RESUMO
Acne vulgaris is a common dermatological diagnosis observed in pediatric patients with skin of color, often resulting in scarring, keloid formation, and post-inflammatory hyperpigmentation, significantly impacting their quality of life. This exploratory retrospective chart review included 77 black pediatric patients seen at a tertiary care center for acne vulgaris between 2018 and 2023. We analyzed demographics, acne descriptors, and treatment modalities. The most common acne morphology was comedonal acne (83.6%), with 71% of the patients being female. Significant age differences were observed particularly for acne at the chin and overall face. Treatment regimens commonly prescribed included combinations of adapalene and benzoyl peroxide (22%), topical antibiotics, tretinoin, and benzoyl peroxide (34%). Given the higher risk of sequelae for patients with darker skin, it is crucial to address their unique treatment needs. This study highlights the distinctive characteristics of acne in black pediatric patients and calls for further research to enhance our understanding and treatment of this population. Limitations include the lack of direct patient interactions and reliance on chart data. Further studies are needed to compare acne presentation in skin of color of other populations, refining our knowledge of acne clinical presentation, complications, and treatment modalities for diverse patient populations.
Assuntos
Acne Vulgar , Antibacterianos , Negro ou Afro-Americano , Fármacos Dermatológicos , Humanos , Acne Vulgar/tratamento farmacológico , Feminino , Criança , Masculino , Estudos Retrospectivos , Adolescente , Fármacos Dermatológicos/uso terapêutico , Antibacterianos/uso terapêutico , Peróxido de Benzoíla/uso terapêutico , Tretinoína/uso terapêutico , Fatores EtáriosRESUMO
A 43-year-old man with pancytopenia was diagnosed with acute promyelocytic leukemia (APL). On the first day of induction therapy with all-trans retinoic acid (ATRA) alone, he presented with high fever and was found to have coronavirus disease 2019 (COVID-19) infection by SARS-CoV2 antigen test. While it is generally recommended to delay treatment for APL patients with COVID-19 unless urgent APL treatment is required, this patient needed to continue treatment due to APL-induced disseminated intravascular coagulation (DIC). Considering the challenge of distinguishing between differentiation syndrome (DS) and COVID-19 exacerbation, the ATRA dosage was reduced to 50%. The patient was able to continue treatment without development of DS or exacerbation of DIC, leading to his recovery from COVID-19 and remission of APL.
Assuntos
COVID-19 , Leucemia Promielocítica Aguda , Indução de Remissão , Tretinoína , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/complicações , Tretinoína/administração & dosagem , Tretinoína/uso terapêutico , Masculino , Adulto , COVID-19/complicações , Resultado do Tratamento , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/etiologiaRESUMO
BACKGROUND: Keloid is a disease characterized by proliferation of fibrous tissue after the healing of skin tissue, which seriously affects the daily life of patients. However, the clinical treatment of keloids still has limitations, that is, it is not effective in controlling keloids, resulting in a high recurrence rate. Thus, it is urgent to identify new signatures to improve the diagnosis and treatment of keloids. METHOD: Bulk RNA seq and scRNA seq data were downloaded from the GEO database. First, we used WGCNA and MEGENA to co-identify keloid/immune-related DEGs. Subsequently, we used three machine learning algorithms (Randomforest, SVM-RFE, and LASSO) to identify hub immune-related genes of keloid (KHIGs) and investigated the heterogeneous expression of KHIGs during fibroblast subpopulation differentiation using scRNA-seq. Finally, we used HE and Masson staining, quantitative reverse transcription-PCR, western blotting, immunohistochemical, and Immunofluorescent assay to investigate the dysregulated expression and the mechanism of retinoic acid in keloids. RESULTS: In the present study, we identified PTGFR, RBP5, and LIF as KHIGs and validated their diagnostic performance. Subsequently, we constructed a novel artificial neural network molecular diagnostic model based on the transcriptome pattern of KHIGs, which is expected to break through the current dilemma faced by molecular diagnosis of keloids in the clinic. Meanwhile, the constructed IG score can also effectively predict keloid risk, which provides a new strategy for keloid prevention. Additionally, we observed that KHIGs were also heterogeneously expressed in the constructed differentiation trajectories of fibroblast subtypes, which may affect the differentiation of fibroblast subtypes and thus lead to dysregulation of the immune microenvironment in keloids. Finally, we found that retinoic acid may treat or alleviate keloids by inhibiting RBP5 to differentiate pro-inflammatory fibroblasts (PIF) to mesenchymal fibroblasts (MF), which further reduces collagen secretion. CONCLUSION: In summary, the present study provides novel immune signatures (PTGFR, RBP5, and LIF) for keloid diagnosis and treatment, and identifies retinoic acid as potential anti-keloid drugs. More importantly, we provide a new perspective for understanding the interactions between different fibroblast subtypes in keloids and the remodeling of their immune microenvironment.
Assuntos
Queloide , RNA-Seq , Queloide/genética , Queloide/diagnóstico , Queloide/patologia , Queloide/imunologia , Queloide/tratamento farmacológico , Humanos , Transcriptoma/genética , Perfilação da Expressão Gênica , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibroblastos/imunologia , Redes Reguladoras de Genes , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Análise de Célula Única/métodos , Diferenciação Celular/genética , Análise de Sequência de RNA/métodos , Aprendizado de Máquina , Análise da Expressão Gênica de Célula ÚnicaRESUMO
The transformation of acute promyelocytic leukemia (APL) from the most fatal to the most curable subtype of acute myeloid leukemia (AML), with long-term survival exceeding 90%, has represented one of the most exciting successes in hematology and in oncology. APL is a paradigm for oncoprotein-targeted cure.APL is caused by a 15/17 chromosomal translocation which generates the PML-RARA fusion protein and can be cured by the chemotherapy-free approach based on the combination of two therapies targeting PML-RARA: retinoic acid (RA) and arsenic. PML-RARA is the key driver of APL and acts by deregulating transcriptional control, particularly RAR targets involved in self-renewal or myeloid differentiation, also disrupting PML nuclear bodies. PML-RARA mainly acts as a modulator of the expression of specific target genes: genes whose regulatory elements recruit PML-RARA are not uniformly repressed but also may be upregulated or remain unchanged. RA and arsenic trioxide directly target PML-RARA-mediated transcriptional deregulation and protein stability, removing the differentiation block at promyelocytic stage and inducing clinical remission of APL patients.
Assuntos
Leucemia Promielocítica Aguda , Proteínas de Fusão Oncogênica , Tretinoína , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Tretinoína/uso terapêutico , Tretinoína/farmacologia , Trióxido de Arsênio/uso terapêutico , Trióxido de Arsênio/farmacologia , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Arsenicais/uso terapêutico , Arsenicais/farmacologia , Óxidos/uso terapêutico , Óxidos/farmacologia , AnimaisRESUMO
Acanthosis nigricans (AN), with an estimated prevalence of 19.4% in the U.S., presents as hyperpigmented, velvety plaques in intertriginous regions. Acanthosis Nigricans negatively affects psychological well-being and particularly impacts skin of color individuals. Addressing the underlying cause of acanthosis nigricans, as current guidelines recommend, is often challenging. This highlights the importance of skin directed treatment for acanthosis nigricans. This systematic review evaluated topical, laser, and oral treatments for acanthosis nigricans and provides evidence-based recommendations for clinical use. Adhering to PRISMA guidelines, we evaluated 19 clinical trials investigating topical, oral, and laser interventions for acanthosis nigricans. Oxford Centre for Evidence-Based Medicine guidelines were used to make clinical recommendations. We strongly recommend topical tretinoin (grade A) and endorse the appropriate use of adapalene gel, urea cream, and fractional carbon dioxide laser therapy (grade B). Further research is essential to enhance our understanding of alternative treatments to determine additional evidence-based recommendations. This review aims to guide clinicians in managing acanthosis nigricans, especially when direct treatment of underlying conditions is impractical.
Assuntos
Acantose Nigricans , Humanos , Acantose Nigricans/diagnóstico , Acantose Nigricans/tratamento farmacológico , Administração Oral , Terapia a Laser/métodos , Ensaios Clínicos como Assunto , Administração Cutânea , Medicina Baseada em Evidências , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/uso terapêutico , Administração Tópica , Lasers de Gás/uso terapêutico , Tretinoína/administração & dosagem , Tretinoína/uso terapêutico , Resultado do TratamentoRESUMO
A promising new therapy option for acute kidney injury (AKI) is mesenchymal stem cells (MSCs). However, there are several limitations to the use of MSCs, such as low rates of survival, limited homing capacity, and unclear differentiation. In search of better therapeutic strategies, we explored all-trans retinoic acid (ATRA) pretreatment of MSCs to observe whether it could improve the therapeutic efficacy of AKI. We established a renal ischemia/reperfusion injury model and treated mice with ATRA-pretreated MSCs via tail vein injection. We found that AKI mice treated with ATRA-MSCs significantly improved renal function compared with DMSO-MSCs treatment. RNA sequencing screened that hyaluronic acid (HA) production from MSCs promoted by ATRA. Further validation by chromatin immunoprecipitation experiments verified that retinoic acid receptor RARα/RXRγ was a potential transcription factor for hyaluronic acid synthase 2. Additionally, an in vitro hypoxia/reoxygenation model was established using human proximal tubular epithelial cells (HK-2). After co-culturing HK-2 cells with ATRA-pretreated MSCs, we observed that HA binds to cluster determinant 44 (CD44) and activates the PI3K/AKT pathway, which enhances the anti-inflammatory, anti-apoptotic, and proliferative repair effects of MSCs in AKI. Inhibition of the HA/CD44 axis effectively reverses the renal repair effect of ATRA-pretreated MSCs. Taken together, our study suggests that ATRA pretreatment promotes HA production by MSCs and activates the PI3K/AKT pathway in renal tubular epithelial cells, thereby enhancing the efficacy of MSCs against AKI.
Assuntos
Injúria Renal Aguda , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Tretinoína , Injúria Renal Aguda/terapia , Injúria Renal Aguda/patologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/tratamento farmacológico , Animais , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Humanos , Camundongos , Masculino , Camundongos Endogâmicos C57BL , Ácido Hialurônico/farmacologia , Receptores de Hialuronatos/metabolismo , Receptores de Hialuronatos/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Traumatismo por Reperfusão/terapia , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/metabolismo , Modelos Animais de Doenças , Apoptose/efeitos dos fármacosRESUMO
Background: Acute myeloid leukemia (AML) is a type of blood cancer characterized by excessive growth of immature myeloid cells. Unfortunately, the prognosis of pediatric AML remains unfavorable. It is imperative to further our understanding of the mechanisms underlying leukemogenesis and explore innovative therapeutic approaches to enhance overall disease outcomes for patients with this condition. Methods: Quantitative reverse-transcription PCR was used to quantify the expression levels of microRNA (miR)-133a and miR-135a in 68 samples from 59 pediatric patients with AML. Dual-luciferase reporter transfection assay, Cell Counting Kit-8 assay, and western blot analysis were used to investigate the functions of miR-133a and miR-135a. Results: Our study found that all-trans-retinoic acid (ATRA) promoted the expression of miR-133a and miR-135a in AML cells, inhibited caudal type homeobox 2 (CDX2) expression, and subsequently inhibited the proliferation of AML cells. Additionally, miR-133a and miR-135a were highly expressed in patients with complete remission and those with better survival. Conclusions: miR-133a and miR-135a may play an antioncogenic role in pediatric AML through the ATRA-miRNA133a/135a-CDX2 pathway. They hold promise as potentially favorable prognostic indicators and novel therapeutic targets for pediatric AML.
Assuntos
Biomarcadores Tumorais , Leucemia Mieloide Aguda , MicroRNAs , Tretinoína , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Biomarcadores Tumorais/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/metabolismo , MicroRNAs/genética , Prognóstico , Tretinoína/farmacologia , Tretinoína/uso terapêuticoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) stands out as one of the most prevalent malignant tumors globally. The combination of all-trans-retinoic acid (ATRA) with FOLFOX chemotherapy has shown promise in enhancing the prognosis of HCC patients. ATRA, serving as a chemosensitizing agent, presents novel possibilities for therapeutic applications. Nevertheless, the responsiveness of HCC cells to ATRA varies. The epigenetic modifier-GSK-126 is currently under investigation as a potential antitumor drug. Our aim is to explore the molecular mechanisms underlying the diverse sensitivity of HCC patients to ATRA, and to propose a new combination regimen. This research aims to lay the groundwork for personalized medication approaches for individuals with HCC. METHODS: A cell model with low expression of retinoic acid receptor Alfa (RARA), retinoic acid receptor belta (RARB), and retinoic acid receptor gamma (RARG) was established through siRNA interference. The impact of reduced expression of RARA, RARB, and RARG on the half maximal inhibitory concentration (IC50) of ATRA in Hep3B cells was assessed using the 3-(4,5-Dimethyl-2-Thiazolyl)-2,5-Diphenyl Tetrazolium Bromide (MTT) cytotoxicity assay. Flow cytometry revealed that RARG emerged as the key receptor influencing the combination's sensitivity. Conducting ChIP-qPCR analysis on genomic DNA from HCC cells through relevant websites demonstrated enrichment of the trimethylation modification of lysine 27 on histone H3 (H3K27me3) upstream of the RARG promoter. ChIP-PCR assay confirmed that GSK-126 could diminish H3K27me3 levels on the RARG promoter, subsequently elevating RARG expression. The synergistic efficacy of GSK-126 and ATRA was validated through MTT assay, flow cytometry apoptosis assay, cell cycle assay, and cell scratch assay. RESULTS: Our study unveiled that the insensitivity of HCC cells to ATRA could be linked to the low expression of RARG. ChIP-qPCR analysis illuminated that GSK-126 activated RARG expression by diminishing H3K27me3 enrichment in the RARG promoter region. Consequently, the concurrent administration of ATRA and GSK-126 to hepatoma cells exhibited a synergistic effect, inhibiting cell proliferation, inducing cell apoptosis, and reducing the proportion of cells in the S-phase. CONCLUSION: Our findings emphasize that the synergistic action of GSK-126 and ATRA enhances the sensitivity of HCC cells by upregulating the expression of RARG. This presents a potential foundation for personalized HCC treatment.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Receptores do Ácido Retinoico , Tretinoína , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Receptores do Ácido Retinoico/metabolismo , Receptores do Ácido Retinoico/genética , Linhagem Celular Tumoral , Receptor gama de Ácido Retinoico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/genética , Sinergismo FarmacológicoRESUMO
Incidents of leukemia in pregnancy are infrequent with only one case found from 75,000 to 100,000 pregnancies. The pathophysiological mechanism of leukemia during pregnancy is still unclear. Leukemia which occurs in pregnancy is usually acute and predominantly the myeloid type.A 35-year-old woman in her fourth pregnancy with a gestational age of 38-39 weeks, came to the emergency department (ED) with complaints of contractions since 4.5 hours before admission. The contraction was not accompanied by discharge, mucus, or blood, and fetal movements was still active. She denied complaints of fever, nausea, vomiting, dizziness, shortness of breath, weakness, fatigue, lethargy, and bleeding. Physical examination results, both palpebral conjunctiva were pale. Laboratory examination results of a complete blood count, white blood cell count were 2,930/uL, hemoglobin 8.3 g/dL, Hct 24.10%, erythrocytes 2.78x106/µL, platelets 62,000/µL. Bone Marrow Aspiration (BMA) revealed Acute Promyelocytic Leukemia (APL).APL is a subtype of Acute Myelogenous Leukemia (AML). Persistent fatigue, recurrent infections, and bleeding are common manifestations of APL. The diagnosis of APL is made by bone marrow aspiration examination, and it is safe for pregnancy. APL therapy in pregnancy uses All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide (ATO). ATRA and ATO are highly teratogenic, but recent studies have reported no fetal abnormalities.Accuracy and speed in diagnosing and initiating APL therapy in pregnancy are essential in preventing serious complications.
Assuntos
Leucemia Promielocítica Aguda , Adulto , Feminino , Humanos , Gravidez , Protocolos de Quimioterapia Combinada Antineoplásica , Trióxido de Arsênio/uso terapêutico , Leucemia Promielocítica Aguda/complicações , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamento farmacológico , Tretinoína/uso terapêuticoAssuntos
Antineoplásicos , Leucemia Promielocítica Aguda , Humanos , Masculino , Leucemia Promielocítica Aguda/complicações , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Pessoa de Meia-Idade , Medula Óssea/patologia , Biópsia , Translocação Genética , Fusão Gênica , Tretinoína/efeitos adversos , Tretinoína/uso terapêutico , Prednisolona/efeitos adversos , Prednisolona/uso terapêutico , Quimioterapia de Indução/efeitos adversos , Trióxido de Arsênio/uso terapêutico , Quimioterapia de Consolidação , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêuticoRESUMO
There is an urgent need for an oral, efficient and safe regimen for high-risk APL under the pandemic of COVID-19. We retrospectively analysed 60 high-risk APL patients. For induction therapy (IT), in addition to all-trans retinoic acid (ATRA) and oral arsenic (RIF), 22 patients received oral etoposide (VP16) as cytotoxic chemotherapy (CC), and 38 patients received intravenous CC as historical control group. The median dose of oral VP16 was 1000 mg [interquartile rage (IQR), 650-1250]. One patient died during IT in the control group, 59 evaluable patients (100%) achieved complete haematological remission (CHR) after IT and complete molecular remission (CMR) after consolidation therapy. The median time to CHR and CMR was 36 days (33.8-44) versus 35 days (32-42; p = 0.75) and 3 months (0.8-3.5) versus 3.3 months (2.4-3.7; p = 0.58) in the oral VP16 group and in the control group. Two (9.1%) and 3 (7.9%) patients experienced molecular relapse in different group respectively. The 2-year estimated overall survival and event-free survival were 100% versus 94.7% (p = 0.37) and 90.9% versus 89.5% (p = 0.97) respectively. A completely oral, efficient and safe induction regimen including oral VP16 as cytoreductive chemotherapy combined with ATRA and RIF is more convenient to administer for patients with high-risk APL.
Assuntos
Etoposídeo , Quimioterapia de Indução , Leucemia Promielocítica Aguda , Humanos , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Administração Oral , Estudos Retrospectivos , Quimioterapia de Indução/métodos , Infusões Intravenosas , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , COVID-19 , Tretinoína/administração & dosagem , Tretinoína/uso terapêutico , SARS-CoV-2 , Indução de Remissão , Arsênio/administração & dosagem , IdosoRESUMO
An 84-year-old woman was diagnosed as having acute promyelocytic leukemia(APL)in July Year X-3. The test for promyelocytic leukemia- retinoic acid receptor alpha(PML-RARA)mRNA was positive, while that for CD56 was negative. Since her white blood cell( WBC) count was <3,000/µL, with a count of APL cells of <1,000/µL, she was started on monotherapy with all-trans retinoic acid(ATRA). In September Year X-3, complete hematological remission(CHR)was confirmed. she refused to provide consent for receiving consolidation therapy. In February Year X-2, hematological relapse occurred. She was started on re-induction therapy with arsenite(ATO), and in June Year X-2, complete molecular remission(CMR)was achieved. She was started on post-remission therapy with ATO. In August Year X-1, she developed molecular relapse and was started on tamibarotene(Am80). In October Year X-1, hematological relapse was detected, and the test for CD56 was positive. She was started on combined venetoclax(VEN)+azacitidine(AZA)(VEN+AZA). After completion of 1 course of treatment, CMR was achieved, but she developed hematological relapse after 5 courses of treatment. She died of gastrointestinal hemorrhage. This is considered a valuable case for accumulating information on the treatment of CD56-positive APL resistant to ATRA and ATO.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Promielocítica Aguda , Sulfonamidas , Humanos , Feminino , Idoso de 80 Anos ou mais , Leucemia Promielocítica Aguda/tratamento farmacológico , Trióxido de Arsênio/uso terapêutico , Azacitidina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Tretinoína/uso terapêutico , RecidivaRESUMO
Stroke is a leading cause of death and long-term disability which can cause oxidative damage and inflammation of the neuronal cells. Retinoic acid is an active metabolite of vitamin A that has various beneficial effects including antioxidant and anti-inflammatory effects. In this study, we investigated whether retinoic acid modulates oxidative stress and inflammatory factors in a stroke animal model. A middle cerebral artery occlusion (MCAO) was performed on adult male rats to induce focal cerebral ischemia. Retinoic acid (5 mg/kg) or vehicle was injected into the peritoneal cavity for four days before MCAO surgery. The neurobehavioral tests were carried out 24 h after MCAO and cerebral cortex tissues were collected. The cortical damage was assessed by hematoxylin-eosin staining and reactive oxygen species assay. In addition, Western blot and immunohistochemical staining were performed to investigate the activation of glial cells and inflammatory cytokines in MCAO animals. Ionized calcium-binding adapter molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP) were used as markers of microglial and astrocyte activation, respectively. Tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were used as representative pro-inflammatory cytokines. Results showed that MCAO damage caused neurobehavioral defects and histopathological changes in the ischemic region and increased oxidative stress. Retinoic acid treatment reduced these changes caused by MCAO damage. We detected increases in Iba-1 and GFAP in MCAO animals treated with vehicle. However, retinoic acid alleviated increases in Iba-1 and GFAP caused by MCAO damage. Moreover, MCAO increased levels of nuclear factor-κB and pro-inflammatory cytokines, including TNF-α and IL-1ß. Retinoic acid alleviated the expression of these inflammatory proteins. These findings elucidate that retinoic acid regulates microglia and astrocyte activation and modulates pro-inflammatory cytokines. Therefore, this study suggests that retinoic acid exhibits strong antioxidant and anti-inflammatory properties by reducing oxidative stress, inhibiting neuroglia cell activation, and preventing the increase of pro-inflammatory cytokines in a cerebral ischemia.
Assuntos
Isquemia Encefálica , Fármacos Neuroprotetores , Acidente Vascular Cerebral , Ratos , Masculino , Animais , Fator de Necrose Tumoral alfa/metabolismo , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Isquemia Encefálica/tratamento farmacológico , Neuroglia/metabolismo , Citocinas/metabolismo , Anti-Inflamatórios/uso terapêutico , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêuticoRESUMO
BACKGROUND: The limited therapies available for treating Merkel cell carcinoma (MCC), a highly aggressive skin neoplasm, still pose clinical challenges, and novel treatments are required. Targeting retinoid signalling with retinoids, such as all-trans retinoic acid (ATRA), is a promising and clinically useful antitumor approach. ATRA drives tumour cell differentiation by modulating retinoid signalling, leading to anti-proliferative and pro-apoptotic effects. Although retinoid signalling is dysregulated in MCC, ATRA activity in this tumour is unknown. This study aimed to evaluate the impact of ATRA on the pathological phenotype of MCC cells. METHODS: The effect of ATRA was tested in various Merkel cell polyomavirus-positive and polyomavirus-negative MCC cell lines in terms of cell proliferation, viability, migration and clonogenic abilities. In addition, cell cycle, apoptosis/cell death and the retinoid gene signature were evaluated upon ATRA treatments. RESULTS: ATRA efficiently impaired MCC cell proliferation and viability in MCC cells. A strong effect in reducing cell migration and clonogenicity was determined in ATRA-treated cells. Moreover, ATRA resulted as strongly effective in arresting cell cycle and inducing apoptosis/cell death in all tested MCC cells. Enrichment analyses indicated that ATRA was effective in modulating the retinoid gene signature in MCC cells to promote cell differentiation pathways, which led to anti-proliferative and pro-apoptotic/cell death effects. CONCLUSIONS: These results underline the potential of retinoid-based therapy for MCC management and might open the way to novel experimental approaches with other retinoids and/or combinatorial treatments.
Assuntos
Apoptose , Carcinoma de Célula de Merkel , Diferenciação Celular , Proliferação de Células , Neoplasias Cutâneas , Tretinoína , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Carcinoma de Célula de Merkel/tratamento farmacológico , Carcinoma de Célula de Merkel/metabolismo , Carcinoma de Célula de Merkel/patologia , Humanos , Proliferação de Células/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Retinoides/farmacologia , Retinoides/uso terapêutico , Movimento Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacosRESUMO
BACKGROUND: The outcome of patients with acute promyelocytic leukemia (APL) has improved significantly since the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) as APL therapies. The optimal therapy for APL relapse is believed to require autologous or allogeneic stem cell transplantation (SCT) based on historical experience. STUDY AIMS: To evaluate the outcome of patients with relapsed APL before and after the era of ATRA-ATO. PATIENTS AND METHODS: We reviewed 61 patients with relapsed APL treated from November 1991 to June 2023; 31 patients (51%) received modern therapy with the combination of ATRA and ATO with and without idarubicin and gemtuzumab ozogamicin (GO). RESULTS: Overall, 56 patients (92%) achieved CR after the first salvage therapy; 20 patients received SCT (10 autologous SCT;10 allogeneic SCT). With a median follow-up time of 138 months, the median survival durations were 32 months and 164 months with historical therapy vs. modern (ATRA-ATO) therapy (P = .035); the 5-year survival rates were 44% vs. 71%. With a 10-month landmark analysis, the median survival durations were 102 months vs. not reached, and the 5-year survival rates were 57% and 70% without SCT vs. with SCT (P = .193). The survival benefit with SCT was more prominent in the historical therapy era. However, patients who received the modern combination therapy of ATRA-ATO with and without idarubicin and GO had similar outcomes without vs. with SCT (P = .848). CONCLUSION: The combination of ATRA-ATO (+/- GO and idarubicin) is a highly effective salvage therapy in relapsed APL. The use of SCT may not be needed after first relapse-second remission but may be considered in subsequent relapses.
Assuntos
Leucemia Promielocítica Aguda , Tretinoína , Humanos , Leucemia Promielocítica Aguda/terapia , Leucemia Promielocítica Aguda/mortalidade , Leucemia Promielocítica Aguda/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Tretinoína/uso terapêutico , Adulto Jovem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resultado do Tratamento , Adolescente , Trióxido de Arsênio/uso terapêutico , Recidiva , Terapia de Salvação/métodos , Estudos Retrospectivos , Idarubicina/uso terapêutico , Idarubicina/administração & dosagemRESUMO
Acute promyelocytic leukemia (APL) is a highly curable hematologic malignancy in the era of all-trans retinoic acid (ATRA) combination treatment. However, only a modest change in early mortality rate has been observed despite the wide availability of ATRA. In addition to the clinical characteristics of APL patients, studies on the hospital volume-outcome relationship and the physician volume-outcome relationship remained limited. We aim to evaluate the association between hospital and physician volume and the early mortality rate among APL patients. The patients were collected from Taiwan's National Health Insurance Research Database (NHIRD). Early mortality is defined as death within 30 days of diagnosis. Patients were categorized into four groups according to individual cumulative hospital and physician volume. The risk of all-cause mortality in APL patients with different cumulative volume groups was compared using a Cox proportional hazard model. The probability of overall survival was estimated using the Kaplan-Meier method. All 741 patients were divided into four quartile volume groups. In the multivariate analysis, only physician volume was significantly associated with early mortality rate. The physician volume of the highest quartile was a protective factor for early mortality compared with the physician volume of the lowest quartile (HR 0.10, 95% CI 0.02-0.65). Hospital characteristics were not associated with early mortality. In the sensitivity analyses, the results remained consistent using two other different definitions of early mortality. Higher physician volume was independently associated with lower early mortality, while hospital volume was not. Enhancing the clinical expertise of low-volume physicians may ensure better outcomes.
Assuntos
Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/complicações , Tretinoína/uso terapêutico , Modelos de Riscos Proporcionais , Terapia Combinada , Resultado do TratamentoRESUMO
BACKGROUND: Recent advances in the treatment of acute promyelocytic leukemia (APML) have seen unprecedented improvements in patient outcomes. However, such rapid growth in understanding often leads to uncertainty regarding superiority among candidate treatment regimens, especially when further scrutinized from an epidemiological perspective. AIMS: The aim of this systematic review with epidemiological analysis was to identify and compare commonly utilized protocols for standard-risk APML with a particular focus on complete remission (CR), overall/disease-free survival (DFS), and reported adverse events. METHODS AND RESULTS: Medline, Scopus, and CINAHL were interrogated to identify studies utilizing all-trans retinoic acid (ATRA) in addition to arsenic trioxide (ATO) and/or anthracyclines such as idarubicin (IDA) in the treatment of de-novo APML. After collation of studies, an epidemiological analysis was subsequently performed to compare protocols with regards to outcomes of interest using number needed to benefit (NNB) and number needed to harm (NNH) measures. Seventeen articles, describing 12 distinct trials, were included in the analysis. These trials made use of three unique protocols; CR rates were 94%-100% for ATO/ATRA regimens, 95%-96% for ATO/ATRA/anthracycline regimens, and 89%-94% for ATRA/anthracycline regimens. Epidemiological analysis demonstrated NNB for CR was 9.09 (ATO/ATRA vs. ATRA/IDA) and 20.00 (ATO/ATRA vs. ATO/ATRA/IDA), NNH for neutropenia was -3.45 (ATO/ATRA vs. ATRA/IDA), and NNH for infection was -3.13 (ATO/ATRA vs. ATRA/IDA) and -1.89 (ATO/ATRA vs. ATO/ATRA/IDA). CONCLUSION: The ATO/ATRA regimen is superior to chemotherapy-containing protocols at inducing remission and promoting survival in patients with APML. The regimen is better tolerated than the proposed alternatives with fewer adverse events. Future research opportunities include quantifying APML epidemiology and pursuing oral arsenic as an option for simplification of therapeutic protocols.
Assuntos
Antraciclinas , Protocolos de Quimioterapia Combinada Antineoplásica , Trióxido de Arsênio , Leucemia Promielocítica Aguda , Tretinoína , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/epidemiologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Tretinoína/administração & dosagem , Tretinoína/efeitos adversos , Tretinoína/uso terapêutico , Trióxido de Arsênio/administração & dosagem , Trióxido de Arsênio/uso terapêutico , Trióxido de Arsênio/efeitos adversos , Antraciclinas/efeitos adversos , Antraciclinas/administração & dosagem , Antraciclinas/uso terapêutico , Idarubicina/administração & dosagem , Idarubicina/efeitos adversos , Intervalo Livre de Doença , Indução de Remissão/métodosRESUMO
BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are evolving as a prominent determinant in cancer occurrence and development and are functionally found to suppress T cells in cancer. Not much research is done regarding its involvement in viral infections. This research was designed to investigate the role of MDSCs in hepatitis B virus (HBV) infection and how targeting these cells with our novel all-trans retinoic acid encapsulated liposomal formulation could improve immunotherapy in C57BL/6 mice. METHODS: Ten micrograms (10 µg) of plasmid adeno-associated virus (pAAV/HBV 1.2, genotype A) was injected hydrodynamically via the tail vein of C57BL/6 mice. An all-trans retinoic acid encapsulated liposomal formulation (L-ATRA) with sustained release properties was used in combination with tenofovir disoproxil fumarate (TDF), a nucleotide analog reverse transcriptase inhibitor (nRTI) to treat the HBV infection. The L-ATRA formulation was given at a dose of 5 mg/kg intravenously (IV) twice a week. The TDF was given orally at 30 mg/kg daily. RESULTS: Our results revealed that L-ATRA suppresses MDSCs in HBV infected mice and enhanced T-cell proliferation in vitro. In vivo studies showed higher and improved immunotherapeutic effect in mice that received L-ATRA and TDF concurrently in comparison with the groups that received monotherapy. Lower HBV DNA copies, lower concentrations of HBsAg and HBeAg, lower levels of ALT and AST and less liver damage were seen in the mice that received the combination therapy of L-ATRA + TDF. CONCLUSIONS: In effect, targeting MDSCs with the combination of L-ATRA and TDF effectively reduced mMDSC and improved immunotherapy in the HBV infected mice. Targeting MDSCs could provide a breakthrough in the fight against hepatitis B virus infection.
Assuntos
Hepatite B Crônica , Hepatite B , Células Supressoras Mieloides , Neoplasias , Animais , Camundongos , Vírus da Hepatite B/genética , Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Antígenos E da Hepatite B/farmacologia , Antígenos E da Hepatite B/uso terapêutico , Resultado do Tratamento , Camundongos Endogâmicos C57BL , Tenofovir/farmacologia , Tenofovir/uso terapêutico , Hepatite B/tratamento farmacológico , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Neoplasias/tratamento farmacológicoRESUMO
INTRODUCTION: Early death (ED) is the unsolved issue of acute promyelocytic leukemia (APL). The disseminated intravascular coagulation (DIC) score has been proposed as a marker of bleeding and death in APL; whether its temporal evolution predicts outcomes in APL is unknown. We evaluated whether an increasing score 48 h after diagnosis associates with ED. METHODS: Retrospective, single-center study, including patients with newly diagnosed APL between 2000 and 2023, treated with all-transretinoic acid (ATRA) plus anthracycline or arsenic trioxide (ATO). "DIC score worsening" was defined as ≥1 point increase in the score after 48 h, and ED as death within 30 days of diagnosis. RESULTS: Eighty-six patients were included, with median age of 46 years (17-82). ED patients (26.7%) more frequently had age >60 years and worsening DIC score after 48 h. These were also the only predictors of ED identified in both univariate and multivariate (OR 4.18, p = .011; OR 7.8, p = .005, respectively) logistic regression analysis. CONCLUSION: This is the first study on DIC score evolution in APL-a worsening DIC score 48 h after diagnosis is a strong independent predictive factor of ED. We propose a reduction of the DIC score from diagnosis as a new treatment goal in APL care.
Assuntos
Coagulação Intravascular Disseminada , Leucemia Promielocítica Aguda , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Leucemia Promielocítica Aguda/complicações , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamento farmacológico , Coagulação Intravascular Disseminada/etiologia , Coagulação Intravascular Disseminada/complicações , Estudos Retrospectivos , Tretinoína/uso terapêutico , Trióxido de Arsênio/efeitos adversosRESUMO
Pancreatic stellate cells (PSCs) are activated following loss of cytoplasmic vitamin A (retinol)-containing lipid droplets, which is a key event in the process of fibrogenesis of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDCA). PSCs are the major source of cancer-associated fibroblasts (CAFs) that produce stroma to induce PDAC cancer cell growth, invasion, and metastasis. As an active metabolite of retinol, retinoic acid (RA) can regulate target gene expression in PSCs through its nuclear receptor complex (RAR/RXR or RXR/RXR) or transcriptional intermediary factor. Additionally, RA also has extranuclear and non-transcriptional effects. In vitro studies have shown that RA induces PSC deactivation which reduces extracellular matrix production through multiple modes of action, such as inhibiting TßRâ ¡, PDGFRß, ß-catenin and Wnt production, downregulating ERK1/2 and JNK phosphorylation and suppressing active TGF-ß1 release. RA alone or in combination with other reagents have been demonstrated to have an effective anti-fibrotic effect on cerulein-induced mouse CP models in vivo studies. Clinical trial data have shown that repurposing all-trans retinoic acid (ATRA) as a stromal-targeting agent for human pancreatic cancer is safe and tolerable, suggesting the possibility of using RA for the treatment of CP and PDCA in humans. This review focuses on RA signaling pathways in PSCs and the effects and mechanisms of RA in PSC-mediated fibrogenesis as well as the anti-fibrotic and anti-tumor effects of RA targeting PSCs or CAFs in vitro and in vivo, highlighting the potential therapies of RA against CP and PDAC.