RESUMEN
A standard treatment for patients with primary intraocular lymphoma (PIOL) remains unclear. This study retrospectively analyzed the clinical features and outcomes of 19 patients with PIOL who were treated with a first-line therapy comprising combined intravenous high-dose methotrexate and intravitreal methotrexate between January 2003 and December 2013. Thirteen (68.4 %) patients were female, and the median age at diagnosis was 57 (39-77 years). Diagnoses were based on the identification of abnormal lymphoid cells in vitreous fluid. Ten (52.6 %) patients had bilateral eye involvement, and six had concurrent central nervous system (CNS) involvement. All 19 patients achieved complete remission (CR) as confirmed by cytological examination of vitreous and cerebrospinal fluid and brain imaging if CNS was involved. Patients with concurrent brain involvement required a longer time to achieve CR. However, the duration of complete remission did not differ between patients with and without CNS involvement. The 5-year overall survival rate was 55.8 % for the total cohort and was higher (68.8 %) in patients with isolated PIOL than in those with concurrent CNS involvement. In all patients, methotrexate treatment was well tolerated, with manageable side effects. We conclude that combined intravitreal methotrexate and systemic high-dose methotrexate treatment is effective in patients with PIOL.
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Antimetabolitos Antineoplásicos/administración & dosificación , Linfoma Intraocular/diagnóstico , Linfoma Intraocular/tratamiento farmacológico , Inyecciones Intravítreas/métodos , Metotrexato/administración & dosificación , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
CXC chemokine receptor 4 (CXCR4) is an essential regulator for homing and maintenance of hematopoietic stem cells within the bone marrow niches. Analysis of clinical implications of bone marrow CXCR4 expression in patients with acute myeloid leukemia showed not only higher CXCR4 expression was an independent poor prognostic factor, irrespective of age, white blood cell counts, cytogenetics, and mutation status of NPM1/FLT3-ITD and CEBPA, but also showed CXCR4 expression was inversely associated with mutations of CEBPA, a gene encoding transcription factor C/EBPα. Patients with wild-type CEBPA had significantly higher CXCR4 expression than those with mutated CEBPA. We hypothesized that CEBPA might influence the expression of CXCR4. To test this hypothesis, we first examined endogenous CXCR4 expression in 293T and K562 cells over-expressing wild-type C/EBPα p42 and demonstrated that CXCR4 levels were increased in these cells, whilst the expression of the N-terminal mutant, C/EBPα p30, diminished CXCR4 transcription. We further showed p42 was bound to the CXCR4 promoter by the chromatin immunoprecipitation assays. Induction of p42 in the inducible K562-C/EBPα cell lines increased the chemotactic migration. Moreover, decreased expression of C/EBPα by RNA interference decreased levels of CXCR4 protein expression in U937 cells, thereby abrogating CXCR4-mediated chemotaxis. Our results provide, for the first time, evidence that C/EBPα indeed regulates the activation of CXCR4, which is critical for the homing and engraftment of acute myeloid leukemia cells, while p30 mutant impairs CXCR4 expression.
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Proteínas Potenciadoras de Unión a CCAAT/genética , Regulación Neoplásica de la Expresión Génica , Leucemia Mieloide Aguda/genética , Mutación/genética , Receptores CXCR4/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Western Blotting , Médula Ósea/metabolismo , Médula Ósea/patología , Proteínas Potenciadoras de Unión a CCAAT/antagonistas & inhibidores , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Estudios de Casos y Controles , Quimiotaxis , Estudios de Cohortes , Femenino , Citometría de Flujo , Estudios de Seguimiento , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Humanos , Células K562 , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Nucleofosmina , Pronóstico , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores CXCR4/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Células U937 , Adulto JovenRESUMEN
A mild and efficient synthetic development of 2-arylbenzothiazoles 5 mediated by ceric ammonium nitrate (CAN) via intramolecular cyclization of N-phenyl-thiobenzamides 4 was achieved. Further compounds 5 were reduced to corresponding amines 6, and their photodynamic therapy (PDT) effect was evaluated on malignant human melanoma A375 cells. Amine 6l plus ultraviolet A (UVA) induced caspase-3 activity, poly(ADP-ribose)polymerase cleavage, M30 positive CytoDeath staining, and subsequent apoptotic cell death. Our data disclosed that treatment of A375 cells with 6l plus UVA resulted in a decrease in mitochondrial membrane potential (ΔΨmt), oxidative phosphorylation system (OXPHOS) subunits, and adenosine triphosphate (ATP) but an increase in mitochondrial DNA 4977-bp deletion via reactive oxygen species (ROS) generation. Transmission electron microscopy (TEM) observations also showed major ultrastructural alterations of mitochondria. Additionally, 6l plus UVA was also shown to reduce murine melanoma size in a mouse model. The present study supports the hypothesis that 6l-PDT may serve as a potential ancillary modality for the treatment of melanoma.
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Benzotiazoles/farmacología , Melanoma Experimental/metabolismo , Mitocondrias/efectos de los fármacos , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Neoplasias Cutáneas/metabolismo , Animales , Apoptosis/efectos de los fármacos , Benzotiazoles/efectos de la radiación , Benzotiazoles/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citocromos c/metabolismo , Femenino , Humanos , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos ICR , Mitocondrias/fisiología , Fármacos Fotosensibilizantes/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Carga Tumoral/efectos de los fármacos , Rayos UltravioletaRESUMEN
Melanoma is one of the most chemoresistant cancers in patient care. The remission rate of current therapy remains low. DC-81, an antitumor antibiotic produced by Streptomyces species, belongs to pyrrolo[2,1-c][1,4]benzodiazepine (PBD), which is a potent inhibitor of nucleic acid synthesis. An enediyne contains either DNA intercalating groups or DNA minor groove binding functions and these are potent DNA-damaging agents due to their ability to generate benzenoid diradicals. We have previously reported an efficient synthesis and antitumor activity of a series of novel PBD hybrids linked with enediyne. The purpose of this study was to examine the mechanism of the antiproliferative effect of DC-81-enediyne agent on human melanoma A375 cells. DC-81-enediyne induced an increase in Ca(2+) level and reactive oxygen species (ROS) generation as detected by flow cytometric assay. Western blot analysis showed that DC-81-enediyne induced the phosphorylation of p38 and activating transcription factor 2 (ATF-2). By using the luciferase reporter assay, activating protein-1 (AP-1) activity was further enhanced after A375 cells were treated with graded concentrations of DC-81-enediyne. DC-81-enediyne treatment-induced A375 cell apoptosis was significantly abrogated by the addition of Ca(2+), ROS, and p38 inhibitors. Collectively, our studies indicate that DC-81-enediyne induces A375 cell apoptosis through an increased Ca(2+) and ROS generation, which involves p38 phosphorylation and enhanced ATF-2/AP-1 expressions, leading to caspase-3 activity, poly(ADP-ribose)polymerase cleavage, M30 CytoDeath staining, and subsequent apoptotic cell death.
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Antraquinonas/farmacología , Apoptosis/efectos de los fármacos , Enediinos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Melanoma/tratamiento farmacológico , Pirroles/farmacología , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN/metabolismo , Daño del ADN/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Imidazoles/farmacología , Melanoma/metabolismo , Fosforilación , Poli(ADP-Ribosa) Polimerasas/metabolismo , Piridinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Factor de Transcripción AP-1/efectos de los fármacos , Factor de Transcripción AP-1/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Agranulocytosis is an uncommon but serious complication of Graves' disease under thionamide therapy. In some patients removal of circulating thyroid hormones and thyroid antibodies by plasmapheresis is an effective adjunctive therapeutic option. In perioperative settings, however, plasmapheresis may cause excess bleeding intraoperatively due to coagulation factor depletion unless fresh frozen plasma (FFP) products are used in the replacement fluid mix. Double filtration plasmapheresis (DFPP) in which only a small amount of albumin supplementation is used may be a potential alternative to conventional apheresis interventions where clotting factor depletion is problematic. We report a case of a patient with Graves' disease complicated with intravenous immunoglobulin responsive methimazole-induced agranulocytosis/hemophagocytosis who underwent successful preoperative DFPP treatment in preparation for thyriodectomy. In addition to conventional apheresis using FFP replacement, DFPP may offer an effective adjunct option in the management of hyperthyroid patients needing emergent surgical interventions.
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Agranulocitosis/terapia , Enfermedad de Graves/complicaciones , Enfermedad de Graves/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/terapia , Plasmaféresis/métodos , Adulto , Agranulocitosis/inducido químicamente , Femenino , Enfermedad de Graves/cirugía , Humanos , Linfohistiocitosis Hemofagocítica/inducido químicamente , Metimazol/efectos adversos , Cuidados Preoperatorios , Resultado del TratamientoRESUMEN
The niche variation hypothesis (NVH) predicts that populations with wider niches exhibit greater morphological variation through increased interindividual differences in both niche and morphology. In this study, we examined niche-trait relationships in three passerine species (Cyanoderma ruficeps, Sinosuthora webbiana, and Zosterops simplex). A total of 289 C. ruficeps from 7 sites, 259 S. webbiana from 8 sites, and 144 Z. simplex from 6 sites were sampled along an elevation gradient (0-2,700 m) in Taiwan from 2009 to 2017. We measured bill traits (length, width, and depth of bill) and body size traits (length of head, tarsus, and wing) of the birds, which were reduced to four principal components (bill PC1, bill PC2, body size PC1, and body size PC2). We collected feather tissues for stable carbon and nitrogen isotope analyses to quantify their isotope niche. We quantified interindividual differences in isotope space and trait space with four diversity metrics (divergence, dispersion, evenness, and uniqueness) and tested whether interindividual differences in isotope space and trait space are positively associated. We quantified population isotope niche width by Bayesian ellipse area and population morphological variation by variances of the PCs. The results showed that individual uniqueness in isotope niche and bill morphology (average closeness of individuals within the population isotope/trait space) were positively associated across three species. Furthermore, isotope niche width and bill PC1 (reflecting the size of bill) variation at population level were also positively associated across the three species, supporting the NVH. Of the three species, C. ruficeps and S. webbiana showed stronger support for the NVH than Z. simplex, possibly due to the latter having narrower elevational distribution and a more specialized, plant-based diet. The diversity metrics represented different aspects of interindividual differences in niche/trait space, and for the passerines, individual uniqueness appeared to play an important role in their niche-trait dynamics.
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AIMS: Angiotensin-converting enzyme 2 (ACE2) is a key negative regulator of the renin-angiotensin system and also a major receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we reveal a role for NF-κB in human lung cell expression of ACE2, and we further explore the potential utility of repurposing NF-κB inhibitors to downregulate ACE2. MAIN METHODS: Expression of ACE2 was assessed by Western blotting and RT-qPCR in multiple human lung cell lines with or without NF-κB inhibitor treatment. Surface ACE2 expression and intracellular reactive oxygen species (ROS) levels were measured with flow cytometry. p50 was knocked down with siRNA. Cytotoxicity was monitored by PARP cleavage and MTS assay. KEY FINDINGS: Pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor, suppressed endogenous ACE2 mRNA and protein expression in H322M and Calu-3 cells. The ROS level in H322M cells was increased after PDTC treatment, and pretreatment with N-acetyl-cysteine (NAC) reversed PDTC-induced ACE2 suppression. Meanwhile, treatment with hydrogen peroxide augmented ACE2 suppression in H322M cells with p50 knockdown. Two repurposed NF-κB inhibitors, the anthelmintic drug triclabendazole and the antiprotozoal drug emetine, also reduced ACE2 mRNA and protein levels. Moreover, zinc supplementation augmented the suppressive effects of triclabendazole and emetine on ACE2 expression in H322M and Calu-3 cells. SIGNIFICANCE: These results suggest that ACE2 expression is modulated by ROS and NF-κB signaling in human lung cells, and the combination of zinc with triclabendazole or emetine shows promise for clinical treatment of ACE2-related disease.
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Enzima Convertidora de Angiotensina 2/genética , Antiparasitarios/farmacología , Regulación hacia Abajo/efectos de los fármacos , Emetina/farmacología , FN-kappa B/antagonistas & inhibidores , Triclabendazol/farmacología , Zinc/farmacología , COVID-19/genética , Línea Celular , Reposicionamiento de Medicamentos , Humanos , Pulmón/citología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pirrolidinas/farmacología , Tiocarbamatos/farmacología , Tratamiento Farmacológico de COVID-19RESUMEN
Lymphoma is a group of blood cancers that develop from the immune system, and one of the main risk factors is associated with exposure to environmental chemicals. Bisphenol A (BPA) is a common chemical used in the manufacture of materials in polycarbonate and epoxy plastic products and can interfere with the immune system. BPA is considered to possibly induce lymphoma development by affecting the immune system, but its potential mechanisms have not been well established. This study performed a gene-network analysis of microarray data sets in human lymphoma tissues as well as in human cells with BPA exposure to explore module genes and construct the potential pathway for lymphomagenesis in response to BPA. This study provided evidence that BPA exposure resulted in disrupted cell cycle and DNA damage by activating CTNNB1, the initiator of the aberrant constructed CTNNB1-NFKB1-AR-IGF1-TWIST1 pathway, which may potentially lead to lymphomagenesis.
RESUMEN
Photodynamic therapy (PDT) employing exogenous photosensitizers is currently being approved for treatment of basal cell carcinoma (BCC). 2-(4-Aminophenyl)benzothiazoles (6) consist of chromophoric structure and absorb light in the UVA (315-400 nm). These results encouraged us to design and synthesize a diversity of 2-phenylbenzothiazoles (6). Studies on the apoptotic mechanism involved in photosensitive effects induced by UVA-activated 6 in BCC cells are carried out in the present article. 6-UVA-treated cells displayed several features of apoptosis, including an increase in the sub-G1 population, a significantly increased annexin V binding, and activation of caspase-3. 6-UVA induced a decrease in mitochondrial membrane potential (Deltapsi(mt)) and ATP via enhanced ROS generation and promoted phosphorylation of extracellular signal-regulated kinase (ERK) and p38 MAPK expression. These results suggest that 6-UVA elicits photosensitive effects in mitochondria processes which involve ERK and p38 activation, and ultimately lead to BCC cell apoptosis.
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Benzotiazoles/química , Benzotiazoles/farmacología , Carcinoma Basocelular/tratamiento farmacológico , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Benzotiazoles/síntesis química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Mitocondrias/efectos de la radiación , Fotoquimioterapia , Fármacos Fotosensibilizantes/síntesis química , Rayos UltravioletaRESUMEN
Niclosamide is an FDAapproved anthelmintic drug, and may elicit antineoplastic effects through direct STAT3 inhibition, which has been revealed in numerous human cancer cells. Chemotherapy is the standard treatment for advanced esophageal cancers, but also causes severe systemic side effects. The present study represents the first study evaluating the anticancer efficacy of niclosamide in esophageal cancers. Through western blot assay, it was demonstrated that niclosamide suppressed the STAT3 signaling pathway in esophageal adenocarcinoma cells (BE3) and esophageal squamous cell carcinoma cells (CE48T and CE81T). In addition, niclosamide inhibited cell proliferation as determined by 3(4,5dimethylthiazol2yl)5(3carboxymethoxyphenyl) 2(4sulfophenyl)-2Htetrazolium)5(3carboxymethoxyphenyl) 2(4sulfophenyl)2Htetrazolium (MTS) assay and soft agar colony forming assay, and induced cell apoptosis as determined by Annexin V and PI staining. The induction of p21 and G1 arrest of the cell cycle also was revealed in niclosamidetreated CE81T cells by qPCR and flow cytometric assays, respectively. Furthermore, in the combination analysis of niclosamide and chemotherapeutic agents by MTS assay, low IC50 values were detected in cells cotreated with niclosamide, with the exception of cisplatintreated CE81T cells. To confirm the results using an apoptosis assay, the apoptotic enhancement of niclosamide was only demonstrated in CE48T cells cotreated with 5FU, cisplatin, or paclitaxel, and in BE3 cells cotreated with paclitaxel, but not in CE81T cells. These findings indicate a future clinical application of niclosamide in esophageal cancers.
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Antineoplásicos/farmacología , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/metabolismo , Niclosamida/farmacología , Factor de Transcripción STAT3/metabolismo , Adenocarcinoma , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Sinergismo Farmacológico , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Fluorouracilo/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Paclitaxel/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
NK cell migration and activation are crucial elements of tumor immune surveillance. In mammary carcinomas, the number and function of NK cells is diminished, despite being positively associated with clinical outcome. MicroRNA-155 (miR-155) has been shown to be an important regulator of NK cell activation through its interaction with SHIP-1 downstream of inhibitory NK receptor signaling, but has not been explored in regard to NK cell migration. Here, we explored the migratory potential and function of NK cells in subcutaneous AT3 in mice lacking miR-155. Without tumor, these bic/miR-155-/- mice possess similar numbers of NK cells that exhibit comparable surface levels of cytotoxic receptors as NK cells from wild-type (WT) mice. Isolated miR-155-/- NK cells also exhibit equivalent cytotoxicity towards tumor targets in vitro compared to isolated WT control NK cells, despite overexpression of known miR-155 gene targets. NK cells isolated from miR-155-/- mice exhibit impaired F-actin polymerization and migratory capacity in Boyden-chamber assays in response chemokine (C-C motif) ligand 2 (CCL2). This migratory capacity could be normalized in the presence of SHIP-1 inhibitors. Of note, miR-155-/- mice challenged with mammary carcinomas exhibited heightened tumor burden which correlated with a lower number of tumor-infiltrating NK1.1+ cells. Our results support a novel, physiological role for SHIP-1 in the control of NK cell tumor trafficking, and implicate miR-155 in the regulation of NK cell chemotaxis, in the context of mammary carcinoma. This may implicate dysfunctional NK cells in the lack of tumor clearance in mice.
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Células Asesinas Naturales/metabolismo , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias Mamarias Experimentales/metabolismo , MicroARNs/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Quimiotaxis/genética , Femenino , Técnicas de Inactivación de Genes , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/genética , Transducción de Señal/genéticaRESUMEN
A series of novel thiobenzanilides is described. These compounds have been previously found to show strong biological activity such as antimycotic and antifungal actions. This is the first demonstration on the mechanism of the anticancer effect of thiobenzanilide agents (4a-c) on human melanoma A375 cells. The cytotoxic studies of compounds 4a-c on human melanoma A375 cells indicate thiobenzanilides induced higher cytotoxicity than nitrobenzanilides (3a-c). In addition, DNA flow cytometric analysis shows that 4a-c displays a significant G2/M phase arrest, which progresses to early apoptosis as detected by flow cytometry after double-staining with annexin V and propidium iodide (PI). Because cellular apoptosis is often preceded by the disruption of mitochondrial function, the assessment of mitochondrial function in 4a-c-treated cells is worthy of investigation. Our data revealed that treatment of A375 cells with 4a-c resulted in the loss of mitochondrial membrane potential (DeltaPsi(mt)), a reduction of ATP synthesis, increased reactive oxygen species (ROS) generation, and activation of caspase-3. Thus, we suggest that 4a-c agents are potent inducers of cell apoptosis in A375 cells.
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Anilidas/síntesis química , Anilidas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzamidas/síntesis química , Benzamidas/farmacología , Adenosina Trifosfato/metabolismo , Anilidas/química , Antineoplásicos/química , Benzamidas/química , Caspasa 3/efectos de los fármacos , Caspasa 3/metabolismo , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , ADN Mitocondrial/química , ADN Mitocondrial/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Citometría de Flujo/métodos , Fase G2/efectos de los fármacos , Humanos , Membranas Mitocondriales/efectos de los fármacos , Membranas Mitocondriales/metabolismo , Estructura Molecular , Especies Reactivas de Oxígeno/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
OBJECTIVES: Primary hepatic lymphoma is an uncommon cause of hepatic space-occupying lesions. METHODS: We describe the case of a 73-year-old man with primary hepatic lymphoma, who presented with a low-grade fever and lower limb weakness which had progressed in the past 2 months. RESULTS: Abdominal ultrasound and computed tomography showed multiple small hepatic tumors. Echo-guided biopsy of the hepatic tumor demonstrated primary hepatic diffuse large B cell lymphoma. Moreover, bone marrow was uninvolved, but the bone marrow smear disclosed hemophagocytosis, which is uncommon in diffuse large B cell lymphoma. Chemotherapy with bendamustine and rituximab treatment was initiated with a dramatic response: hepatic tumors markedly shrank in size shown by follow-up computed tomography and the patient returned to his normal life. Nevertheless, the response was sustained for only 8 months. Finally, the disease resisted further chemotherapy and this patient died of a severe Klebsiella pneumoniae infection. CONCLUSION: Chemotherapy with bendamustine and rituximab has shown a dramatic, but not durable, response in the present case with old age and multiple comorbidities.
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BACKGROUND: Robo4 is involved in hematopoietic stem/progenitor cell homeostasis and essential for tumor angiogenesis. Expression of Robo4 was recently found in solid tumors and leukemia stem cells. However, the clinical implications of Robo4 expression in patients with acute myeloid leukemia (AML) remain unclear. METHODS: We investigated the clinical and prognostic relevance of mRNA expression of Robo4 in bone marrow (BM) mononuclear cells from 218 adult patients with de novo AML. We also performed immunohistochemical staining to assess the Robo4 protein expression in the BM biopsy specimens from 30 selected AML patients in the cohort. RESULTS: Higher Robo4 expression was closely associated with lower white blood cell counts, expression of HLA-DR, CD13, CD34 and CD56 on leukemia cells, t(8;21) and ASXL1 mutation, but negatively correlated with t(15;17) and CEBPA mutation. Compared to patients with lower Robo4 expression, those with higher expression had significantly shorter disease-free survival (DFS) and overall survival (OS). This result was confirmed in an independent validation cohort. Furthermore, multivariate analyses showed that higher Robo4 expression was an independent poor prognostic factor for DFS and OS in total cohort and patients with intermediate-risk cytogenetics, irrespective of age, WBC count, karyotype, and mutation status of NPM1/FLT3-ITD, and CEBPA. CONCLUSIONS: BM Robo4 expression can serve as a new biomarker to predict clinical outcomes in AML patients and Robo4 may serve as a potential therapeutic target in patients with higher Robo4 expression.
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Leucemia Mieloide Aguda/genética , Receptores de Superficie Celular/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Médula Ósea/metabolismo , Médula Ósea/patología , Aberraciones Cromosómicas , Femenino , Expresión Génica , Humanos , Estimación de Kaplan-Meier , Cariotipo , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Mutación , Nucleofosmina , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Superficie Celular/metabolismo , Inducción de Remisión , Resultado del Tratamiento , Adulto JovenRESUMEN
Superparamagnetic iron oxide (SPIO) nanoparticles are very useful in cell imaging; meanwhile, however, biosafety concerns associated with their use, especially on therapeutic stem cells, have arisen. Most studies of biosafety issues focus on whether the nanoparticles have deleterious effects. Here, we report that Ferucarbotran, an ionic SPIO, is not toxic to human mesenchymal stem cells (hMSCs) under the conditions of these experiments but instead increases cell growth. Ferucarbotran-promoted cell growth is due to its ability to diminish intracellular H2O2 through intrinsic peroxidase-like activity. Also, Ferucarbotran can accelerate cell cycle progression, which may be mediated by the free iron (Fe) released from lysosomal degradation and involves the alteration of Fe on the expression of the protein regulators of the cell cycle.