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1.
Nat Protoc ; 16(1): 405-430, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33311713

RESUMO

Here we describe two protocols for the construction of responsive and activable nanomedicines that regulate the tumor microenvironment (TME). The TME is composed of all non-cellular and cellular components surrounding a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules, and extracellular matrix and has a crucial role in tumor initiation, growth, and metastasis. Owing to the relatively stable properties of the TME compared to tumor cells, which exhibit frequent genetic mutations and epigenetic changes, therapeutic strategies targeting the TME using multifunctional nanomedicines hold great potential for anti-tumor therapy. By regulating tumor-associated platelets and pancreatic stellate cells (PSCs), the two major players in the TME, we can effectively manipulate the physiological barriers for enhanced drug delivery and significantly improve the tumor penetration and therapeutic efficacy of chemotherapeutics. The preparation and characterization of the multifunctional nanoparticles takes ~10 h for tumor-associated platelet regulation and 16 h for PSC regulation. These nanoformulations can be readily applied to regulate other components in the TME to realize synergistic or additive anti-tumor activity.


Assuntos
Antineoplásicos/administração & dosagem , Preparações de Ação Retardada/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Feminino , Ouro/química , Humanos , Camundongos Endogâmicos BALB C , Nanomedicina/métodos , Neoplasias/patologia , Polímeros/química , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/uso terapêutico , Tretinoína/administração & dosagem , Tretinoína/uso terapêutico
2.
Medicine (Baltimore) ; 99(43): e22923, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120845

RESUMO

RATIONALE: Most acute promyelocytic leukemia (APL) patients respond to all-trans-retinoic acid (ATRA)and have a good prognosis. However, variants APL who carry PLZF/RARа, STAT5B/RARа, and STAT3/RARа are insensitive to ATRA and have poor prognoses. The standard treatment for variants APL is still unclear due to the small sample size. PATIENT CONCERNS: Here we reported a Chinese male who was admitted to our hospital with the complaint of rib pain, dyspnea, and fever (37.5°C). Blood tests showed leukopenia (1.83 × 10/L), anemia (hemoglobin 73 g/L), and thrombocytopenia (54 × 10/L). Prothrombin time and activated partial thromboplastin time were normal. DIAGNOSES: The patient was diagnosed as STAT5b-RARa-positive APL based on the clinical and laboratory findings. INTERVENTIONS: ATRA was used immediately for induction treatment, then he was treated with ATRA + arsenic trioxide and got the severe cardiac insufficiency. Subsequently, consolidation chemotherapy was added with ATRA + Huangdai tablets + idarubicin and decitabine, cytarabine, aclamycin (DCAG). OUTCOMES: The patient relapsed soon after his first molecular complete remission (CRm), fortunately, he got a second CRm with DCAG. He has survived for more than 9 months and remains CRm, now he is looking for a suitable donor to prepare for hematopoietic stem cell transplantation (HSCT). LESSONS: APL patients with STAT5B-RARa is not only resistant to ATRA, but also to conventional combination chemotherapy such as daunorubicin and cytarabine/idarubicin and cytarabine or other regimens. Relapse and extramedullary infiltration is common, HSCT is a effective treatment, and the best time for HSCT is after the first CR. It should be noted that this patient got CRm with DCAG after relapse, so the role of decitabine in APL with STAT5B-RARa needs to be considered.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Decitabina/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Adolescente , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Trióxido de Arsênio/administração & dosagem , Trióxido de Arsênio/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Quimioterapia de Consolidação , Citarabina/administração & dosagem , Citarabina/uso terapêutico , Decitabina/administração & dosagem , Quimioterapia Combinada , Feminino , Hospitalização , Humanos , Idarubicina/administração & dosagem , Idarubicina/uso terapêutico , Leucemia Promielocítica Aguda/genética , Masculino , Pessoa de Meia-Idade , Recidiva , Receptor alfa de Ácido Retinoico/metabolismo , Fator de Transcrição STAT5/metabolismo , Resultado do Tratamento , Tretinoína/efeitos adversos , Tretinoína/uso terapêutico
3.
Nat Commun ; 11(1): 4841, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973176

RESUMO

Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1-15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6-15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Tretinoína/uso terapêutico , Biomarcadores Tumorais , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Dose Máxima Tolerável , Neoplasias Pancreáticas/diagnóstico por imagem , Receptores do Ácido Retinoico/metabolismo , Resultado do Tratamento , Tretinoína/efeitos adversos , Tretinoína/farmacocinética
4.
Ugeskr Laeger ; 182(29)2020 07 13.
Artigo em Dinamarquês | MEDLINE | ID: mdl-32734862

RESUMO

This is a case report of a 68-year-old female referred to the SARS-CoV-2 ward with one week of intermittent fever and three days of progressive loss of vision. Laboratory work-up revealed severe coagulopathy, thrombocytopenia and hyperleukocytosis. MRI showed multiple ischaemic cortical lesions. Acute treatment with all-trans retinoic acid and cytoreduction was started and coagulation parameters corrected. Patients referred to pandemic wards must undergo stringent examination and be referred for further evaluation irrespective of suspected severe acute respiratory syndrome coronavirus-2 infection.


Assuntos
Cegueira/virologia , Infecções por Coronavirus/diagnóstico , Febre/virologia , Leucemia Promielocítica Aguda/complicações , Pneumonia Viral/diagnóstico , Idoso , Betacoronavirus , Infecções por Coronavirus/complicações , Procedimentos Cirúrgicos de Citorredução , Feminino , Humanos , Pandemias , Pneumonia Viral/complicações , Tretinoína/uso terapêutico
5.
Life Sci ; 258: 118152, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32735881

RESUMO

AIMS: Cancer stem cells (CSCs) are the source of tumors and play a key role in the resistance of cancer to therapies. To improve the current therapies against CSCs, in this work we developed a novel system of electrospun polycaprolactone (PCL) nanofibers containing hydroxylated multi-walled carbon nanotubes (MWCNTs-OH) and all-trans retinoic acid (ATRA). MATERIALS AND METHODS: The nanofiber membranes were forged by electrospinning, and the physical and chemical properties of the nanofiber membranes were evaluated by scanning electron microscopy, XRD and Raman etc. The photothermal properties of nanofiber membranes and their effects on CSCs differentiation and cytotoxicity were investigated. Finally, the anti-tumor effect of nanofiber membranes in vivo was evaluated. KEY FINDINGS: The nanofibers formed under optimal conditions were smooth without beads. The nanofibrous membranes with MWCNTs-OH could increase temperature of the medium under near-infrared (NIR) illumination to suppress the viability of glioma stem cells (GSCs). Meanwhile, the added ATRA could further induce the differentiation of GSCs to destroy their stemness and reduce their resistance to heat treatment. Compared with no NIR irradiation, after 2min NIR irradiation, the membranes reduced the in-vitro viability of GSCs by 13.41%, 14.83%, and 26.71% after 1, 2, and 3 days, respectively. After 3 min daily illumination for 3 days, the viability of GSCs was only 22.75%, and similar results were observed in vivo. SIGNIFICANCE: These results showed efficiently cytotoxicity to CSCs by combining heat therapy and differentiation therapy. The nanofiber membranes if inserted at the site after surgical tumor removal, may hinder tumor recurrence.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/terapia , Glioma/terapia , Nanofibras/uso terapêutico , Células-Tronco Neoplásicas/efeitos dos fármacos , Tretinoína/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Glioma/patologia , Humanos , Hipertermia Induzida/métodos , Masculino , Camundongos Endogâmicos BALB C , Nanofibras/química , Nanotubos de Carbono/química , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Células-Tronco Neoplásicas/patologia , Poliésteres/química , Poliésteres/uso terapêutico , Tretinoína/administração & dosagem
6.
Tokai J Exp Clin Med ; 45(2): 92-96, 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32602108

RESUMO

A 69-year-old man was referred to the hematology department for the evaluation of pancytopenia. He had been treated with radiation and epirubicin for hepatocellular carcinoma, and with docetaxel and pembrolizumab for lung adenocarcinoma. Bone marrow smears exhibited markedly increased promyelocytes, and polymerase chain reaction (PCR) study demonstrated chimeric fusion genes of PML-RARA. He was diagnosed with therapy-related acute promyelocytic leukemia (t-APL) and treated with all trans-retinoic acid (ATRA). After 30 days of ATRA treatment, complete hematological response was achieved. To the best of our knowledge, this case represents the first description of successfully treated t-APL diagnosed after treatment with pembrolizumab.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma/tratamento farmacológico , Docetaxel/efeitos adversos , Epirubicina/efeitos adversos , Leucemia Promielocítica Aguda/induzido quimicamente , Leucemia Promielocítica Aguda/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Primárias Múltiplas , Tretinoína/uso terapêutico , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Docetaxel/uso terapêutico , Epirubicina/uso terapêutico , Humanos , Masculino , Resultado do Tratamento
7.
Medicine (Baltimore) ; 99(26): e20896, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590800

RESUMO

INTRODUCTION: Metastatic neuroblastoma (NB) is an aggressive malignancy with a poor prognosis. Many patients present with relapsed high-risk NB after undergoing first-line treatment, and there is no standard therapy available in this setting. PATIENT CONCERNS: The present study aimed to present the cases of 2 patients with recurrent high-risk NB. DIAGNOSIS: Two children with International Neuroblastoma Stage System stage 4 high-risk NB chemotherapy. The disease recurrent after finishing the treatment. INTERVENTIONS: Both patients (34 months old and 41 months old) experienced recurrence, received second-line treatment, and then received maintenance treatment using apatinib plus retinoic acid. The apatinib (10 mg/kg per day) and retinoic acid (160 mg/m per day) were administered on alternating 2-week cycles, which was continued for 1 year. OUTCOMES: The 2 patients had achieved complete response by the 1-year follow-up after starting apatinib plus retinoic acid, and did not experience any adverse drug reactions. CONCLUSION: The outcomes from these cases suggest that apatinib plus isotretinoin might be an option for maintenance therapy in patients with recurrent high-risk NB.


Assuntos
Neuroblastoma/complicações , Neuroblastoma/tratamento farmacológico , Piridinas/uso terapêutico , Tretinoína/uso terapêutico , Dor Abdominal/etiologia , Antineoplásicos/uso terapêutico , Pré-Escolar , Tratamento Farmacológico/métodos , Tratamento Farmacológico/normas , Humanos , Masculino , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/fisiopatologia , Neuroblastoma/fisiopatologia , Recidiva
8.
Int J Hematol ; 112(3): 349-360, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32524309

RESUMO

We stratified patients with newly diagnosed acute promyelocytic leukemia (APL) according to a white blood cell (WBC) count of ≥ 3 × 109/L (high risk) or < 3 × 109/L (low risk) before administering risk-adapted chemotherapy in combination with all-trans retinoic acid (ATRA). In total, 27 low-risk and 23 high-risk patients were assigned to receive induction and three courses of consolidation with ATRA and anthracycline, followed by 2-year maintenance regimen. High-risk group additionally received cytarabine during 1st consolidation and another one-shot idarubicin treatment during 3rd consolidation. We prospectively monitored measurable residual disease (MRD) after induction and each consolidation. In the low-risk and high-risk groups, 5-year disease-free survival (DFS) rates were 86.5% and 81.2% (p = 0.862), and 5-year overall survival rates were 100% and 84.8% (p = 0.062), respectively. In the MRD-negative and MRD-positive groups, 5-year DFS rates were 91.7% and 78.4% (p = 0.402) and 84.7% and 60.0% (p = 0.102) after induction and 1st consolidation, respectively. Relapse rates were 8.3% and 13.3% (p = 0.570) and 9.0% and 40.0% (p = 0.076) after induction and 1st consolidation, respectively. Achieving MRD-negativity after 1st consolidation, rather than after induction, was a potential predictor of relapse and DFS in patients with APL treated with ATRA + chemotherapy.


Assuntos
Quimioterapia de Consolidação , Leucemia Promielocítica Aguda/tratamento farmacológico , Neoplasia Residual/mortalidade , Tretinoína/uso terapêutico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/administração & dosagem , Feminino , Previsões , Humanos , Idarubicina/administração & dosagem , Leucemia Promielocítica Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/diagnóstico , Prognóstico , Estudos Prospectivos , Recidiva , Taxa de Sobrevida , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto Jovem
9.
Cochrane Database Syst Rev ; 5: CD011368, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32356369

RESUMO

BACKGROUND: Acne is an inflammatory disorder with a high global burden. It is common in adolescents and primarily affects sebaceous gland-rich areas. The clinical benefit of the topical acne treatments azelaic acid, salicylic acid, nicotinamide, sulphur, zinc, and alpha-hydroxy acid is unclear. OBJECTIVES: To assess the effects of topical treatments (azelaic acid, salicylic acid, nicotinamide, zinc, alpha-hydroxy acid, and sulphur) for acne. SEARCH METHODS: We searched the following databases up to May 2019: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers. SELECTION CRITERIA: Clinical randomised controlled trials of the six topical treatments compared with other topical treatments, placebo, or no treatment in people with acne. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Key outcomes included participants' global self-assessment of acne improvement (PGA), withdrawal for any reason, minor adverse events (assessed as total number of participants who experienced at least one minor adverse event), and quality of life. MAIN RESULTS: We included 49 trials (3880 reported participants) set in clinics, hospitals, research centres, and university settings in Europe, Asia, and the USA. The vast majority of participants had mild to moderate acne, were aged between 12 to 30 years (range: 10 to 45 years), and were female. Treatment lasted over eight weeks in 59% of the studies. Study duration ranged from three months to three years. We assessed 26 studies as being at high risk of bias in at least one domain, but most domains were at low or unclear risk of bias. We grouped outcome assessment into short-term (less than or equal to 4 weeks), medium-term (from 5 to 8 weeks), and long-term treatment (more than 8 weeks). The following results were measured at the end of treatment, which was mainly long-term for the PGA outcome and mixed length (medium-term mainly) for minor adverse events. Azelaic acid In terms of treatment response (PGA), azelaic acid is probably less effective than benzoyl peroxide (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.72 to 0.95; 1 study, 351 participants), but there is probably little or no difference when comparing azelaic acid to tretinoin (RR 0.94, 95% CI 0.78 to 1.14; 1 study, 289 participants) (both moderate-quality evidence). There may be little or no difference in PGA when comparing azelaic acid to clindamycin (RR 1.13, 95% CI 0.92 to 1.38; 1 study, 229 participants; low-quality evidence), but we are uncertain whether there is a difference between azelaic acid and adapalene (1 study, 55 participants; very low-quality evidence). Low-quality evidence indicates there may be no differences in rates of withdrawal for any reason when comparing azelaic acid with benzoyl peroxide (RR 0.88, 95% CI 0.60 to 1.29; 1 study, 351 participants), clindamycin (RR 1.30, 95% CI 0.48 to 3.56; 2 studies, 329 participants), or tretinoin (RR 0.66, 95% CI 0.29 to 1.47; 2 studies, 309 participants), but we are uncertain whether there is a difference between azelaic acid and adapalene (1 study, 55 participants; very low-quality evidence). In terms of total minor adverse events, we are uncertain if there is a difference between azelaic acid compared to adapalene (1 study; 55 participants) or benzoyl peroxide (1 study, 30 participants) (both very low-quality evidence). There may be no difference when comparing azelaic acid to clindamycin (RR 1.50, 95% CI 0.67 to 3.35; 1 study, 100 participants; low-quality evidence). Total minor adverse events were not reported in the comparison of azelaic acid versus tretinoin, but individual application site reactions were reported, such as scaling. Salicylic acid For PGA, there may be little or no difference between salicylic acid and tretinoin (RR 1.00, 95% CI 0.92 to 1.09; 1 study, 46 participants; low-quality evidence); we are not certain whether there is a difference between salicylic acid and pyruvic acid (1 study, 86 participants; very low-quality evidence); and PGA was not measured in the comparison of salicylic acid versus benzoyl peroxide. There may be no difference between groups in withdrawals when comparing salicylic acid and pyruvic acid (RR 0.89, 95% CI 0.53 to 1.50; 1 study, 86 participants); when salicylic acid was compared to tretinoin, neither group had withdrawals (both based on low-quality evidence (2 studies, 74 participants)). We are uncertain whether there is a difference in withdrawals between salicylic acid and benzoyl peroxide (1 study, 41 participants; very low-quality evidence). For total minor adverse events, we are uncertain if there is any difference between salicylic acid and benzoyl peroxide (1 study, 41 participants) or tretinoin (2 studies, 74 participants) (both very low-quality evidence). This outcome was not reported for salicylic acid versus pyruvic acid, but individual application site reactions were reported, such as scaling and redness. Nicotinamide Four studies evaluated nicotinamide against clindamycin or erythromycin, but none measured PGA. Low-quality evidence showed there may be no difference in withdrawals between nicotinamide and clindamycin (RR 1.12, 95% CI 0.49 to 2.60; 3 studies, 216 participants) or erythromycin (RR 1.40, 95% CI 0.46 to 4.22; 1 study, 158 participants), or in total minor adverse events between nicotinamide and clindamycin (RR 1.20, 95% CI 0.73 to 1.99; 3 studies, 216 participants; low-quality evidence). Total minor adverse events were not reported in the nicotinamide versus erythromycin comparison. Alpha-hydroxy (fruit) acid There may be no difference in PGA when comparing glycolic acid peel to salicylic-mandelic acid peel (RR 1.06, 95% CI 0.88 to 1.26; 1 study, 40 participants; low-quality evidence), and we are uncertain if there is a difference in total minor adverse events due to very low-quality evidence (1 study, 44 participants). Neither group had withdrawals (2 studies, 84 participants; low-quality evidence). AUTHORS' CONCLUSIONS: Compared to benzoyl peroxide, azelaic acid probably leads to a worse treatment response, measured using PGA. When compared to tretinoin, azelaic acid probably makes little or no difference to treatment response. For other comparisons and outcomes the quality of evidence was low or very low. Risk of bias and imprecision limit our confidence in the evidence. We encourage the comparison of more methodologically robust head-to-head trials against commonly used active drugs.


Assuntos
Acne Vulgar/tratamento farmacológico , Fármacos Dermatológicos/uso terapêutico , Adapaleno/efeitos adversos , Adapaleno/uso terapêutico , Adolescente , Adulto , Antibacterianos/uso terapêutico , Peróxido de Benzoíla/uso terapêutico , Viés , Criança , Clindamicina/efeitos adversos , Clindamicina/uso terapêutico , Fármacos Dermatológicos/efeitos adversos , Ácidos Dicarboxílicos/efeitos adversos , Ácidos Dicarboxílicos/uso terapêutico , Eritromicina/efeitos adversos , Eritromicina/uso terapêutico , Feminino , Glicolatos/uso terapêutico , Humanos , Ceratolíticos/uso terapêutico , Masculino , Ácidos Mandélicos/uso terapêutico , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Ácido Pirúvico/efeitos adversos , Ácido Pirúvico/uso terapêutico , Qualidade de Vida , Ácido Salicílico/uso terapêutico , Enxofre/uso terapêutico , Tretinoína/uso terapêutico , Adulto Jovem , Zinco/uso terapêutico
10.
Leuk Res ; 94: 106356, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32445941

RESUMO

Hemorrhagic death is the leading cause of treatment failure in acute promyelocytic leukemia (APL). Our ability to identify patients at greatest risk of hemorrhage, and to actively prevent hemorrhage, remains limited. Nevertheless, some data is available to guide contemporary clinical practice and future investigation. Circulating disease burden, best represented by the peripheral WBC / blast count, is the most consistent predictor of major and fatal bleeding risk. In contrast, laboratory markers of disseminated intravascular coagulation (DIC) appear to be poor predictors. A number of interventions have been posited to reduce bleeding risk. Prompt initiation of all-trans retinoic acid (ATRA), avoidance of invasive procedures, transfusion support, and cytoreduction all have theoretical merit. Though they lack strong evidence to support their benefit with respect to bleeding, they are associated with limited risks, and are therefore advisable. Low-dose therapeutic heparin and antifibrinolytics have not shown the ability to positively modify bleeding risk, and heparin has been associated with harm. Thrombomodulin has shown promise in limited retrospective studies however further prospective data are needed. rFVIIa may have a role in cases of life-threatening bleeding however evidence is largely anecdotal. Additional studies evaluating the above interventions, and investigating other potential interventions are needed.


Assuntos
Crise Blástica , Hemorragia , Leucemia Promielocítica Aguda , Crise Blástica/sangue , Crise Blástica/complicações , Crise Blástica/tratamento farmacológico , Crise Blástica/patologia , Fator VIII/uso terapêutico , Hemorragia/sangue , Hemorragia/tratamento farmacológico , Hemorragia/etiologia , Hemorragia/patologia , Heparina/uso terapêutico , Humanos , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/complicações , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/patologia , Trombomodulina/uso terapêutico , Tretinoína/uso terapêutico
12.
Acta Cir Bras ; 35(1): e202000106, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32236320

RESUMO

PURPOSE: To explore the role of all-trans retinoic acid (ATRA) in renal ischemia/reperfusion injury of diabetic rats. METHODS: Sixty adult male rats were randomly divided into 6 groups, including sham group (S group), ischemia-reperfusion group (I/R group), ischemia-reperfusion+ATRA group (A group), diabetic group (D group), diabetic ischemia-reperfusion group (DI/R group), diabetic ischemia-reperfusion +ATRA group (DA group). The levels of creatinine (Cr), cystatin C (Cys-C) and ß2-microglobulin (ß2-MG) were measured. Morphology of renal tissue was observed under light microscope. RESULTS: DJ-1, Nrf2, HO-1 and caspase-3 were detected by western blot. DJ-1, Nrf2, HO-1 and caspase-3 in I/R group, D group and DI/R group was higher than that in S group. Compared with I/R group, Nrf2 and HO-1 in A group was decreased, but caspase-3 was increased. However, Nrf2 in DA group was higher than that in DI/R group, HO-1 and caspase-3 in DA group were lower than that in DI/R group. Compared with group S, Cr, Cys-C and ß2-MG in I/R group, A group, D group, and DI/R group were higher. Whereas the levels of Cr, Cys-C, ß2-MG and renal injury score in DA group were lower than those in DI/R group. CONCLUSION: ATRA has a protective effect on renal ischemia-reperfusion injury in diabetic rats, maybe relating to DJ/Nrf2 pathway.


Assuntos
Diabetes Mellitus Experimental/induzido quimicamente , Rim/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Tretinoína/uso terapêutico , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Rim/patologia , Masculino , Fator 2 Relacionado a NF-E2/farmacologia , Ratos , Traumatismo por Reperfusão/patologia , Estreptozocina , Tretinoína/farmacologia
14.
Colloids Surf B Biointerfaces ; 188: 110749, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31927466

RESUMO

Repair of tissue damaged in diabetic wounds is essential to minimize the cases of amputation of the limbs in millions of diabetic people around the world. Although the all-trans retinoic acid (ATRA) is described as a potential wound healing agent, however its effects are controversial due to adverse reactions that may impair the wound healing during the treatment schedules. Our aim was to design and characterize an ATRA-loaded solid lipid nanoparticles surrounded by chitosan film to promote an ATRA controlled release and to evaluate its effectiveness in promoting wound healing in a diabetic mouse model. The SLN-ATRA were developed using biocompatible lipids without using organic solvent. The SLN-ATRA had high drug entrapment efficiency (98.0 %) and low polydispersity index (PDI) and average diameter, respectively, 0.24 ± 0.02 and 83.0 ± 6 nm. The transmission electron microscope (TEM) image presented that the SLN-ATRA were homogeneous in size and had spherical structures. The incorporation of SLN-ATRA in the chitosan films propitiated a homogeneous distribution of the drug and a controlled drug release. Furthermore, in vivo assay proved that chitosan films containing SLN-ATRA accelerated the closure of wounds of diabetic mice when compared to the control chitosan films without ATRA. SLN-ATRA chitosan films also reduced leukocyte infiltrate in the wound bed, improved collagen deposition, and reduced scar tissue. No sign of skin irritation was observed. These results indicated that SLN-ATRA surrounded in chitosan films are a promising candidate to treat diabetic wounds, improving tissue healing.


Assuntos
Quitosana/química , Diabetes Mellitus Experimental/tratamento farmacológico , Lipídeos/química , Nanopartículas/química , Tretinoína/uso terapêutico , Cicatrização/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Portadores de Fármacos/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Propriedades de Superfície , Tretinoína/química
15.
Lasers Med Sci ; 35(5): 1153-1158, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31953736

RESUMO

Acanthosis nigricans is a common dermatological problem. There are currently limited clinical trials to determine the efficacy and safety of laser treatments. To compare the efficacy of fractional 1550-nm erbium fiber laser versus 0.05% tretinoin cream for the treatment of acanthosis nigricans at neck, a randomized, controlled, assessor-blinded study was conducted in 18 subjects with acanthosis nigricans at the neck. All patients were treated with both fractional 1550-nm erbium fiber laser and 0.05% tretinoin cream on each side of the neck. The laser side was treated with three treatment sessions, with a 4-week interval of 1550-nm fractional erbium laser. Another side was treated with 0.05% tretinoin cream daily at bedtime for 12 weeks. We evaluated at baseline, with a 4-week interval until 4 weeks after the last treatment. The efficacy was assessed by skin color ratio, melanin index, average roughness, photographic evaluation, patients' satisfaction, and the adverse effects. At the study endpoint, week 12, the mean Visiometer-average roughness showed greater reduction in laser-treated side (24.65%) than tretinoin side (22.94%) (p = 0.004). Laser-treated side also showed greater percentage of skin color ratio reduction, melanin index reduction, and better mean of photographic-based evaluation percentage change from the baseline than tretinoin side with no significant different (p = 0.331, p = 0.116, p = 0.327, respectively). The study showed one post-inflammatory hyperpigmentation in tretinoin side. Regarding to the average roughness, fractional 1550-nm erbium fiber laser was superior to 0.05% tretinoin cream for treatment of neck-acanthosis nigricans with less side effect. Fractional 1550-nm erbium fiber laser could be considered as an alternative treatment for acanthosis nigricans.


Assuntos
Acantose Nigricans/tratamento farmacológico , Acantose Nigricans/cirurgia , Lasers de Estado Sólido/uso terapêutico , Tretinoína/uso terapêutico , Adulto , Terapia Combinada , Érbio , Feminino , Humanos , Masculino , Melaninas/metabolismo , Pessoa de Meia-Idade , Satisfação do Paciente , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
16.
Cancer Lett ; 473: 130-138, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-31904486

RESUMO

All-trans retinoic acid (ATRA) is known to be a potent inhibitor of FLT3-ITD acute myeloid leukemia (AML) cells, although the exact mechanism remains unclear. In this work, we report that ATRA causes fatal mitotic catastrophe in FLT3-ITD AML cells by degrading Chk1 kinase, and therefore preventing DNA damage repair. In order to explore a further enhancement in the inhibitory effect of ATRA on FLT3-ITD AML cells, we investigated the suitability of a combination of ATRA and DNA damage drug SN38. In vitro experiments showed that this combinatorial approach effectively inhibited the proliferation of FLT3-ITD cells and induced cell apoptosis in AML. In vivo experiments confirmed that the combination could substantially improve the anti-tumor effect of SN38. Taken together, our results indicate that ATRA down-regulates Chk1 in FLT3-ITD AML cells, and the combination of ATRA and SN38 significantly improves the anti-tumor effect of either ATRA or SN38 when used alone.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Tretinoína/farmacologia , Adulto , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/metabolismo , Pré-Escolar , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Irinotecano/farmacologia , Irinotecano/uso terapêutico , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Mitose/efeitos dos fármacos , Cultura Primária de Células , Inibidores de Proteínas Quinases/uso terapêutico , Sequências de Repetição em Tandem/genética , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Tretinoína/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Tirosina Quinase 3 Semelhante a fms/genética
17.
Int J Cancer ; 146(2): 400-412, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31271662

RESUMO

Histone demethylases are promising therapeutic targets as they play fundamental roles for survival of Mixed lineage leukemia rearranged acute leukemia (MLLr AL). Here we focused on the catalytic Jumonji domain of histone H3 lysine 9 (H3K9) demethylase JMJD1C to screen for potential small molecular modulators from 149,519 natural products and 33,765 Chinese medicine components via virtual screening. JMJD1C Jumonji domain inhibitor 4 (JDI-4) and JDI-12 that share a common structural backbone were detected within the top 15 compounds. Surface plasmon resonance analysis showed that JDI-4 and JDI-12 bind to JMJD1C and its family homolog KDM3B with modest affinity. In vitro demethylation assays showed that JDI-4 can reverse the H3K9 demethylation conferred by KDM3B. In vivo demethylation assays indicated that JDI-4 and JDI-12 could induce the global increase of H3K9 methylation. Cell proliferation and colony formation assays documented that JDI-4 and JDI-12 kill MLLr AL and other malignant hematopoietic cells, but not leukemia cells resistant to JMJD1C depletion or cord blood cells. Furthermore, JDI-16, among multiple compounds structurally akin to JDI-4/JDI-12, exhibits superior killing activities against malignant hematopoietic cells compared to JDI-4/JDI-12. Mechanistically, JDI-16 not only induces apoptosis but also differentiation of MLLr AL cells. RNA sequencing and quantitative PCR showed that JDI-16 induced gene expression associated with cell metabolism; targeted metabolomics revealed that JDI-16 downregulates lactic acids, NADP+ and other metabolites. Moreover, JDI-16 collaborates with all-trans retinoic acid to repress MLLr AML cells. In summary, we identified bona fide JMJD1C inhibitors that induce preferential death of MLLr AL cells.


Assuntos
Antineoplásicos/farmacologia , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Leucemia Aguda Bifenotípica/tratamento farmacológico , Oxirredutases N-Desmetilantes/antagonistas & inibidores , Adulto , Idoso , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Medula Óssea/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desmetilação do DNA/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/química , Histona Desmetilases com o Domínio Jumonji/metabolismo , Leucemia Aguda Bifenotípica/patologia , Masculino , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Oxirredutases N-Desmetilantes/química , Oxirredutases N-Desmetilantes/metabolismo , Domínios Proteicos , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície , Tretinoína/farmacologia , Tretinoína/uso terapêutico
18.
Oncogene ; 39(3): 530-545, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31501521

RESUMO

Renal cell carcinoma (RCC) is one of the most lethal urological tumors. Using sunitinib to improve the survival has become the first-line therapy for metastatic RCC patients. However, the occurrence of sunitinib resistance in the clinical application has curtailed its efficacy. Here we found TR4 nuclear receptor might alter the sunitinib resistance to RCC via altering the TR4/lncTASR/AXL signaling. Mechanism dissection revealed that TR4 could modulate lncTASR (ENST00000600671.1) expression via transcriptional regulation, which might then increase AXL protein expression via enhancing the stability of AXL mRNA to increase the sunitinib resistance in RCC. Human clinical surveys also linked the expression of TR4, lncTASR, and AXL to the RCC survival, and results from multiple RCC cell lines revealed that targeting this newly identified TR4-mediated signaling with small molecules, including tretinoin, metformin, or TR4-shRNAs, all led to increase the sunitinib sensitivity to better suppress the RCC progression, and our preclinical study using the in vivo mouse model further proved tretinoin had a better synergistic effect to increase sunitinib sensitivity to suppress RCC progression. Future successful clinical trials may help in the development of a novel therapy to better suppress the RCC progression.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , RNA Longo não Codificante/genética , Receptores Proteína Tirosina Quinases/genética , Receptores de Esteroides/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Sunitinibe/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Hipóxia Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores de Esteroides/genética , Receptores dos Hormônios Tireóideos/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sunitinibe/uso terapêutico , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Int J Hematol ; 111(2): 311-316, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31515708

RESUMO

A 68-year-old male was diagnosed with acute promyelocytic leukemia (APL). A G-banding chromosomal analysis revealed the co-existence of two clones: one with del(20q) and t(15;17)(q22;q12) and another with del(20q) alone. During the remission of APL following treatment with all-trans-retinoic acid, del(20q) was persistently identified, indicating a diagnosis of cytogenetic abnormalities of undetermined significance (CCAUS) with isolated del(20q). Bicytopenia developed 48 months after the remission of APL. The presence of isolated del(20q) was detected in the G-banding analysis, whereas morphological dysplasia of hematopoietic cells was not confirmed. This case showed indolent progression from CCAUS after the remission of APL to clonal cytopenia of undetermined significance (CCUS). CCUS with isolated del(20q) persisted for 24 months without any finding of hematological malignancies. At the most recent follow-up, targeted capture sequencing showed the U2AF1 S34F mutation. Considerable attention needs to be paid in follow-ups for CCAUS with del(20q) after the treatment of leukemia.


Assuntos
Aberrações Cromossômicas , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Idoso , Células Clonais , Seguimentos , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Masculino , Indução de Remissão , Tretinoína/uso terapêutico
20.
J Dermatolog Treat ; 31(2): 160-167, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30935257

RESUMO

Background: Topical tretinoin's role in acne has been established through evidence-based guidelines. Cutaneous irritation and potential to cause or exacerbate postinflammatory hyperpigmentation (PIH) may limit use.Objective: Evaluate safety and tolerability of novel polymeric formulation of tretinoin 0.05% lotion in moderate-to-severe acne.Methods: One thousand six hundred and forty patients randomized to tretinoin 0.05% lotion or vehicle in two double-blind placebo-controlled 12-week studies. Investigator-evaluated cutaneous safety (erythema and scaling) and patient-reported tolerability (itching, burning/stinging) assessed using a scale of 0 (none) to 3 (severe). Hyper- and hypo-pigmentation evaluated at each study visit. A number of subpopulations were investigated.Results: Tretinoin 0.05% lotion was considered safe and very well tolerated. Only application site pain (3.1%), dryness (3.7%) and erythema (1.4%) were reported by >1% or patients. Treatment-related adverse events were particularly rare (≤2%) in Hispanic and male subpopulations, and lower in adult females. The severity of cutaneous safety and tolerability scores remained <0.5 (where 1 = mild) and were generally lower than baseline severity. Tretinoin 0.05% lotion did not appear to cause or exacerbate PIH.Conclusions: A novel polymeric formulation of tretinoin 0.05% lotion provides a highly favorable safety and tolerability profile, with an incidence of erythema, dryness, and skin burning lower than that previously reported with other formulations of tretinoin.


Assuntos
Acne Vulgar/tratamento farmacológico , Ceratolíticos/uso terapêutico , Tretinoína/uso terapêutico , Acne Vulgar/patologia , Adolescente , Adulto , Criança , Método Duplo-Cego , Esquema de Medicação , Tolerância a Medicamentos , Feminino , Humanos , Hiperpigmentação/patologia , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Efeito Placebo , Prurido/patologia , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
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