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1.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209188

RESUMO

Coronavirus disease (COVID)-19 is the leading global health threat to date caused by a severe acute respiratory syndrome coronavirus (SARS-CoV-2). Recent clinical trials reported that the use of Bruton's tyrosine kinase (BTK) inhibitors to treat COVID-19 patients could reduce dyspnea and hypoxia, thromboinflammation, hypercoagulability and improve oxygenation. However, the mechanism of action remains unclear. Thus, this study employs structure-based virtual screening (SBVS) to repurpose BTK inhibitors acalabrutinib, dasatinib, evobrutinib, fostamatinib, ibrutinib, inositol 1,3,4,5-tetrakisphosphate, spebrutinib, XL418 and zanubrutinib against SARS-CoV-2. Molecular docking is conducted with BTK inhibitors against structural and nonstructural proteins of SARS-CoV-2 and host targets (ACE2, TMPRSS2 and BTK). Molecular mechanics-generalized Born surface area (MM/GBSA) calculations and molecular dynamics (MD) simulations are then carried out on the selected complexes with high binding energy. Ibrutinib and zanubrutinib are found to be the most potent of the drugs screened based on the results of computational studies. Results further show that ibrutinib and zanubrutinib could exploit different mechanisms at the viral entry and replication stage and could be repurposed as potential inhibitors of SARS-CoV-2 pathogenesis.


Assuntos
Adenina/análogos & derivados , Reposicionamento de Medicamentos , Simulação de Dinâmica Molecular , Piperidinas/química , Inibidores de Proteínas Quinases/química , Pirazóis/química , Pirimidinas/química , Adenina/química , Adenina/metabolismo , Adenina/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Sítios de Ligação , COVID-19/tratamento farmacológico , COVID-19/patologia , COVID-19/virologia , Humanos , Simulação de Acoplamento Molecular , Piperidinas/metabolismo , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/metabolismo , Pirazóis/uso terapêutico , Pirimidinas/metabolismo , Pirimidinas/uso terapêutico , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo , Serina Endopeptidases/química , Serina Endopeptidases/metabolismo , Termodinâmica , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo
2.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: covidwho-1288906

RESUMO

Coronavirus disease (COVID)-19 is the leading global health threat to date caused by a severe acute respiratory syndrome coronavirus (SARS-CoV-2). Recent clinical trials reported that the use of Bruton's tyrosine kinase (BTK) inhibitors to treat COVID-19 patients could reduce dyspnea and hypoxia, thromboinflammation, hypercoagulability and improve oxygenation. However, the mechanism of action remains unclear. Thus, this study employs structure-based virtual screening (SBVS) to repurpose BTK inhibitors acalabrutinib, dasatinib, evobrutinib, fostamatinib, ibrutinib, inositol 1,3,4,5-tetrakisphosphate, spebrutinib, XL418 and zanubrutinib against SARS-CoV-2. Molecular docking is conducted with BTK inhibitors against structural and nonstructural proteins of SARS-CoV-2 and host targets (ACE2, TMPRSS2 and BTK). Molecular mechanics-generalized Born surface area (MM/GBSA) calculations and molecular dynamics (MD) simulations are then carried out on the selected complexes with high binding energy. Ibrutinib and zanubrutinib are found to be the most potent of the drugs screened based on the results of computational studies. Results further show that ibrutinib and zanubrutinib could exploit different mechanisms at the viral entry and replication stage and could be repurposed as potential inhibitors of SARS-CoV-2 pathogenesis.


Assuntos
Adenina/análogos & derivados , Reposicionamento de Medicamentos , Simulação de Dinâmica Molecular , Piperidinas/química , Inibidores de Proteínas Quinases/química , Pirazóis/química , Pirimidinas/química , Adenina/química , Adenina/metabolismo , Adenina/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Sítios de Ligação , COVID-19/tratamento farmacológico , COVID-19/patologia , COVID-19/virologia , Humanos , Simulação de Acoplamento Molecular , Piperidinas/metabolismo , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/metabolismo , Pirazóis/uso terapêutico , Pirimidinas/metabolismo , Pirimidinas/uso terapêutico , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo , Serina Endopeptidases/química , Serina Endopeptidases/metabolismo , Termodinâmica , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo
4.
Medicine (Baltimore) ; 100(22): e26211, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34087896

RESUMO

BACKGROUND: Riociguat is a novel soluble guanylate cyclase stimulator, and has been widely used for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (CTEPH). Some studies found that riociguat had better effects on CTEPH and proved to be safe, but the results were not utterly consistent. Therefore, the purpose of this study was to comprehensively evaluate the efficacy and safety of riociguat in the treatment of CTEPH. METHODS: Randomized controlled trials on riociguat for the treatment of CTEPH were searched through such electronic databases as PubMed, Embase, Cochrane Library, Web of Science, China national knowledge internet, and Wanfang. The outcomes included exercise capacity, pulmonary hemodynamics, and side effects. The fixed-effects or random-effects models were used to analyze the pooled data, and heterogeneity was assessed by the I2 test. RESULTS: Four studies involving 520 patients were included in this meta-analysis. Compared with the placebo group, riociguat significantly improved the hemodynamic indexes and increased 6-min walking distance (P < .0001, standardized mean difference (SMD) = -0.24, 95%CI -0.35 to -0.12; P < .00001, SMD = 0.52, 95%CI 0.33 to 0.71), and decreased the Borg dyspnea score (P = .002, SMD = -0.31, 95%CI -0.51 to -0.12). In addition, riociguat could also significantly reduce the living with pulmonary hypertension scores and increase the EQ-5D scores (P = .01, SMD=-0.23, 95%CI -0.42 to -0.05; P < .00001, SMD = 0.47, 95%CI 0.27 to 0.66), but there was no significant difference in the change level of N-terminal pro-hormone B-type natriuretic peptide in patients with riociguat (P = .20, SMD = -0.24, 95%CI -0.61 to -0.13). The common adverse events of riociguat were dyspepsia and peripheral edema, and no other serious adverse reactions were observed. CONCLUSIONS: We confirmed that riociguat had better therapeutic effects in improving the hemodynamic parameters and exercise capacity in patients with CTEPH without inducing serious adverse events. This will provide a reasonable medication regimen for the treatment of CTEPH.


Assuntos
Ativadores de Enzimas/uso terapêutico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Embolia Pulmonar/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Estudos de Casos e Controles , China/epidemiologia , Doença Crônica , Gerenciamento de Dados , Ativadores de Enzimas/administração & dosagem , Ativadores de Enzimas/efeitos adversos , Tolerância ao Exercício/efeitos dos fármacos , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Hipertensão Arterial Pulmonar/complicações , Embolia Pulmonar/complicações , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Segurança , Guanilil Ciclase Solúvel/efeitos dos fármacos , Resultado do Tratamento
5.
Aging (Albany NY) ; 13(12): 16425-16444, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34156352

RESUMO

To identify novel prognostic and therapeutic targets for osteosarcoma patients, we compared the gene expression profiles of osteosarcoma and control tissues from the GSE42352 dataset in the Gene Expression Omnibus. Differentially expressed genes were subjected to Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment and protein-protein interaction network analyses. Survival curve analyses indicated that osteosarcoma patients with lower mRNA levels of cyclin-dependent kinase 1 (CDK1) and topoisomerase II alpha had better prognoses. Various computer-aided techniques were used to identify potential CDK1 inhibitors for osteosarcoma patients, and PHA-793887 was predicted to be a safe drug with a high binding affinity for CDK1. In vitro, MTT and colony formation assays demonstrated that PHA-793887 reduced the viability and clonogenicity of osteosarcoma cells, while a scratch assay suggested that PHA-793887 impaired the migration of these cells. Flow cytometry experiments revealed that PHA-793887 dose-dependently induced apoptosis in osteosarcoma cells. Western blotting and enzyme-linked immunosorbent assays indicated that CDK1 expression in osteosarcoma cells declined with increasing PHA-793887 concentrations. These results suggest that PHA-793887 could be a promising new treatment for osteosarcoma.


Assuntos
Biologia Computacional , Simulação de Acoplamento Molecular , Osteossarcoma/tratamento farmacológico , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Sítios de Ligação , Proteína Quinase CDC2/antagonistas & inibidores , Proteína Quinase CDC2/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Ligantes , Osteossarcoma/genética , Osteossarcoma/patologia , Mapas de Interação de Proteínas/genética , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/química , Pirazóis/farmacologia , Pirróis/química , Pirróis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Análise de Sobrevida
6.
Lancet Oncol ; 22(7): 959-969, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34118197

RESUMO

BACKGROUND: Oncogenic alterations in RET have been identified in multiple tumour types, including 1-2% of non-small-cell lung cancers (NSCLCs). We aimed to assess the safety, tolerability, and antitumour activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion-positive NSCLC. METHODS: ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites (community and academic cancer centres) in 13 countries (Belgium, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, the UK, and the USA). Patients aged 18 years or older with locally advanced or metastatic solid tumours, including RET fusion-positive NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment) were enrolled. In phase 2, patients received 400 mg once-daily oral pralsetinib, and could continue treatment until disease progression, intolerance, withdrawal of consent, or investigator decision. Phase 2 primary endpoints were overall response rate (according to Response Evaluation Criteria in Solid Tumours version 1·1 and assessed by blinded independent central review) and safety. Tumour response was assessed in patients with RET fusion-positive NSCLC and centrally adjudicated baseline measurable disease who had received platinum-based chemotherapy or were treatment-naive because they were ineligible for standard therapy. This ongoing study is registered with ClinicalTrials.gov, NCT03037385, and enrolment of patients with treatment-naive RET fusion-positive NSCLC was ongoing at the time of this interim analysis. FINDINGS: Of 233 patients with RET fusion-positive NSCLC enrolled between March 17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based chemotherapy and 29 who were treatment-naive received pralsetinib before July 11, 2019 (efficacy enrolment cutoff); 87 previously treated patients and 27 treatment-naive patients had centrally adjudicated baseline measurable disease. Overall responses were recorded in 53 (61%; 95% CI 50-71) of 87 patients with previous platinum-based chemotherapy, including five (6%) patients with a complete response; and 19 (70%; 50-86) of 27 treatment-naive patients, including three (11%) with a complete response. In 233 patients with RET fusion-positive NSCLC, common grade 3 or worse treatment-related adverse events were neutropenia (43 patients [18%]), hypertension (26 [11%]), and anaemia (24 [10%]); there were no treatment-related deaths in this population. INTERPRETATION: Pralsetinib is a new, well-tolerated, promising, once-daily oral treatment option for patients with RET fusion-positive NSCLC. FUNDING: Blueprint Medicines.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Fusão Gênica , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ret/genética , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Pirimidinas/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
7.
Hematology ; 26(1): 460-464, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34184610

RESUMO

Objectives The aim of this retrospective analysis was to assess the incidence of hepatitis B virus (HBV) reactivation among patients with myeloproliferative neoplasms (MPN) during and after ruxolitinib treatment. Methods Between February 2013 and February 2020, 224 patients with MPN were treated using ruxolitinib at Peking Union Medical College Hospital. Of these, 6 had chronic, and 56 had resolved HBV infection, including 43 patients who received combination treatment with thalidomide, prednisone, and stanozolol (TSP) during ruxolitinib treatment. Results Two patients with chronic HBV infection who did not take any antiviral prophylaxis developed HBV reactivation and hepatitis flare. The other four patients with chronic HBV infection, who took antiviral prophylaxis before ruxolitinib treatment, did not develop HBV reactivation. Also, no patients with resolved HBV infection received antiviral prophylaxis and developed HBV reactivation. Conclusion This study demonstrated that HBV reactivation and hepatitis flare might commonly occur a few months after initiating ruxolitinib treatment in patients with chronic HBV infection who did not take antiviral prophylaxis, especially in combination with TSP. Still, it was extremely rare in patients with resolved HBV infection.


Assuntos
Vírus da Hepatite B/fisiologia , Hepatite B/etiologia , Infecção Latente/etiologia , Transtornos Mieloproliferativos/tratamento farmacológico , Pirazóis/uso terapêutico , Adulto , Idoso , Feminino , Hepatite B/complicações , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Incidência , Infecção Latente/complicações , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/complicações , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
8.
Med Clin North Am ; 105(4): 627-641, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34059242

RESUMO

Psoriasis is a systemic inflammatory condition that negatively affects the quality of life and medical health of 125 million individuals globally. Although psoriasis has historically been viewed as a skin-limited disease and managed with topical agents (eg, coal tar, corticosteroids, and vitamin D analogues), the recontextualization of psoriasis as a systemic condition involving multiple organ systems has prompted the development of numerous immunomodulating, systemic agents with more targeted mechanisms of action. This article briefly discusses the indications and nuances of new and developing therapeutic agents for psoriasis management.


Assuntos
Interleucinas/antagonistas & inibidores , Psoríase/patologia , Psoríase/terapia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Administração Tópica , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Ensaios Clínicos como Assunto , Alcatrão/administração & dosagem , Alcatrão/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Psoríase/diagnóstico , Psoríase/psicologia , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Qualidade de Vida/psicologia , Receptores de Hidrocarboneto Arílico , Vitamina D/administração & dosagem , Vitamina D/análogos & derivados , Vitamina D/uso terapêutico
9.
Medicine (Baltimore) ; 100(19): e25786, 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34106613

RESUMO

RATIONALE: Significant concerns about the adverse effects following chimeric antigen receptor T cell (CAR-T) therapy are still remained including cytokine release syndrome (CRS). In rare circumstances, CRS may be refractory to tocilizumab and/or corticosteroids, a new treatment is needed for the management of CRS. PATIENT CONCERNS: We present a case of a 20-year-old male patient with acute lymphoblastic leukemia developed CRS after CD19/CD22 bispecific CAR-T treatment. DIAGNOSIS: The patient was diagnosed with BCR-ABL(P210) positive B-ALL and developed CRS after CD19/CD22 bispecific CAR-T treatment. INTERVENTIONS: Tocilizumab and methylprednisolone were administered, unfortunately the patient's symptoms of CRS were still not resolved. Another methylprednisolone and ruxolitinib were administered. OUTCOMES: The persistent fever and hypotension of this patient achieved a rapid clinical remission within hours after ruxolitinib administration. LESSONS: Ruxolitinib can be used as an alternative therapeutic approach for severe and refractory CRS without impairing CAR-T amplification and anti-tumor effect.


Assuntos
Síndrome da Liberação de Citocina/tratamento farmacológico , Imunoterapia Adotiva/efeitos adversos , Inibidores de Janus Quinases/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pirazóis/uso terapêutico , Receptores de Antígenos Quiméricos/uso terapêutico , Síndrome da Liberação de Citocina/etiologia , Humanos , Imunoterapia Adotiva/métodos , Masculino , Adulto Jovem
10.
Cancer Sci ; 112(7): 2870-2883, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33931924

RESUMO

Wnt, PI3K-Akt-mTOR, and NF-κB pathways were reported to be involved in DNA damage repair (DDR). DDR-deficient cancers become critically dependent on backup DNA repair pathways. Neuritin 1 (NRN1) is reported to be involved in PI3K-Akt-mTOR, and its role in DDR remains unclear. Methylation-specific PCR, siRNA, flow cytometry, esophageal cancer cell lines, and xenograft mouse models were used to examine the role of NRN1 in esophageal cancer. The expression of NRN1 is frequently repressed by promoter region methylation in human esophageal cancer cells. NRN1 was methylated in 50.4% (510/1012) of primary esophageal cancer samples. NRN1 methylation is associated significantly with age (P < .001), tumor size (P < .01), TNM stage (P < .001), differentiation (P < .001) and alcohol consumption (P < .05). We found that NRN1 methylation is an independent prognostic factor for poor 5-y overall survival (P < .001). NRN1 inhibits colony formation, cell proliferation, migration, and invasion, and induces apoptosis and G1/S arrest in esophageal cancer cells. NRN1 suppresses KYSE150 and KYSE30 cells xenografts growth in nude mice. PI3K signaling is reported to activate ATR signaling by targeting CHK1, the downstream component of ATR. By analyzing the synthetic efficiency of NVP-BEZ235 (PI3K inhibitor) and VE-822 (an ATR inhibitor), we found that the combination of NVP-BEZ235 and VE-822 increased cytotoxicity in NRN1 methylated esophageal cancer cells, as well as KYSE150 cell xenografts. In conclusion, NRN1 suppresses esophageal cancer growth both in vitro and in vivo by inhibiting PI3K-Akt-mTOR signaling. Methylation of NRN1 is a novel synthetic lethal marker for PI3K-Akt-mTOR and ATR inhibitors in human esophageal cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Reparo do DNA , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Neuropeptídeos/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas , Animais , Apoptose , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Dano ao DNA , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Xenoenxertos , Humanos , Masculino , Metilação , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Transplante de Neoplasias , Neuropeptídeos/genética , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Prognóstico , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazinas/uso terapêutico , Pirazóis/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Carga Tumoral
11.
BMC Infect Dis ; 21(1): 427, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: covidwho-1219337

RESUMO

PURPOSE: Hyperinflammation in severe COVID-19 infection increases the risk of respiratory failure and one of the cogent reasons of mortality associated with COVID-19. Baricitinib, a janus kinases inhibitor, can potentially suppress inflammatory cascades in severe COVID-19 pneumonia. METHODS: The objective of this study was to compare the clinical outcomes of high dose of baricitinib with its usual dose in patients with severe COVID-19 pneumonia. This prospective cohort study was conducted on 238 adult patients with severe COVID-19 pneumonia. Eight milligram and 4 mg of baricitinib was given orally to 122 patients in the high dose (HD) group and 116 patients the usual dose (UD) group, respectively daily for 14 days, and clinical outcomes were compared among the groups. RESULTS: Blood oxygen saturation level was stabilized (≥94% on room air) earlier in the HD group compared to the UD group [5 (IQR: 4-5)/8 (IQR: 6-9), P < 0.05]. Patients in the HD group required intensive care unit (ICU) and intubation supports more in the UD group than that in patients of the HD group [17.2%/9%, P < 0.05; 11.2%/4.1%, P > 0.05; N = 116/122, respectively]. The 30-day mortality and 60-day rehospitalization rate were higher in the UD group than the HD group [6%/3.3%, P < 0.01; 11.9%/7.6%, P > 0.05; N = 116/122, respectively]. CONCLUSION: The daily high dose of baricitinib in severe COVID-19 results in early stabilization of the respiratory functions, declined requirements of critical care supports, reduced rehospitalization with mortality rate compared to its daily usual dose.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Azetidinas/administração & dosagem , COVID-19/tratamento farmacológico , Purinas/administração & dosagem , Pirazóis/administração & dosagem , Sulfonamidas/administração & dosagem , Administração Oral , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Azetidinas/uso terapêutico , Bangladesh , COVID-19/mortalidade , Comorbidade , Cuidados Críticos , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente , Estudos Prospectivos , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/virologia , Sulfonamidas/uso terapêutico , Resultado do Tratamento
12.
J Immunother Cancer ; 9(5)2021 05.
Artigo em Inglês | MEDLINE | ID: covidwho-1228897

RESUMO

COVID-19, the syndrome caused by the infection with SARS-CoV-2 coronavirus, is characterized, in its severe form, by interstitial diffuse pneumonitis and acute respiratory distress syndrome (ARDS). ARDS and systemic manifestations of COVID-19 are mainly due to an exaggerated immune response triggered by the viral infection. Cytokine release syndrome (CRS), an inflammatory syndrome characterized by elevated levels of circulating cytokines, and endothelial dysfunction are systemic manifestations of COVID-19. CRS is also an adverse event of immunotherapy (IMTX), the treatment of diseases using drugs, cells, and antibodies to stimulate or suppress the immune system. Graft-versus-host disease complications after an allogeneic stem cell transplant, toxicity after the infusion of chimeric antigen receptor-T cell therapy and monoclonal antibodies can all lead to CRS. It is hypothesized that anti-inflammatory drugs used for treatment of CRS in IMTX may be useful in reducing the mortality in COVID-19, whereas IMTX itself may help in ameliorating effects of SARS-CoV-2 infection. In this paper, we focused on the potential shared mechanisms and differences between COVID-19 and IMTX-related toxicities. We performed a systematic review of the clinical trials testing anti-inflammatory therapies and of the data published from prospective trials. Preliminary evidence suggests there might be a benefit in targeting the cytokines involved in the pathogenesis of COVID-19, especially by inhibiting the interleukin-6 pathway. Many other approaches based on novel drugs and cell therapies are currently under investigation and may lead to a reduction in hospitalization and mortality due to COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/terapia , Síndrome da Liberação de Citocina/tratamento farmacológico , Imunoterapia/métodos , Interleucina-6/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/patologia , Síndrome da Liberação de Citocina/patologia , Humanos , Imunização Passiva/métodos , Imunoterapia/efeitos adversos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/sangue , Interleucina-6/sangue , Pirazóis/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Fator de Necrose Tumoral alfa/sangue
13.
Aging (Albany NY) ; 13(10): 14234-14257, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34016786

RESUMO

Pulmonary arterial hypertension (PAH) is a devastating cardiovascular disease without a clear mechanism or drugs for treatment. Therefore, it is crucial to reveal the underlying molecular mechanism and identify potential drugs for PAH. In this study, we first integrated three human lung tissue datasets (GSE113439, GSE53408, GSE117261) from GEO. A total of 151 differentially expressed genes (DEGs) were screened, followed by KEGG and GO enrichment analyses and PPI network construction. Five hub genes (CSF3R, NT5E, ANGPT2, FGF7, and CXCL9) were identified by Cytoscape (Cytohubba). GSEA and GSVA were performed for each hub gene to uncover the potential mechanism. Moreover, to repurpose known and therapeutic drugs, the CMap database was retrieved, and nine candidate compounds (lypressin, ruxolitinib, triclabendazole, L-BSO, tiaprofenic acid, AT-9283, QL-X-138, huperzine-a, and L-741742) with a high level of confidence were obtained. Then ruxolitinib was selected to perform molecular docking simulations with ANGPT2, FGF7, NT5E, CSF3R, JAK1, JAK2, JAK3, TYK2. A certain concentration of ruxolitinib could inhibit the proliferation and migration of rat pulmonary artery smooth muscle cells (rPASMCs) in vitro. Together, these analyses principally identified CSF3R, NT5E, ANGPT2, FGF7 and CXCL9 as candidate biomarkers of PAH, and ruxolitinib might exert promising therapeutic action for PAH.


Assuntos
Biologia Computacional , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/genética , Animais , Hipóxia Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Simulação de Acoplamento Molecular , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Análise de Componente Principal , Mapas de Interação de Proteínas/genética , Hipertensão Arterial Pulmonar/patologia , Artéria Pulmonar/patologia , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
14.
J Clin Exp Hematop ; 61(2): 114-119, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33994432

RESUMO

A 62-year-old woman, who had a 16-year history of JAK2V617F-mutated myeloproliferative neoplasm (MPN), developed Burkitt leukemia (BL) 16 months after treatment with ruxolitinib to control hydroxyurea-refractory conditions. BL cells were CD10+, CD19+, CD20-, CD34-, cytoplasmic CD79a+, and TdT+, and lacked surface immunoglobulins but expressed the cytoplasmic µ heavy chain. In the bone marrow, nuclear MYC+ BL cells displaced the MPN tissues. t(8;14)(q24;q32) occurred at a CG dinucleotide within MYC exon 1 and at the IGHJ3 segment, and an N-like segment was inserted at the junction. The V-D-J sequence of the non-translocated IGH allele had the unmutated configuration. DNA from peripheral blood at a time of the course of MPN exhibited homozygous JAK2V617F mutation, while that at BL development included both JAK2V617F and wild-type DNAs. Although the association between JAK1/2 inhibitor therapy for MPN and secondary development of aggressive B-cell neoplasm remains controversial, this report suggests that, in selected patients, close monitoring of clonal B-cells in the BM is required before and during treatment with JAK1/2 inhibitors.


Assuntos
Linfoma de Burkitt/etiologia , Hidroxiureia/uso terapêutico , Transtornos Mieloproliferativos/tratamento farmacológico , Células Precursoras de Linfócitos B/patologia , Pirazóis/uso terapêutico , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Feminino , Humanos , Janus Quinase 2/genética , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Mutação Puntual
15.
BMC Infect Dis ; 21(1): 427, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33962573

RESUMO

PURPOSE: Hyperinflammation in severe COVID-19 infection increases the risk of respiratory failure and one of the cogent reasons of mortality associated with COVID-19. Baricitinib, a janus kinases inhibitor, can potentially suppress inflammatory cascades in severe COVID-19 pneumonia. METHODS: The objective of this study was to compare the clinical outcomes of high dose of baricitinib with its usual dose in patients with severe COVID-19 pneumonia. This prospective cohort study was conducted on 238 adult patients with severe COVID-19 pneumonia. Eight milligram and 4 mg of baricitinib was given orally to 122 patients in the high dose (HD) group and 116 patients the usual dose (UD) group, respectively daily for 14 days, and clinical outcomes were compared among the groups. RESULTS: Blood oxygen saturation level was stabilized (≥94% on room air) earlier in the HD group compared to the UD group [5 (IQR: 4-5)/8 (IQR: 6-9), P < 0.05]. Patients in the HD group required intensive care unit (ICU) and intubation supports more in the UD group than that in patients of the HD group [17.2%/9%, P < 0.05; 11.2%/4.1%, P > 0.05; N = 116/122, respectively]. The 30-day mortality and 60-day rehospitalization rate were higher in the UD group than the HD group [6%/3.3%, P < 0.01; 11.9%/7.6%, P > 0.05; N = 116/122, respectively]. CONCLUSION: The daily high dose of baricitinib in severe COVID-19 results in early stabilization of the respiratory functions, declined requirements of critical care supports, reduced rehospitalization with mortality rate compared to its daily usual dose.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Azetidinas/administração & dosagem , COVID-19/tratamento farmacológico , Purinas/administração & dosagem , Pirazóis/administração & dosagem , Sulfonamidas/administração & dosagem , Administração Oral , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Azetidinas/uso terapêutico , Bangladesh , COVID-19/mortalidade , Comorbidade , Cuidados Críticos , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente , Estudos Prospectivos , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/virologia , Sulfonamidas/uso terapêutico , Resultado do Tratamento
16.
J Immunother Cancer ; 9(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33986127

RESUMO

COVID-19, the syndrome caused by the infection with SARS-CoV-2 coronavirus, is characterized, in its severe form, by interstitial diffuse pneumonitis and acute respiratory distress syndrome (ARDS). ARDS and systemic manifestations of COVID-19 are mainly due to an exaggerated immune response triggered by the viral infection. Cytokine release syndrome (CRS), an inflammatory syndrome characterized by elevated levels of circulating cytokines, and endothelial dysfunction are systemic manifestations of COVID-19. CRS is also an adverse event of immunotherapy (IMTX), the treatment of diseases using drugs, cells, and antibodies to stimulate or suppress the immune system. Graft-versus-host disease complications after an allogeneic stem cell transplant, toxicity after the infusion of chimeric antigen receptor-T cell therapy and monoclonal antibodies can all lead to CRS. It is hypothesized that anti-inflammatory drugs used for treatment of CRS in IMTX may be useful in reducing the mortality in COVID-19, whereas IMTX itself may help in ameliorating effects of SARS-CoV-2 infection. In this paper, we focused on the potential shared mechanisms and differences between COVID-19 and IMTX-related toxicities. We performed a systematic review of the clinical trials testing anti-inflammatory therapies and of the data published from prospective trials. Preliminary evidence suggests there might be a benefit in targeting the cytokines involved in the pathogenesis of COVID-19, especially by inhibiting the interleukin-6 pathway. Many other approaches based on novel drugs and cell therapies are currently under investigation and may lead to a reduction in hospitalization and mortality due to COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/terapia , Síndrome da Liberação de Citocina/tratamento farmacológico , Imunoterapia/métodos , Interleucina-6/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/patologia , Síndrome da Liberação de Citocina/patologia , Humanos , Imunização Passiva/métodos , Imunoterapia/efeitos adversos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/sangue , Interleucina-6/sangue , Pirazóis/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Fator de Necrose Tumoral alfa/sangue
17.
Br J Hosp Med (Lond) ; 82(3): 1-9, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: covidwho-1168180

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread and have grave health and socioeconomic consequences worldwide. Researchers have raced to understand the pathophysiological mechanisms underpinning the disease caused by SARS-CoV-2 so that effective therapeutic targets can be discovered. This review summarises the key pharmacotherapies that are being investigated for treatment of COVID-19, including antiviral, immunomodulator and anticoagulation strategies.


Assuntos
Anticoagulantes/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Glucocorticoides/uso terapêutico , Fatores Imunológicos/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/uso terapêutico , COVID-19/terapia , Colchicina/uso terapêutico , Dexametasona/uso terapêutico , Humanos , Imunização Passiva , Ivermectina/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Purinas/uso terapêutico , Pirazóis/uso terapêutico , SARS-CoV-2 , Sulfonamidas/uso terapêutico
18.
Trials ; 22(1): 270, 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: covidwho-1181120

RESUMO

OBJECTIVES: The primary objective of MATIS is to determine the efficacy of ruxolitinib (RUX) or fostamatinib (FOS) compared to standard of care (SOC) with respect to reducing the proportion of hospitalised patients progressing from mild or moderate to severe COVID-19 pneumonia. Secondary objectives, at 14 and 28 days, are to: Determine the efficacy of RUX or FOS to reduce mortality Determine the efficacy of RUX or FOS to reduce the need for invasive ventilation or ECMO Determine the efficacy of RUX or FOS to reduce the need for non-invasive ventilation Determine the efficacy of RUX or FOS to reduce the proportion of participants suffering significant oxygen desaturation Determine the efficacy of RUX or FOS to reduce the need for renal replacement therapy Determine the efficacy of RUX and FOS to reduce the incidence of venous thromboembolism Determine the efficacy of RUX and FOS to reduce the severity of COVID-19 pneumonia [graded by a 9-point modified WHO Ordinal Scale* Determine the efficacy of RUX or FOS to reduce systemic inflammation Determine the efficacy of RUX or FOS to the incidence of renal impairment Determine the efficacy of RUX or FOS to reduce duration of hospital stay Evaluate the safety of RUX and FOS for treatment of COVID-19 pneumonia. TRIAL DESIGN: A multi-arm, multi-stage (3-arm parallel-group, 2-stage) randomised controlled trial that allocates participants 1:1:1 and tests for superiority in experimental arms versus standard of care. PARTICIPANTS: Patients will be recruited while inpatients during hospitalisation for COVID-19 in multiple centres throughout the UK including Imperial College Healthcare NHS Trust. INCLUSION: Patients age ≥ 18 years at screening Patients with mild or moderate COVID-19 pneumonia, defined as Grade 3 or 4 severity by the WHO COVID-19 Ordinal Scale Patients meeting criteria: Hospitalization AND SARS-CoV2 infection (clinically suspected or laboratory confirmed) AND Radiological change consistent with COVID-19 disease CRP ≥ 30mg/L at any time point Informed consent from patient or personal or professional representative Agreement to abstain from sexual intercourse or use contraception that is >99% effective for all participants of childbearing potential for 42 days after the last dose of study drug. For male participants, agreement to abstain from sperm donation for 42 days after the last dose of study drug. EXCLUSION: Requiring either invasive or non-invasive ventilation including CPAP or high flow nasal oxygen at any point after hospital admission but before baseline, not related to a pre-existing condition (e.g., obstructive sleep apnoea) Grade ≥ 5 severity on the modified WHO COVID-19 Ordinal Scale, i.e. SpO2 < 90% on ≥ 60% inspired oxygen by facemask at baseline; non-invasive ventilation; or invasive mechanical ventilation In the opinion of the investigator, progression to death is inevitable within the next 24 hours, irrespective of the provision of therapy Known severe allergic reactions to the investigational agents Child-Pugh B or C grade hepatic dysfunction Use of drugs within the preceding 14 days that are known to interact with any study treatment (FOS or RUX), as listed in the Summary of Product Characteristics Pregnant or breastfeeding Any medical condition or concomitant medication that in the opinion of the investigator would compromise subjects' safety or compliance with study procedures. Any medical condition which in the opinion of the principal investigator would compromise the scientific integrity of the study Non-English speakers will be able to join the study. If participants are unable to understand verbal or written information in English, then hospital translation services will be requested at the participating site for the participant where possible. INTERVENTION AND COMPARATOR: RUXOLITINIB (RUX) (14 days): An oral selective and potent inhibitor of Janus Associated Kinases (JAK1 and JAK2) and cell proliferation (Verstovek, 2010). It is approved for the treatment of disease-related splenomegaly or constitutional symptoms in myelofibrosis, polycythaemia vera and graft-versus-host-disease. RUX will be administered orally 10mg bd Day 1-7 and 5mg bd Day 8-14. FOSTAMATINIB (FOS) (14 days): An oral spleen tyrosine kinase inhibitor approved for the treatment of thrombocytopenia in adult participants with chronic immune thrombocytopenia. FOS will be administered orally 150mg bd Day 1-7 and 100mg bd Day 8-14. Please see protocol for recommended dose modifications where required. COMPARATOR (Standard of Care, SOC): experimental arms will be compared to participants receiving standard of care. It is accepted that SOC may change during a rapidly evolving pandemic. Co-enrolment to other trials and rescue therapy, either pre- or post-randomisation, is permitted and will be accounted for in the statistical analysis. MAIN OUTCOMES: Pairwise comparison (RUX vs SOC and FOS vs SOC) of the proportion of participants diagnosed with severe COVID-19 pneumonia within 14 days. Severe COVID-19 pneumonia is defined by a score ≥ 5 on a modified WHO COVID-19 Ordinal Scale, comprising the following indicators of disease severity: Death OR Requirement for invasive ventilation OR Requirement for non-invasive ventilation including CPAP or high flow oxygen OR O2 saturation < 90% on ≥60% inspired oxygen RANDOMISATION: Participants will be allocated to interventions using a central web-based randomisation service that generates random sequences using random permuted blocks (1:1:1), with stratification by age (<65 and ≥65 years) and site. BLINDING (MASKING): No participants or caregivers are blinded to group assignment. Clinical outcomes will be compared blind to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): For an early informal dose examination by the Data Monitoring Committee a minimum of 30 participants will be recruited. For Stage 1 of this multi-arm multi-stage study, 171 participants will be randomised, with 57 participants in each arm. If at least one experimental intervention shows promise, then Stage 2 will recruit a further 95 participants per arm. Sample size calculations are given in the protocol. TRIAL STATUS: Recruitment is ongoing and started 2nd October 2020. We anticipate completion of Stage 1 by July 2021 and Stage 2 by April 2022. The current protocol version 2.0 of 11th February 2021 is appended. TRIAL REGISTRATION: EudraCT: 2020-001750-22 , 9th July 2020 ClinicalTrials.gov: NCT04581954 , 9th October 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
COVID-19/tratamento farmacológico , Oxazinas/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Adulto , Humanos , Pandemias , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial , Resultado do Tratamento , Tromboembolia Venosa/prevenção & controle
19.
J Med Chem ; 64(9): 5404-5428, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33844533

RESUMO

The connection with acute myelogenous leukemia (AML) of dihydroorotate dehydrogenase (hDHODH), a key enzyme in pyrimidine biosynthesis, has attracted significant interest from pharma as a possible AML therapeutic target. We recently discovered compound 1, a potent hDHODH inhibitor (IC50 = 1.2 nM), able to induce myeloid differentiation in AML cell lines (THP1) in the low nM range (EC50 = 32.8 nM) superior to brequinar's phase I/II clinical trial (EC50 = 265 nM). Herein, we investigate the 1 drug-like properties observing good metabolic stability and no toxic profile when administered at doses of 10 and 25 mg/kg every 3 days for 5 weeks (Balb/c mice). Moreover, in order to identify a backup compound, we investigate the SAR of this class of compounds. Inside the series, 17 is characterized by higher potency in inducing myeloid differentiation (EC50 = 17.3 nM), strong proapoptotic properties (EC50 = 20.2 nM), and low cytotoxicity toward non-AML cells (EC30(Jurkat) > 100 µM).


Assuntos
Compostos de Bifenilo/química , Inibidores Enzimáticos/química , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Pirazóis/química , Piridinas/química , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Fármacos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Meia-Vida , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Pirazóis/metabolismo , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridinas/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
20.
Int J Mol Sci ; 22(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33925883

RESUMO

Childhood acute lymphoblastic leukemia is a genetically heterogeneous cancer that accounts for 10-15% of T-cell acute lymphoblastic leukemia (T-ALL) cases. The T-ALL event-free survival rate (EFS) is 85%. The evaluation of structural and numerical chromosomal changes is important for a comprehensive biological characterization of T-ALL, but there are currently no genetic prognostic markers. Despite chemotherapy regimens, steroids, and allogeneic transplantation, relapse is the main problem in children with T-ALL. Due to the development of high-throughput molecular methods, the ability to define subgroups of T-ALL has significantly improved in the last few years. The profiling of the gene expression of T-ALL has led to the identification of T-ALL subgroups, and it is important in determining prognostic factors and choosing an appropriate treatment. Novel therapies targeting molecular aberrations offer promise in achieving better first remission with the hope of preventing relapse. The employment of precisely targeted therapeutic approaches is expected to improve the cure of the disease and quality of life of patients. These include therapies that inhibit Notch1 activation (bortezomib), JAK inhibitors in ETP-ALL (ruxolitinib), BCL inhibitors (venetoclax), and anti-CD38 therapy (daratumumab). Chimeric antigen receptor T-cell therapy (CAR-T) is under investigation, but it requires further development and trials. Nelarabine-based regimens remain the standard for treating the relapse of T-ALL.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Adolescente , Anticorpos Monoclonais/uso terapêutico , Bortezomib/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Criança , Perfilação da Expressão Gênica , Terapia Genética , Humanos , Imunoterapia Adotiva , Pediatria , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Intervalo Livre de Progressão , Pirazóis/uso terapêutico , Qualidade de Vida , Recidiva , Sulfonamidas/uso terapêutico , Linfócitos T/imunologia , Linfócitos T/patologia
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