemnogene abeparvovec is administered through a single intravenous infusion, delivering a new working copy of the SMN gene into a patient's cells. Intravenous administration of onasemnogene abeparvovec to SMA model mice resulted in sustained expression of survival motor neuron (SMN) protein, weight gain, improvement of motor function, and prolongation of survival. Its clinical efficacy and safety have been demonstrated through the Phase I START and Phase III STR1VE-US, STR1VE-EU, and SPR1NT trials, and their long-term extension studies. SMA and presymptomatic patients treated with onasemnogene abeparvovec have achieved rates of survival not observed in the natural history of SMA. Treatment has led to rapid motor function improvement, often within one month of dosing, and developmental milestone achievement, including the ability to sit without support. The most commonly observed adverse effects after treatment were elevated liver enzymes, which often resolved with a course of prednisolone, and vomiting. This review discusses the rationale underlying gene replacement therapy for SMA, and describes the basic science, clinical trial experience, and use of onasemnogene abeparvovec.
Assuntos
Atrofia Muscular Espinal , Atrofias Musculares Espinais da Infância , Animais , Terapia Genética , Humanos , Infusões Intravenosas , Camundongos , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND AIMS: Cell-based regenerative medicine is an innovative field that can potentially alter the overall survival and quality of life of patients with devastating diseases. Several cell therapy products (CTPs) have been approved within the last two decades, and more are under development. The establishment of an effective developmental strategy in accordance with the regulatory bodies of each country/region is crucial for fast delivery of each respective CTP. In particular, facilitating investigational new drug (IND) approval is important for accelerating the transition from non-clinical to clinical research/trial phases. METHODS: Here the authors compared the non-clinical prerequisites for initiating clinical studies in five Asian countries/regions (India, China, Korea, Taiwan and Japan) from an industry viewpoint. The authors first identified the differences and tried to clarify the perspectives/considerations underpinning the different requirements. RESULTS: The authors' findings revealed that differences in regulations and development experiences, especially with CTPs, have led to clear differences in the non-clinical study package and its corresponding study design. CONCLUSIONS: By sharing experiences of the research and development of CTPs among Asian countries/regions and including not only industry but also regulatory authorities, we will be able to expedite cross-border IND approval and eventually contribute to the early delivery of innovative CTPs to many Asian patients.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Qualidade de Vida , Ásia , China , Humanos , JapãoRESUMO
Nrf2 is a master regulator of oxidative stresses through the induction of anti-oxidative genes. Nrf2 plays roles in maintaining murine hematopoietic stem cells and fly intestinal stem cells. The canonical Notch signaling pathway is also crucial for maintaining several types of adult stem cells including muscle stem cells (satellite cells). Here, we show that Dll1 induced Nrf2 expression in myogenic cells. In addition, primary targets of Notch signaling, Hesr1 and Hesr3, were involved in the up-regulation of Nrf2 mRNA and expression of its target genes. In vitro, Nrf2 had anti-myogenic and anti-proliferative effects on primary myoblasts. In vivo, although Nrf2-knockout mice showed decreased expression of its target genes in muscle stem cells, adult muscle stem cells of Nrf2-knockout mice did not exhibit the phenotype. Taken together, in muscle stem cells, the Notch-Hesr-Nrf2 axis is a pathway potentially inducing anti-oxidative genes, but muscle stem cells either do not require Nrf2-mediated anti-oxidative gene expression or they have a complementary system compensating for the loss of Nrf2.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Ciclo Celular/genética , Fator 2 Relacionado a NF-E2/genética , Receptores Notch/metabolismo , Células Satélites de Músculo Esquelético/citologia , Células-Tronco Adultas/citologia , Animais , Antioxidantes/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células CHO , Proteínas de Ligação ao Cálcio , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular/genética , Linhagem Celular , Cricetulus , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Camundongos Knockout , Células Musculares/citologia , Células Musculares/metabolismo , Desenvolvimento Muscular/genética , Fator 2 Relacionado a NF-E2/metabolismo , Células Satélites de Músculo Esquelético/metabolismo , Transdução de SinaisRESUMO
Accumulation of adipocytes and collagen type-I-producing cells (fibrosis) is observed in muscular dystrophies. The origin of these cells had been largely unknown, but recently we identified mesenchymal progenitors positive for platelet-derived growth factor receptor alpha (PDGFRα) as the origin of adipocytes in skeletal muscle. However, the origin of muscle fibrosis remains largely unknown. In this study, clonal analyses show that PDGFRα(+) cells also differentiate into collagen type-I-producing cells. In fact, PDGFRα(+) cells accumulated in fibrotic areas of the diaphragm in the mdx mouse, a model of Duchenne muscular dystrophy. Furthermore, mRNA of fibrosis markers was expressed exclusively in the PDGFRα(+) cell fraction in the mdx diaphragm. Importantly, TGF-ß isoforms, known as potent profibrotic cytokines, induced expression of markers of fibrosis in PDGFRα(+) cells but not in myogenic cells. Transplantation studies revealed that fibrogenic PDGFRα(+) cells mainly derived from pre-existing PDGFRα(+) cells and that the contribution of PDGFRα(-) cells and circulating cells was limited. These results indicate that mesenchymal progenitors are the main origin of not only fat accumulation but also fibrosis in skeletal muscle.
Assuntos
Adipogenia , Fibrose/fisiopatologia , Células-Tronco Mesenquimais/citologia , Músculo Esquelético/citologia , Adipócitos/citologia , Adipócitos/metabolismo , Animais , Diferenciação Celular , Modelos Animais de Doenças , Fibrose/genética , Fibrose/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Músculo Esquelético/metabolismo , Distrofias Musculares/genética , Distrofias Musculares/metabolismo , Distrofias Musculares/fisiopatologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismoRESUMO
Satellite cells, which are skeletal muscle stem cells, divide to provide new myonuclei to growing muscle fibers during postnatal development, and then are maintained in an undifferentiated quiescent state in adult skeletal muscle. This state is considered to be essential for the maintenance of satellite cells, but their molecular regulation is unknown. We show that Hesr1 (Hey1) and Hesr3 (Heyl) (which are known Notch target genes) are expressed simultaneously in skeletal muscle only in satellite cells. In Hesr1 and Hesr3 single-knockout mice, no obvious abnormalities of satellite cells or muscle regenerative potentials are observed. However, the generation of undifferentiated quiescent satellite cells is impaired during postnatal development in Hesr1/3 double-knockout mice. As a result, myogenic (MyoD and myogenin) and proliferative (Ki67) proteins are expressed in adult satellite cells. Consistent with the in vivo results, Hesr1/3-null myoblasts generate very few Pax7(+) MyoD(-) undifferentiated cells in vitro. Furthermore, the satellite cell number gradually decreases in Hesr1/3 double-knockout mice even after it has stabilized in control mice, and an age-dependent regeneration defect is observed. In vivo results suggest that premature differentiation, but not cell death, is the reason for the reduced number of satellite cells in Hesr1/3 double-knockout mice. These results indicate that Hesr1 and Hesr3 are essential for the generation of adult satellite cells and for the maintenance of skeletal muscle homeostasis.