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1.
Curr Opin Obstet Gynecol ; 33(1): 53-58, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33337614

RESUMO

PURPOSE OF REVIEW: The present review summarizes recent original publications addressing the topic of risk-adapted adjuvant therapy in early breast cancer (EBC). As neoadjuvant therapy has become a standard for triple negative and HER2+ EBC, it focusses on luminal EBC. RECENT FINDINGS: Gene expression assays have become standard of care in luminal EBC, at least for patients with node negative disease. Two prospective randomized clinical trials, TAILORx (Oncotype DX) and MINDACT (MammaPrint) have presented additional analyses underlining the clinical utility of the tests. In times of COVID-19, immunohistochemically determined ER, PR, and Ki67 and early Ki67 response to endocrine therapy can be used to safely allocate patients for preoperative endocrine therapy and delay surgeries if resources are scarce. In patients with luminal high-risk disease, adding a CDK 4/6 inhibitor (abemaciclib) improves patient outcome already after short-term follow-up. SUMMARY: Determination of recurrence risk will remain important in luminal EBC for optimal therapy decisions. In the future, risk-adapted treatment concepts will include decision making for chemotherapy but also for endocrine-based approaches.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Inibidores de Proteínas Quinases/uso terapêutico , Aminopiridinas/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Feminino , Perfilação da Expressão Gênica , Humanos , Antígeno Ki-67/metabolismo , Terapia Neoadjuvante , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Medição de Risco
2.
Cochrane Database Syst Rev ; 12: CD010966, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33331662

RESUMO

BACKGROUND: Cystic fibrosis (CF) is a common life-shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class II CFTR variant F508del (found in up to 90% of people with CF (pwCF)) is the commonest CF-causing variant. The faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. The F508del variant lacks meaningful CFTR function and corrective therapy could benefit many pwCF. Therapies in this review include single correctors and any combination of correctors and potentiators. OBJECTIVES: To evaluate the effects of CFTR correctors (with or without potentiators) on clinically important benefits and harms in pwCF of any age with class II CFTR mutations (most commonly F508del). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register, reference lists of relevant articles and online trials registries. Most recent search: 14 October 2020. SELECTION CRITERIA: Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to control in pwCF with class II mutations. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and evidence quality (GRADE); we contacted investigators for additional data. MAIN RESULTS: We included 19 RCTs (2959 participants), lasting between 1 day and 24 weeks; an extension of two lumacaftor-ivacaftor studies provided additional 96-week safety data (1029 participants). We assessed eight monotherapy RCTs (344 participants) (4PBA, CPX, lumacaftor, cavosonstat and FDL169), six dual-therapy RCTs (1840 participants) (lumacaftor-ivacaftor or tezacaftor-ivacaftor) and five triple-therapy RCTs (775 participants) (elexacaftor-tezacaftor-ivacaftor or VX-659-tezacaftor-ivacaftor); below we report only the data from elexacaftor-tezacaftor-ivacaftor combination which proceeded to Phase 3 trials. In 14 RCTs participants had F508del/F508del genotypes, in three RCTs F508del/minimal function (MF) genotypes and in two RCTs both genotypes. Risk of bias judgements varied across different comparisons. Results from 11 RCTs may not be applicable to all pwCF due to age limits (e.g. adults only) or non-standard design (converting from monotherapy to combination therapy). Monotherapy Investigators reported no deaths or clinically-relevant improvements in quality of life (QoL). There was insufficient evidence to determine any important effects on lung function. No placebo-controlled monotherapy RCT demonstrated differences in mild, moderate or severe adverse effects (AEs); the clinical relevance of these events is difficult to assess with their variety and small number of participants (all F508del/F508del). Dual therapy Investigators reported no deaths (moderate- to high-quality evidence). QoL scores (respiratory domain) favoured both lumacaftor-ivacaftor and tezacaftor-ivacaftor therapy compared to placebo at all time points. At six months lumacaftor 600 mg or 400 mg (both once daily) plus ivacaftor improved Cystic Fibrosis Questionnaire (CFQ) scores slightly compared with placebo (mean difference (MD) 2.62 points (95% confidence interval (CI) 0.64 to 4.59); 1061 participants; high-quality evidence). A similar effect was observed for twice-daily lumacaftor (200 mg) plus ivacaftor (250 mg), but with low-quality evidence (MD 2.50 points (95% CI 0.10 to 5.10)). The mean increase in CFQ scores with twice-daily tezacaftor (100 mg) and ivacaftor (150 mg) was approximately five points (95% CI 3.20 to 7.00; 504 participants; moderate-quality evidence). At six months, the relative change in forced expiratory volume in one second (FEV1) % predicted improved with combination therapies compared to placebo by: 5.21% with once-daily lumacaftor-ivacaftor (95% CI 3.61% to 6.80%; 504 participants; high-quality evidence); 2.40% with twice-daily lumacaftor-ivacaftor (95% CI 0.40% to 4.40%; 204 participants; low-quality evidence); and 6.80% with tezacaftor-ivacaftor (95% CI 5.30 to 8.30%; 520 participants; moderate-quality evidence). More pwCF reported early transient breathlessness with lumacaftor-ivacaftor, odds ratio 2.05 (99% CI 1.10 to 3.83; 739 participants; high-quality evidence). Over 120 weeks (initial study period and follow-up) systolic blood pressure rose by 5.1 mmHg and diastolic blood pressure by 4.1 mmHg with twice-daily 400 mg lumacaftor-ivacaftor (80 participants; high-quality evidence). The tezacaftor-ivacaftor RCTs did not report these adverse effects. Pulmonary exacerbation rates decreased in pwCF receiving additional therapies to ivacaftor compared to placebo: lumacaftor 600 mg hazard ratio (HR) 0.70 (95% CI 0.57 to 0.87; 739 participants); lumacaftor 400 mg, HR 0.61 (95% CI 0.49 to 0.76; 740 participants); and tezacaftor, HR 0.64 (95% CI, 0.46 to 0.89; 506 participants) (moderate-quality evidence). Triple therapy Three RCTs of elexacaftor to tezacaftor-ivacaftor in pwCF (aged 12 years and older with either one or two F508del variants) reported no deaths (high-quality evidence). All other evidence was graded as moderate quality. In 403 participants with F508del/minimal function (MF) elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (MD 20.2 points (95% CI 16.2 to 24.2)) and absolute change in FEV1 (MD 14.3% predicted (95% CI 12.7 to 15.8)) compared to placebo at 24 weeks. At four weeks in 107 F508del/F508del participants, elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (17.4 points (95% CI 11.9 to 22.9)) and absolute change in FEV1 (MD 10.0% predicted (95% CI 7.5 to 12.5)) compared to tezacaftor-ivacaftor. There was probably little or no difference in the number or severity of AEs between elexacaftor-tezacaftor-ivacaftor and placebo or control (moderate-quality evidence). In 403 F508del/F508del participants, there was a longer time to protocol-defined pulmonary exacerbation with elexacaftor-tezacaftor-ivacaftor over 24 weeks (moderate-quality evidence). AUTHORS' CONCLUSIONS: There is insufficient evidence that corrector monotherapy has clinically important effects in pwCF with F508del/F508del. Both dual therapies (lumacaftor-ivacaftor, tezacaftor-ivacaftor) result in similar improvements in QoL and respiratory function with lower pulmonary exacerbation rates. Lumacaftor-ivacaftor was associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (not observed for tezacaftor-ivacaftor). Tezacaftor-ivacaftor has a better safety profile, although data are lacking in children under 12 years. In this population, lumacaftor-ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns; but this should be balanced against the blood pressure increase and shortness of breath seen in longer-term adult data when considering lumacaftor-ivacaftor. There is high-quality evidence of clinical efficacy with probably little or no difference in AEs for triple (elexacaftor-tezacaftor-ivacaftor) therapy in pwCF with one or two F508del variants aged 12 years or older. Further RCTs are required in children (under 12 years) and those with more severe respiratory function.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Mutação , Adulto , Aminofenóis/uso terapêutico , Aminopiridinas/uso terapêutico , Benzodioxóis/uso terapêutico , Viés , Criança , Combinação de Medicamentos , Humanos , Indóis/uso terapêutico , Fenilbutiratos/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Qualidade de Vida , Quinolinas/uso terapêutico , Quinolonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
Medicine (Baltimore) ; 99(43): e22788, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120793

RESUMO

RATIONALE: The prognosis of patients with aggressive relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) remains poor. Both immunomodulatory drugs and histone deacetylase inhibitors have demonstrated activity against R/R NHL; yet, the combination of these 2 targeted therapies has rarely been explored. PATIENT CONCERNS: Here, we report 3 cases. Case 1 was a 68-year-old woman who presented to our hospital with dyspnea. Case 2 was a 75-year-old man with massive upper gastrointestinal bleeding. Case 3 was a 62-year-old woman with cough, dyspnea, and lymphadenopathy. DIAGNOSIS: The biopsy results revealed diffuse large B cell lymphoma (DLBCL), DLBCL, and angioimmunoblastic T-cell lymphoma, for Case 1, 2, and 3 respectively. INTERVENTION: All 3 patients experienced relapse after first-line therapy and multiple lines of salvage therapy. Finally, they all received lenalidomide combined with chidamide. OUTCOMES: All 3 patients achieved complete and durable remission. Case 1 relapsed again after 3 months, while the other 2 cases remained in complete remission. LESSONS: To our knowledge, this is the first report of lenalidomide combined with chidamide for the treatment of R/R NHL. Our findings warrant further evaluation of this novel chemo-free therapy in future prospective clinical trials.


Assuntos
Aminopiridinas/uso terapêutico , Benzamidas/uso terapêutico , Lenalidomida/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Idoso , Aminopiridinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/administração & dosagem , Feminino , Humanos , Lenalidomida/administração & dosagem , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Terapia de Salvação
5.
AJNR Am J Neuroradiol ; 41(5): 866-873, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32354716

RESUMO

BACKGROUND AND PURPOSE: 2D measurements of diffuse intrinsic pontine gliomas are limited by variability, and volumetric response criteria are poorly defined. Semiautomated 2D measurements may improve consistency; however, the impact on tumor response assessments is unknown. The purpose of this study was to compare manual 2D, semiautomated 2D, and volumetric measurement strategies for diffuse intrinsic pontine gliomas. MATERIALS AND METHODS: This study evaluated patients with diffuse intrinsic pontine gliomas through a Phase I/II trial (NCT02607124). Clinical 2D cross-product values were derived from manual linear measurements (cross-product = long axis × short axis). By means of dedicated software (mint Lesion), tumor margins were traced and maximum cross-product and tumor volume were automatically derived. Correlation and bias between methods were assessed, and response assessment per measurement strategy was reported. RESULTS: Ten patients (median age, 7.6 years) underwent 58 MR imaging examinations. Correlation and mean bias (95% limits) of percentage change in tumor size from prior examinations were the following: clinical and semiautomated cross-product, r = 0.36, -1.5% (-59.9%, 56.8%); clinical cross-product and volume, r = 0.61, -2.1% (-52.0%, 47.8%); and semiautomated cross-product and volume, r = 0.79, 0.6% (-39.3%, 38.1%). Stable disease, progressive disease, and partial response rates per measurement strategy were the following: clinical cross-product, 82%, 18%, 0%; semiautomated cross-product, 54%, 42%, 4%; and volume, 50%, 46%, 4%, respectively. CONCLUSIONS: Manual 2D cross-product measurements may underestimate tumor size and disease progression compared with semiautomated 2D and volumetric measurements.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Neuroimagem/métodos , Adolescente , Aminopiridinas/uso terapêutico , Neoplasias do Tronco Encefálico/tratamento farmacológico , Quimiorradioterapia/métodos , Quimioterapia Adjuvante/métodos , Criança , Glioma Pontino Intrínseco Difuso/tratamento farmacológico , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Purinas/uso terapêutico , Software , Carga Tumoral/efeitos dos fármacos , Adulto Jovem
6.
Zhonghua Xue Ye Xue Za Zhi ; 41(4): 292-296, 2020 Apr 14.
Artigo em Chinês | MEDLINE | ID: mdl-32447932

RESUMO

Objective: To explore the effect and mechanism of low-dose chidamide on the treatment of primary immune thrombocytopenia (ITP) . Methods: Passive ITP animal model and active ITP animal model were established by C57BL/6J mice. Different doses of chidamide (0, 0.01, 0.1, 0.5, and 5 mg/kg) were orally administrated twice a week for 120 hours in passive ITP mice. Secondly, low-dose chidamine (0.1 mg/kg) was given intragastrically administrated twice a week in active ITP mice. The platelet counts in the peripheral blood before and after treatment were detected. Four weeks later, mice were executed to prepare splenocyte suspension; natural regulatory T cells (CD4(+)CD25(+)Foxp3(+) nTreg cells) in splenocyte suspension were detected by flow cytometry. Serum IL-6 was measured by ELISA. Peripheral blood mononuclear cells from ITP patients were co-cultured with low-dose chidamide in vitro. After incubation for 72 hours, CD4(+)CD25(+)Foxp3(+) Treg cells of mononuclear cells was detected. CD4(+)CD25(+) Treg cells and CD4(+)CD25(-) effector T cells were separated by immunomagnetic beads. The Treg cells and effector T cells were co cultured in a ratio of 1∶4, and treated with low-dose chidamide. The proliferation of effector T cells was detected. Results: Chidamide with low dose (0.1 mg/kg) significantly improved platelet counts in passive ITP mouse model, as well as in the ITP active mouse model and reduced the mortality related to bleeding. Low-dose chidamide significantly increased the number and proportion of nTreg cells in mouse splenocytes, and decreased serum IL-6 level in active ITP mice. In ITP patients, low-dose chidamide also significantly expanded Treg cells in the PBMC culture system. Besides, the proliferation of effector T cells was suppressed. Conclusion: Low-dose chidamide enhances the proliferation of CD4(+)CD25(+)Foxp3(+) regulatory T cells to mediate immunosuppressive function. Serum IL-6 is inhibited for further immune tolerance. In vivo animal study suggestes that low-dose chidamide has a novel therapeutic effect on ITP.


Assuntos
Aminopiridinas/uso terapêutico , Benzamidas/uso terapêutico , Púrpura Trombocitopênica Idiopática , Animais , Fatores de Transcrição Forkhead , Humanos , Leucócitos Mononucleares , Camundongos , Camundongos Endogâmicos C57BL , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Linfócitos T Reguladores
7.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 32(2): 204-209, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32275007

RESUMO

OBJECTIVE: To investigate the role of Ribociclib in sepsis induced-acute kidney injury (AKI) and its possible mechanisms. METHODS: (1) Twenty adult male C57BL/6 mice were divided into sham operation group (Sham group; only open the abdomen without ligating or perforating the cecum, administered with sodium lactate buffer 12 hours before the sham operation), Ribociclib control group (administered with 150 mg/kg Ribociclib), cecal ligation and puncture (CLP) group (sepsis model induced by CLP; lactate buffer was given by intragastric administration 12 hours before CLP), and Ribociclib pretreatment group (administered with 150 mg/kg Ribociclib 12 hours before CLP) according to random number table, with 5 mice in each group. Kidneys were harvested 12 hours after the operation. Pathological changes in kidney were observed by hematoxylin-eosin (HE) staining. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels in mice kidney homogenate were measured by enzyme linked immunosorbent assay (ELISA). Western Blot was used to detect the expression of cell cycle-related protein phosphorylate retinoblastoma protein (p-Rb), apoptosis-related protein Bcl-2 and Bax. (2) Mouse renal tubular epithelial (TCMK-1) cell line was used for in vitro experiment. The cells were divided into control group, Ribociclib group (treated with 5 µmol/L Ribociclib for 24 hours), lipopolysaccharide (LPS) group (treated with 200 mg/L LPS for 6 hours), Ribociclib+LPS group (replaced with the medium containing 5 µmol/L Ribociclib and 200 mg/L LPS for 6 hours after exposing with 5 µmol/L Ribociclib for 18 hours). Inflammatory cytokines in cell culture medium were detected by ELISA. The expression of p-Rb, Bcl-2 and Bax, autophagy-related proteins microtubule associated protein 1 light chain LC3b (LC3b II, LC3b I) and p62, phosphate protein kinase B (p-AKT), phosphorylated mammalian target of rapamycin (p-mTOR) were measured by Western Blot. RESULTS: (1) Animal experiments showed that, compared with the Sham group, the kidney tissue of mice were significantly damaged, the levels of TNF-α and IL-6 were increased, the expressions of p-Rb and Bcl-2/Bax ratio were decreased in kidney tissue in CLP group; but there was no significant difference in indexes between Ribociclib control group and Sham group. Compared with the CLP group, kidney injury in mice pretreated with Ribociclib was significantly ameliorated, the pathological score was significantly decreased (1.48±0.16 vs. 2.68±0.16, P < 0.01), the levels of TNF-α and IL-6 in kidney homogenate were significantly decreased [TNF-α (ng/g): 340.55±34.96 vs. 745.08±58.86, IL-6 (mg/g): 17.33±1.01 vs. 114.20±20.49, both P < 0.01], the expression of p-Rb was furtherly decreased (p-Rb/ß-tubulin: 0.14±0.01 vs. 0.73±0.06, P < 0.01), Bcl-2/Bax ratio was increased (0.89±0.06 vs. 0.62±0.10, P < 0.01). (2) In vitro experiments showed that, compared with the control group, the releases of TNF-α and IL-6 were increased, the expression of p-Rb was decreased, the ratios of Bcl-2/Bax and LC3b II/I were decreased, the expressions of p62, p-AKT and p-mTOR were increased in LPS group; the expression of p-Rb was decreased after Ribociclib treatment in TCMK-1 cells. Compared with the LPS group, TNF-α and IL-6 were decreased [TNF-α (ng/L): 2.73±0.23 vs. 4.96±0.10, IL-6 (ng/L): 36.05±5.83 vs. 53.78±24.08, both P < 0.01], the expression of p-Rb was furtherly decreased (p-Rb/ß-tubulin: 0.25±0.05 vs. 0.65±0.05, P < 0.01), the ratios of Bcl-2/Bax and LC3b II/I were increased (Bcl-2/Bax: 1.01±0.07 vs. 0.73±0.05, LC3b II/I: 2.08±0.31 vs. 1.04±0.01, both P < 0.05), the expressions of p62, p-AKT and p-mTOR were decreased (p62/ß-tubulin: 0.59±0.01 vs. 1.09±0.08, p-AKT/ß-tubulin: 0.61±0.03 vs. 1.20±0.06, p-mTOR/ß-tubulin: 0.50±0.05 vs. 1.15±0.08, all P < 0.01) in the Ribociclib+LPS group. CONCLUSIONS: Ribociclib pretreatment ameliorated sepsis-induced AKI and AKT/mTOR pathway may be involved in the protective role of Ribociclib on kidney.


Assuntos
Lesão Renal Aguda , Aminopiridinas/uso terapêutico , Substâncias Protetoras/uso terapêutico , Purinas/uso terapêutico , Sepse , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa
8.
Proc Natl Acad Sci U S A ; 117(11): 6103-6113, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123069

RESUMO

Clinical observation of the association between cancer aggressiveness and embryonic development stage implies the importance of developmental signals in cancer initiation and therapeutic resistance. However, the dynamic gene expression during organogenesis and the master oncofetal drivers are still unclear, which impeded the efficient elimination of poor prognostic tumors, including human hepatocellular carcinoma (HCC). In this study, human embryonic stem cells were induced to differentiate into adult hepatocytes along hepatic lineages to mimic liver development in vitro. Combining transcriptomic data from liver cancer patients with the hepatocyte differentiation model, the active genes derived from different hepatic developmental stages and the tumor tissues were selected. Bioinformatic analysis followed by experimental assays was used to validate the tumor subtype-specific oncofetal signatures and potential therapeutic values. Hierarchical clustering analysis revealed the existence of two subtypes of liver cancer with different oncofetal properties. The gene signatures and their clinical significance were further validated in an independent clinical cohort and The Cancer Genome Atlas database. Upstream activator analysis and functional screening further identified E2F1 and SMAD3 as master transcriptional regulators. Small-molecule inhibitors specifically targeting the oncofetal drivers extensively down-regulated subtype-specific developmental signaling and inhibited tumorigenicity. Liver cancer cells and primary HCC tumors with different oncofetal properties also showed selective vulnerability to their specific inhibitors. Further precise targeting of the tumor initiating steps and driving events according to subtype-specific biomarkers might eliminate tumor progression and provide novel therapeutic strategy.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Regulação da Expressão Gênica no Desenvolvimento , Regulação Neoplásica da Expressão Gênica , Hepatócitos/patologia , Neoplasias Hepáticas/genética , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Animais , Biomarcadores Tumorais/antagonistas & inibidores , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Estudos de Coortes , Intervalo Livre de Doença , Fator de Transcrição E2F1/antagonistas & inibidores , Fator de Transcrição E2F1/metabolismo , Feminino , Perfilação da Expressão Gênica , Hepatectomia , Células-Tronco Embrionárias Humanas , Humanos , Hidroxiquinolinas/farmacologia , Hidroxiquinolinas/uso terapêutico , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Estimativa de Kaplan-Meier , Fígado/crescimento & desenvolvimento , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Camundongos , Pessoa de Meia-Idade , Prognóstico , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Transdução de Sinais/genética , Proteína Smad3/antagonistas & inibidores , Proteína Smad3/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Lancet Haematol ; 7(4): e309-e319, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32145771

RESUMO

BACKGROUND: Mutations in isocitrate dehydrogenase-2 (IDH2) occur in around 5% of patients with myelodysplastic syndromes. Neomorphic activity of mutant IDH2 proteins results in hypermethylation of DNA and histones, leading to blocked haemopoietic differentiation. Enasidenib, an inhibitor of mutated IDH2 proteins, induces responses in patients with IDH2-mutated, relapsed or refractory acute myeloid leukaemia. We aimed to establish the clinical outcomes of enasidenib monotherapy in a subgroup of patients with myelodysplastic syndromes harbouring mutations in IDH2 from the AG221-C-001 trial. METHODS: The multicentre, open-label, phase 1-2 AG221-C-001 trial enrolled patients with advanced haematological malignancies (2008 WHO criteria) harbouring an IDH2 mutation. The present study is a subgroup analysis of patients with IDH2-mutated myelodysplastic syndromes in the phase 1 dose-escalation and expansion portions of the trial. Patients with myelodysplastic syndromes were aged 18 years or older with an ECOG performance status score of 2 or lower, and were relapsed or refractory to, or ineligible for, standard treatments. Patients received oral doses of enasidenib at 60-300 mg per day in repeated 28-day treatment cycles. In this subgroup analysis, we focused on the safety and activity of enasidenib as main outcomes. Overall response rate, duration of response, and overall and event-free survival analyses were by intention-to-treat. Safety was assessed in all participants who received at least one dose of study drug in terms of treatment-emergent adverse events. The AG221-C-001 trial is registered on ClinicalTrials.gov, NCT01915498, status ongoing but closed to recruitment. FINDINGS: 17 patients with myelodysplastic syndromes harbouring an IDH2 mutation (median age, 67·0 years [IQR 60·5-73·0]) were enrolled between Feb 18, 2014, and Sept 1, 2015. At data cutoff (Oct 1, 2018), after a median follow-up of 11·0 months (IQR 6·8-23·0), all patients had discontinued enasidenib, with a median of 3 treatment cycles (2-15) for all patients (five [29%] received ≥12 cycles). At entry, three (18%) patients had relapsed after allogeneic stem-cell transplants, 13 (76%) had previously received therapy with hypomethylating agents, and ten (59%) had received at least two previous therapies. No dose-limiting toxicities were reported. The most common treatment-emergent adverse events were diarrhoea and nausea (in nine [53%] patients each). Most common grade 3-4 treatment-emergent adverse events were indirect hyperbilirubinaemia (in six [35%] patients), pneumonia (in five [29%] patients), and thrombocytopaenia (in four [24%] patients). Serious treatment-emergent adverse events in more than one patient were pneumonia (in five [29% patients); tumor lysis syndrome (in three [18%] patients); and sepsis, atrial flutter, indirect hyperbilirubinaemia, cerebral hemorrhage, and mental status change (in two [12%] patients each). No treatment-related deaths occurred. An overall response was achieved in 9 patients (53% [95% CI 28-77]), with a median duration of response of 9·2 months (95% CI 1·0-not reached). Six (46%) of 13 patients previously treated with hypomethylating agents responded. Median overall survival was 16·9 months (95% CI 1·5-32·3), and median event-free survival was 11·0 months (1·5-16·7). INTERPRETATION: Enasidenib is generally well tolerated and can induce responses in patients with mutant IDH2 myelodysplastic syndromes, including in those who have had previous therapy with hypomethylating agents. Testing for IDH2 mutations in myelodysplastic syndromes is essential for identifying patients who might benefit from enasidenib therapy, including those patients in whom conventional treatments have been unsuccessful. FUNDING: Celgene and Agios Pharmaceuticals.


Assuntos
Aminopiridinas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Isocitrato Desidrogenase/genética , Síndromes Mielodisplásicas/tratamento farmacológico , Triazinas/uso terapêutico , Idoso , Aminopiridinas/efeitos adversos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Hiperbilirrubinemia/etiologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Polimorfismo de Nucleotídeo Único , Taxa de Sobrevida , Resultado do Tratamento , Triazinas/efeitos adversos
10.
Bull Cancer ; 107(2): 148-156, 2020 Feb.
Artigo em Francês | MEDLINE | ID: mdl-32057466

RESUMO

Over the past years, planet oncology has kept changing and moving forward. Recent results of important clinical trials are challenging our daily practices. With modesty, the Editorial Board of BulletinduCancer has selected some clinical trials they consider as "must-know about" even if they go beyond our medical fields.


Assuntos
Ensaios Clínicos como Assunto , Neoplasias/terapia , Aminopiridinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias do Sistema Digestório/terapia , Feminino , Neoplasias dos Genitais Femininos/terapia , Humanos , Neoplasias Pulmonares/terapia , Masculino , Terapia de Alvo Molecular , Neoplasias Primárias Desconhecidas/terapia , Neoplasias da Próstata/terapia , Purinas/uso terapêutico
11.
BMJ Open ; 10(1): e033667, 2020 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-31988233

RESUMO

INTRODUCTION: Despite the development of new therapies for advanced prostate cancer, it remains the most common cause of cancer and the second leading cause of cancer death in men. It is critical to develop novel agents for the treatment of prostate cancer, particularly those that target aspects of androgen receptor (AR) signalling or prostate biology other than inhibition of androgen synthesis or AR binding. Neoadjuvant pharmacodynamic studies allow for a rational approach to the decisions regarding which targeted therapies should progress to phase II/III trials. CDK4/6 inhibitors have evidence of efficacy in breast cancer, and have been shown to have activity in preclinical models of hormone sensitive and castrate resistant prostate cancer. The LEEP trial aims to assess the pharmacodynamic effects of LEE011 (ribociclib), an orally bioavailable and highly selective CDK4/6 inhibitor, in men undergoing radical prostatectomy for high-risk, localised prostate cancer. METHODS AND ANALYSIS: The multicentre randomised, controlled 4:1 two-arm, phase II, open label pharmacodynamic study will recruit 47 men with high risk, localised prostate cancer who are planned to undergo radical prostatectomy. Participants who are randomised to receive the study treatment will be treated with LEE011 400 mg daily for 21 days for one cycle. The primary endpoint is the frequency of a 50% reduction in Ki-67 proliferation index from the pretreatment prostate biopsy compared to that present in prostate cancer tissue from radical prostatectomy. Secondary and tertiary endpoints include pharmacodynamic assessment of CDK4/6 cell cycle progression via E2F levels, apoptotic cell death by cleaved caspase-3, changes in serum and tumour levels of Prostate Specific Antigen (PSA), pathological regression, safety via incidence of adverse events and exploratory biomarker analysis. ETHICS AND DISSEMINATION: The protocol was approved by a central ethics review committee (St Vincent's Hospital HREC) for all participating sites (HREC/17/SVH/294). Results will be disseminated in peer-reviewed journals and at scientific conferences. DRUG SUPPLY: Novartis. PROTOCOL VERSION: 2.0, 30 May 2019 TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12618000354280).


Assuntos
Aminopiridinas/farmacologia , Terapia Neoadjuvante , Próstata/efeitos dos fármacos , Prostatectomia , Neoplasias da Próstata , Purinas/farmacologia , Adolescente , Adulto , Aminopiridinas/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Caspase 3/metabolismo , Ciclo Celular , Proliferação de Células , Ensaios Clínicos Fase II como Assunto , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Intervalo Livre de Doença , Fatores de Transcrição E2F/metabolismo , Humanos , Calicreínas , Masculino , Próstata/patologia , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/cirurgia , Purinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
12.
Jpn J Infect Dis ; 73(1): 1-7, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31474702

RESUMO

In addition to tube drains, pleural empyema is treated with antibiotics and anti-inflammatory drugs. We aimed to evaluate the anti-inflammatory activity of roflumilast combined with linezolid in a rat model of pleural empyema induced by Staphylococcus aureus. A total of 40 rats were divided into 7 groups: sham (n = 4), S. aureus inoculation (n = 6), S. aureus + 10 mg/kg linezolid (n = 6), S. aureus + 5 mg/kg roflumilast (n = 6), S. aureus + 10 mg/kg linezolid + 5 mg/kg roflumilast (n = 6), S. aureus + 10 mg/kg roflumilast (n = 6), and S. aureus + 10 mg/kg linezolid + 10 mg/kg roflumilast (n = 6). Animals were administered linezolid 1 h before and 12 h after inoculation with S. aureus. Roflumilast was administered orally as a single dose 30 min before inoculation with S. aureus. Compared to linezolid treatment alone, linezolid combined with 5 mg/kg roflumilast significantly improved TNF-α, IL-1ß, vasodilation/congestion, and tissue/pleural polynuclear leukocyte (PNL) infiltration (p < 0.05). Linezolid combined with 10 mg/kg roflumilast also provided a significant improvement in TNF-α, IL-1ß, IL-6, endothelin-1, vasodilation/congestion, mesothelial cell damage, lung tissue PNL, and pleural PNL compared to linezolid alone (p < 0.05). Due to its anti-inflammatory effects and significant impact on recovery, roflumilast can be used in conjunction with antibiotherapy for the treatment of pleural empyema.


Assuntos
Aminopiridinas/uso terapêutico , Antibacterianos/uso terapêutico , Benzamidas/uso terapêutico , Empiema Pleural/tratamento farmacológico , Linezolida/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Aminopiridinas/administração & dosagem , Animais , Antibacterianos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Benzamidas/administração & dosagem , Ciclopropanos/administração & dosagem , Ciclopropanos/uso terapêutico , Quimioterapia Combinada , Empiema Pleural/microbiologia , Linezolida/administração & dosagem , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/patologia , Masculino , Ratos , Ratos Wistar , Staphylococcus aureus
13.
Am J Respir Crit Care Med ; 201(2): 188-197, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31601120

RESUMO

Rationale: Lumacaftor-ivacaftor is a CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination recently approved for patients with cystic fibrosis (CF) homozygous for the Phe508del mutation.Objectives: To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life postapproval setting.Methods: The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society's recommendations.Measurements and Main Results: Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV1 (ppFEV1) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV1 (+3.67%), an increase in body mass index (+0.73 kg/m2), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV1, without improvement in body mass index or decrease in intravenous antibiotic courses.Conclusions: Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.


Assuntos
Aminofenóis/uso terapêutico , Aminopiridinas/uso terapêutico , Antibacterianos/uso terapêutico , Benzodioxóis/uso terapêutico , Fibrose Cística/tratamento farmacológico , Estado Nutricional , Quinolonas/uso terapêutico , Administração Intravenosa , Adolescente , Adulto , Índice de Massa Corporal , Espasmo Brônquico/induzido quimicamente , Tosse/induzido quimicamente , Fibrose Cística/fisiopatologia , Desprescrições , Combinação de Medicamentos , Dispneia/induzido quimicamente , Fadiga/induzido quimicamente , Feminino , Volume Expiratório Forçado , França , Gastroenteropatias/induzido quimicamente , Cefaleia/induzido quimicamente , Humanos , Modelos Logísticos , Masculino , Metrorragia/induzido quimicamente , Análise Multivariada , Mialgia/induzido quimicamente , Vigilância de Produtos Comercializados , Resultado do Tratamento , Adulto Jovem
14.
Invest New Drugs ; 38(1): 99-110, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-30825104

RESUMO

Background Pexidartinib, a novel, orally administered small-molecule tyrosine kinase inhibitor, has strong selectivity against colony-stimulating factor 1 receptor. This phase I, nonrandomized, open-label multiple-dose study evaluated pexidartinib safety and efficacy in Asian patients with symptomatic, advanced solid tumors. Materials and Methods Patients received pexidartinib: cohort 1, 600 mg/d; cohort 2, 1000 mg/d for 2 weeks, then 800 mg/d. Primary objectives assessed pexidartinib safety and tolerability, and determined the recommended phase 2 dose; secondary objectives evaluated efficacy and pharmacokinetic profile. Results All 11 patients (6 males, 5 females; median age 64, range 23-82; cohort 1 n = 3; cohort 2 n = 8) experienced at least one treatment-emergent adverse event; 5 experienced at least one grade ≥ 3 adverse event, most commonly (18%) for each of the following: increased aspartate aminotransferase, blood alkaline phosphatase, gamma-glutamyl transferase, and anemia. Recommended phase 2 dose was 1000 mg/d for 2 weeks and 800 mg/d thereafter. Pexidartinib exposure, area under the plasma concentration-time curve from zero to 8 h (AUC0-8h), and maximum observed plasma concentration (Cmax) increased on days 1 and 15 with increasing pexidartinib doses, and time at Cmax (Tmax) was consistent throughout all doses. Pexidartinib exposure and plasma levels of adiponectin and colony-stimulating factor 1 increased following multiple daily pexidartinib administrations. One patient (13%) with tenosynovial giant cell tumor showed objective tumor response. Conclusions This was the first study to evaluate pexidartinib in Asian patients with advanced solid tumors. Pexidartinib was safe and tolerable in this population at the recommended phase 2 dose previously determined for Western patients (funded by Daiichi Sankyo; clinicaltrials.gov number, NCT02734433).


Assuntos
Aminopiridinas/uso terapêutico , Neoplasias/tratamento farmacológico , Pirróis/uso terapêutico , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminopiridinas/farmacocinética , Biomarcadores Tumorais , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia , Ensaios Clínicos Controlados não Aleatórios como Assunto , Prognóstico , Pirróis/farmacocinética , Distribuição Tecidual , Adulto Jovem
15.
Gut ; 69(1): 122-132, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31076405

RESUMO

OBJECTIVE: We investigated how pancreatic cancer developed resistance to focal adhesion kinase (FAK) inhibition over time. DESIGN: Pancreatic ductal adenocarcinoma (PDAC) tumours from KPC mice (p48-CRE; LSL-KRasG12D/wt; p53flox/wt) treated with FAK inhibitor were analysed for the activation of a compensatory survival pathway in resistant tumours. We identified pathways involved in the regulation of signal transducer and activator of transcription 3 (STAT3) signalling on FAK inhibition by gene set enrichment analysis and verified these outcomes by RNA interference studies. We also tested combinatorial approaches targeting FAK and STAT3 in syngeneic transplantable mouse models of PDAC and KPC mice. RESULTS: In KPC mice, the expression levels of phosphorylated STAT3 (pSTAT3) were increased in PDAC cells as they progressed on FAK inhibitor therapy. This progression corresponded to decreased collagen density, lowered numbers of SMA+ fibroblasts and downregulation of the transforming growth factor beta (TGF-ß)/SMAD signalling pathway in FAK inhibitor-treated PDAC tumours. Furthermore, TGF-ß production by fibroblasts in vitro drives repression of STAT3 signalling and enhanced responsiveness to FAK inhibitor therapy. Knockdown of SMAD3 in pancreatic cancer cells abolished the inhibitory effects of TGF-ß on pSTAT3. We further found that tumour-intrinsic STAT3 regulates the durability of the antiproliferative activity of FAK inhibitor, and combinatorial targeting of FAK and Janus kinase/STAT3 act synergistically to suppress pancreatic cancer progression in mouse models. CONCLUSION: Stromal depletion by FAK inhibitor therapy leads to eventual treatment resistance through the activation of STAT3 signalling. These data suggest that, similar to tumour-targeted therapies, resistance mechanisms to therapies targeting stromal desmoplasia may be critical to treatment durability.


Assuntos
Aminopiridinas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Aminopiridinas/farmacologia , Animais , Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/enzimologia , Carcinoma Ductal Pancreático/patologia , Colágeno/metabolismo , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Fibroblastos/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Camundongos Endogâmicos , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/patologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/metabolismo , Células Estromais/efeitos dos fármacos , Células Estromais/patologia , Fator de Crescimento Transformador beta/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Blood ; 135(2): 85-96, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31765470

RESUMO

The acute myeloid leukemia (AML) treatment landscape has changed substantially since 2017. New targeted drugs have emerged, including venetoclax to target B-cell lymphoma 2, midostaurin and gilteritinib to target FLT3, and ivosidenib and enasidenib to target mutant isocitrate dehydrogenase 1 and 2, respectively. Other additions include reapproval of gemtuzumab ozogomycin to target CD33, glasdegib to target the hedgehog pathway, and a liposomal formulation of daunorubicin and cytarabine (CPX-351). Genomically heterogeneous AML has a tendency to evolve, particularly under selective treatment pressure. For decades, treatment decisions have largely centered around chemotherapy drug intensity. Physicians now have access to an increasing number of drugs with novel mechanisms of action and distinctive side-effect profiles. Key issues faced by hematologists in this era of new drugs include (1) the timely identification of actionable mutations at diagnosis and at relapse; (2) deciding which drug to use among several therapeutic options; and (3) increasing awareness of how to anticipate, mitigate, and manage common complications associated with these new agents. This article will use 3 case presentations to discuss some of the new treatment challenges encountered in AML management, with the goal of providing practical guidance to aid the practicing physician.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Alvo Molecular , Mutação , Adulto , Idoso , Aminopiridinas/uso terapêutico , Compostos de Anilina/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Feminino , Glicina/análogos & derivados , Glicina/uso terapêutico , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Prognóstico , Pirazinas/uso terapêutico , Piridinas/uso terapêutico , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/antagonistas & inibidores , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Estaurosporina/análogos & derivados , Estaurosporina/uso terapêutico , Sulfonamidas/uso terapêutico , Triazinas/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética
17.
Am J Respir Crit Care Med ; 201(10): 1193-1208, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31860331

RESUMO

Cystic fibrosis (CF) remains the most common life-shortening hereditary disease in white populations, with high morbidity and mortality related to chronic airway mucus obstruction, inflammation, infection, and progressive lung damage. In 1989, the discovery that CF is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene that encodes a cAMP-dependent anion channel vital for proper Cl- and HCO3- transport across epithelial surfaces provided a solid foundation for unraveling underlying disease mechanisms and the development of therapeutics targeting the basic defect in people with CF. In this review, we focus on recent advances in our understanding of the molecular defects caused by different classes of CFTR mutations, implications for pharmacological rescue of mutant CFTR, and insights into how CFTR dysfunction impairs key host defense mechanisms, such as mucociliary clearance and bacterial killing in CF airways. Furthermore, we review the path that led to the recent breakthrough in the development of highly effective CFTR-directed therapeutics, now applicable for up to 90% of people with CF who carry responsive CFTR mutations, including those with just a single copy of the most common F508del mutation. Finally, we discuss the remaining challenges and strategies to develop highly effective targeted therapies for all patients and the unprecedented potential of these novel therapies to transform CF from a fatal to a treatable chronic condition.


Assuntos
Agonistas dos Canais de Cloreto/uso terapêutico , Fibrose Cística/tratamento farmacológico , Bloqueadores do Canal de Sódio Epitelial/uso terapêutico , Medicina de Precisão , Aminofenóis/uso terapêutico , Aminopiridinas/uso terapêutico , Benzodioxóis/uso terapêutico , Fibrose Cística/genética , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos , Indóis/uso terapêutico , Terapia de Alvo Molecular , Depuração Mucociliar , Mutação , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Pirrolidinas/uso terapêutico , Quinolonas/uso terapêutico
18.
Oral Dis ; 26(4): 766-777, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31837283

RESUMO

OBJECTIVE: We reported previously that T-cell-specific RORγt-transgenic mice under human CD2 promoter (RORγt-Tg mice) developed severe spontaneous Sjögren's syndrome (SS)-like sialadenitis, induced by RORγt-overexpressing CD4+ T cells and reduced regulatory T cells. The purpose of this study was to clarify the effectiveness and mechanisms of action of A213, a RORγt antagonist, in RORγt-Tg mice with SS-like sialadenitis. METHODS: Six-week-old RORγt-Tg mice were administered orally of A213 or phosphate-buffered saline every 3 days for 2 weeks. We analyzed saliva volume, histopathology of salivary glands, populations of T cells in splenocytes and cervical lymph nodes (cLNs), and the protein expression levels of CD69 on CD4+ CD25+ Foxp3- and CD4+ CD25+ Foxp3+ cells in cLNs. We also investigated in vitro the potential immunomechanisms of action of A213. RESULTS: A213 significantly increased saliva volume, reduced mononuclear cell infiltration in salivary glands, and reduced the focus score of sialadenitis. Analysis of the immunomechanisms using cLNs showed A213 significantly reduced the proportion of CD4+ CD25+ /CD4+ T cells and the protein expression levels of CD69 on CD4+ CD25+ Foxp3- cells. In vitro experiments showed that A213 suppressed CD25 expression on CD4+ T cells and reduced IL-2 production from CD4+ T cells derived from RORγt-Tg mice. CONCLUSION: A213 improves SS-like sialadenitis through the inhibition of CD4+ CD25+ cells in cLNs.


Assuntos
Aminopiridinas/uso terapêutico , Subunidade alfa de Receptor de Interleucina-2/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Sialadenite/tratamento farmacológico , Síndrome de Sjogren/tratamento farmacológico , Sulfonamidas/uso terapêutico , Animais , Linfócitos T CD4-Positivos/imunologia , Regulação para Baixo , Humanos , Camundongos , Camundongos Transgênicos , Glândulas Salivares
19.
PLoS One ; 14(12): e0226564, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31860681

RESUMO

Here we describe a collaboration between industry, the National Health Service (NHS) and academia that sought to demonstrate how early understanding of both pharmacology and genomics can improve strategies for the development of precision medicines. Diseased tissue ethically acquired from patients suffering from chronic obstructive pulmonary disease (COPD), was used to investigate inter-patient variability in drug efficacy using ex vivo organocultures of fresh lung tissue as the test system. The reduction in inflammatory cytokines in the presence of various test drugs was used as the measure of drug efficacy and the individual patient responses were then matched against genotype and microRNA profiles in an attempt to identify unique predictors of drug responsiveness. Our findings suggest that genetic variation in CYP2E1 and SMAD3 genes may partly explain the observed variation in drug response.


Assuntos
Genômica/métodos , Pulmão/crescimento & desenvolvimento , Técnicas de Cultura de Órgãos/métodos , Variantes Farmacogenômicos , Doença Pulmonar Obstrutiva Crônica/genética , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Ciclopropanos/farmacologia , Ciclopropanos/uso terapêutico , Fluticasona/farmacologia , Fluticasona/uso terapêutico , Fumarato de Formoterol/farmacologia , Fumarato de Formoterol/uso terapêutico , Humanos , Pulmão/química , Pulmão/efeitos dos fármacos , MicroRNAs/genética , Modelos Biológicos , Medicina de Precisão , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Medicina Estatal , Sequenciamento Completo do Exoma
20.
Life Sci ; 239: 117010, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31672578

RESUMO

AIMS: Amlexanox, an inhibitor of nuclear factor κB kinase epsilon (IKKε) and TANK-binding kinase 1(TBK1), was demonstrated to be effective in diabetes and obesity. The aim of this study was to explore the molecular mechanisms of its role in non-alcoholic fatty liver disease (NAFLD). MAIN METHODS: NAFLD mouse models were established by using eight-week-old male C57BL/6 mice fed with high-fat diet (HFD) or (and) lipopolysaccharide (LPS) for 18 weeks. From the beginning of HFD, HFD-induced mice were subjected to amlexanox or vehicle for 18 weeks. HFD + LPS-induced mice were treated with amlexanox or vehicle for the last 6 weeks. Blood biochemistry parameters were determined using automatic biochemistry analyzer. Histological changes of liver tissue were observed by hematoxylin-eosin (H&E) staining and Oil Red O staining. The expressions of IKKε and smooth muscle actin-α (α-SMA) were evaluated through immunohistochemistry. Serum inflammatory mediator was determined by enzyme linked immunosorbent assay (ELISA). Gene expressions involved in glucose and lipid metabolism, insulin signaling pathway were examined using quantitative RT-PCR or Western blotting. KEY FINDINGS: This study demonstrated that amlexanox reversed glucose and lipid metabolic disturbance and hepatic steatosis in NAFLD mice model. IKKε was specific expressed in hepatic stellate cells (HSCs) instead of hepatocytes. This study also found that amlexanox improved insulin signaling (Insulin-IRS-1-Akt) in hepatocytes through inhibiting inflammation (IKKε-NF-κB-TNF-α/IL-1α) in HSCs. SIGNIFICANCE: The present study confirmed that IKKε was specific expressed in HSCs. Inhibition of activated HSCs was responsible for effects of amlexanox on NAFLD, with improving insulin signal pathway in hepatocytes.


Assuntos
Aminopiridinas/uso terapêutico , Células Estreladas do Fígado/efeitos dos fármacos , Quinase I-kappa B/antagonistas & inibidores , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Actinas/antagonistas & inibidores , Aminopiridinas/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais/efeitos dos fármacos
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