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mRNA biogenesis in the eukaryotic nucleus is a highly complex process. The numerous RNA processing steps are tightly coordinated to ensure that only fully processed transcripts are released from chromatin for export from the nucleus. Here, we present the hypothesis that fission yeast Dbp2, a ribonucleoprotein complex (RNP) remodelling ATPase of the DEAD-box family, is the key enzyme in an RNP assembly checkpoint at the 3'-end of genes. We show that Dbp2 interacts with the cleavage and polyadenylation complex (CPAC) and localises to cleavage bodies, which are enriched for 3'-end processing factors and proteins involved in nuclear RNA surveillance. Upon loss of Dbp2, 3'-processed, polyadenylated RNAs accumulate on chromatin and in cleavage bodies, and CPAC components are depleted from the soluble pool. Under these conditions, cells display an increased likelihood to skip polyadenylation sites and a delayed transcription termination, suggesting that levels of free CPAC components are insufficient to maintain normal levels of 3'-end processing. Our data support a model in which Dbp2 is the active component of an mRNP remodelling checkpoint that licenses RNA export and is coupled to CPAC release.
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ARN Helicasas DEAD-box , Ribonucleoproteínas , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Ribonucleoproteínas/metabolismo , Ribonucleoproteínas/genética , ARN Helicasas DEAD-box/metabolismo , ARN Helicasas DEAD-box/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Poliadenilación , ARN Mensajero/metabolismo , ARN Mensajero/genética , Factores de Escisión y Poliadenilación de ARNm/metabolismo , Factores de Escisión y Poliadenilación de ARNm/genética , Cromatina/metabolismo , ARN de Hongos/metabolismo , ARN de Hongos/genética , Núcleo Celular/metabolismoRESUMEN
Preclinical studies imply that surgery triggers inflammation that may entail tumor outgrowth and metastasis. The potential impact of surgery-induced inflammation in human pancreatic cancer is insufficiently explored. This study included 17 patients with periampullary cancer [pancreatic ductal adenocarcinoma (PDAC) n = 14, ampullary carcinoma n = 2, cholangiocarcinoma n = 1] undergoing major pancreatic cancer surgery with curative intent. We analyzed the potential impact of preoperative and postoperative immune phenotypes and function on postoperative survival with >30 months follow-up. The surgery entailed prompt expansion of monocytic myeloid-derived suppressor cells (M-MDSC) that generated NOX2-derived reactive oxygen species (ROS). Strong induction of immunosuppressive M-MDSC after surgery predicted poor postoperative survival and coincided with reduced functionality of circulating natural killer (NK) cells. The negative impact of surgery-induced M-MDSC on survival remained significant in separate analysis of patients with PDAC. M-MDSC-like cells isolated from patients after surgery significantly suppressed NK cell function ex vivo, which was reversed by inhibition of NOX2-derived ROS. High NOX2 subunit expression within resected tumors from patients with PDAC correlated with poor survival whereas high expression of markers of cytotoxic cells associated with longer survival. The surgery-induced myeloid inflammation was recapitulated in vivo in a murine model of NK cell-dependent metastasis. Surgical stress thus induced systemic accumulation of M-MDSC-like cells and promoted metastasis of NK cell-sensitive tumor cells. Genetic or pharmacologic suppression of NOX2 reduced surgery-induced inflammation and distant metastasis in this model. We propose that NOX2-derived ROS generated by surgery-induced M-MDSC may be targeted for improved outcome after pancreatic cancer surgery. SIGNIFICANCE: Pancreatic cancer surgery triggered pronounced accumulation of NOX2+ myeloid-derived suppressor cells that inhibited NK cell function and negatively prognosticated postoperative patient survival. We propose the targeting of M-MDSC as a conceivable strategy to reduce postoperative immunosuppression in pancreatic cancer.
Asunto(s)
Células Supresoras de Origen Mieloide , NADPH Oxidasa 2 , Neoplasias Pancreáticas , Especies Reactivas de Oxígeno , Femenino , Humanos , Masculino , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/mortalidad , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/inmunología , NADPH Oxidasa 2/metabolismo , NADPH Oxidasa 2/genética , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Periodo Posoperatorio , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Red cabbage, a highly nutritious cool-season cruciferous vegetable, is rich in anthocyanins; however, the instability of anthocyanins during processing and storage poses challenges. This study aimed to optimize the foam-mat drying process of red cabbage juice (RCJ) with a high anthocyanin content using a hybrid microwave hot air-drying system (MW-HAD) as a dehydration method compared to conventional techniques (HAD) using response surface methodology (RSM). Additionally, the produced red cabbage juice powder (RCJP) was used to enrich the pancake formulation. The developed model exhibited a high degree of reliability with optimal conditions and was determined for microwave power, temperature, foaming agent carboxymethylcellulose (CMC), and egg white protein (EWP) as 360 W, 60°C, 0.3%, and 1.2%, respectively. Moisture content (%) was decreased from 93.47 to 8.62 at optimum process conditions. In comparison to the control (60°C), foam mat drying with the MW-HAD hybrid system reduced the drying time (DT) by more than 90.9% due to the higher drying rate, while many physicochemical properties, especially total anthocyanin content (TAC), were better preserved. Utilization of RCJP in the production of anthocyanin-rich functional pancakes resulted in enhanced nutritional qualities compared to control pancakes with increased protein (35.07%), total phenolic (75.8%), dietary fiber (82.9%), and anthocyanin content (100%). In conclusion, MW-HAD demonstrates significant potential as a promising drying method to reduce the DT and preserve the physicochemical properties of RCJP. Furthermore, the application of the optimized RCJP in anthocyanin-rich functional pancakes highlights improved nutritional qualities, making a substantial contribution to the advancement of functional foods.
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Avocado tree pruning activities generate a substantial amount of residual biomass, which includes different parts of the plant, such as leaves, twigs, branches, and small fruits. This study aimed to investigate the impact of different green extraction methods of microwave-assisted extraction (MAE) and ohmic heating-assisted extraction (OHAE) for the phenolic extraction of avocado leaves based on a statistical approach, central composite design (CCD), and response surface methodology (RSM). Water was preferred using as an environmentally and health-friendly solvent for both methods. The phenolic composition, antioxidant activity, and antidiabetic potential of the extracts were identified and comparatively assessed. The developed models exhibited a high degree of reliability with optimal conditions for OHAE and MAE, which were determined as 9.38 V/cm voltage gradient, 6 min extraction time, at 60°C, 5 min, and 1 g dried leaf/100 mL water. Epicatechin was identified as the primary phenolic compound in OHAE extracts, while chlorogenic acid was the dominant compound in MAE extracts. The extracts obtained from OHAE and MAE were tested for their ability to inhibit α-glucosidase activity, with IC50 (mg/mL) values of 0.85 and 1.14, respectively. The DPPH radicals scavenging activity (IC50 mg/L) of OHAE and MAE were detected as 2.96 and 3.41, respectively. In conclusion, both methods yielded extracts rich in polyphenols that displayed high antioxidant activity, but OHAE was found to be superior to MAE in terms of TPC, DPPH, and antidiabetic activities. The results of this study have the potential to make significant contributions toward promoting the principles of a circular economy by facilitating the valorization of the avocado pruning waste.
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The significant protein and dietary fiber content of cold-pressed pumpkin (PSF) and okra (OSF) seed byproducts are well-known. However, their impact on noodles' nutritional quality has never been studied. For the first time, noodle formulation was developed employing a genetic algorithm in the R programming language to achieve the most optimal sensory attributes as well as nutritional composition, color, cooking, and textural properties. The optimized noodle formulation was detected for OSF, PSF, gluten-free flour, salt, and egg with the following amounts: 11.5 g, 87.0 g, 0.9 g, 0.6 g, and 40 g, respectively, with 10.5 mL of water. The total protein (TP%), total fat (TF%), total carbohydrate (TC%), total dietary fiber content (TDF%), ash (%), total phenolic content (TPC mg GAE/100 g), and ABTS (%) of PSF were found to be 39%, 17%, 7%, 18%, 3%, 19%, and 48%, respectively, whereas for OSF, 33%, 8%, 21%, 32%, 5%, 16%, and 38%, respectively, were detected. In addition, TP (42.88%), TF (15.6%), ash (5.68%), TDF (40.48%), TPC (25.5 mg GAE/100 g), and ABTS (70%) values were obtained for the noodles. Consequently, the valorization of the cold oil press industry's byproducts may be used as ingredients that add high value to gluten-free protein and fiber-rich noodle production, and they may gain interest from both processors and consumers.
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To date, information on the polyphenolic composition of Kluai Hin banana peel and pulp and the potential antidiabetic activity of its major active compounds is limited. This study aimed to identify polyphenols in extracts of fresh and freeze-dried Kluai Hin banana peel and pulp (methanol:water; M:W, 80:20 for flavonoids and acetone:water:acetic acid; A:W:A, 50:49:1 for phenolic acids) by RP-HPLC-DAD and HPLC-ESI-QTOF-MS. Additionally, inhibition of α-amylase and α-glucosidase activities was investigated with crude extracts from Kluai Hin banana peel and pulp, and compared with its major polyphenols ((+)-catechin, (-)-epicatechin and gallic acid) and the antidiabetic drug acarbose. (-)-Gallocatechin was the most abundant polyphenol and was detected in all fresh and freeze-dried pulp and peel extracts by RP-HPLC-DAD. Furthermore, unidentified polyphenol peaks of Kluai Hin were further explored by HPLC-ESI-QTOF-MS. The A:W:A fresh peel extract contained more total phenolic content (811.56 mg GAE/100 g) than the freeze-dried peel (565.03 mg GAE/100 g). A:W:A extraction of the fresh and freeze-dried peel of exhibited IC50 values for α-amylase activity 2.66 ± 0.07 mg/ml and 2.97 ± 0.00 mg/ml, respectively, but its inhibitory activity was lower than acarbose (IC50 = 0.25 ± 0.01 mg/ml). Peel extracts inhibited α-glucosidase activity, whereas pulp extracts had no effect. In addition, all standards, except gallocatechin, activated α-amylase activity, while, gallocatechin inhibited α-glucosidase activity better than acarbose. Therefore, we propose a further investigation into the use of Kluai Hin banana peel as a potential functional food for the management of postprandial glycaemic response to reduce diabetes risk and in the management of diabetes with a commercial drug.
Asunto(s)
Musa , Polifenoles , Acarbosa/farmacología , Antioxidantes/farmacología , Cromatografía Líquida de Alta Presión , Hipoglucemiantes/farmacología , Extractos Vegetales/farmacología , Polifenoles/análisis , Polifenoles/farmacología , Agua , alfa-Amilasas , alfa-GlucosidasasRESUMEN
Gluten-free products have been developed due to increasing consumer demand. The improvement of the sensory quality and nutritional value of these products may support functional food development and provide health benefits. The purpose of this study was to develop a gluten-free waffle formulation with Riceberry rice flour by replacing the sucrose with maltitol and palm sugar powder. Evaluations of the sensory acceptability of these products and the blood glucose levels of healthy volunteers after consuming Riceberry and wheat flour waffles were carried out. The glycemic responses of the volunteers to the Riceberry and wheat flour waffles at 0, 15, 30, 45, 60, 90, 120, 150, and 180 min were monitored. In addition, the glycemic index of the products was calculated. The finding revealed that replacing sugar with 50% (w/w of total sugar) palm sugar powder and 50% maltitol was the most acceptable formulation that received the highest acceptability scores in terms of overall acceptability and texture. The blood glucose levels of both Riceberry waffle and wheat flour were not significantly different. The glycemic index of Riceberry waffle and wheat flour waffle were 94.73 ± 7.60 and 91.96 ± 6.93, respectively. Therefore, Riceberry waffle could be used as an alternative gluten-free product for celiac patients, but not for diabetic patients.
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Interleukin-1 beta (IL-1ß), a pro-inflammatory cytokine, has been ascribed a role in the expansion of myeloid progenitors in acute myeloid leukemia (AML) and in promoting myeloid cell-induced suppression of lymphocyte-mediated immunity against malignant cells. This study aimed at defining the potential impact of IL-1ß in the post-remission phase of AML patients receiving immunotherapy for relapse prevention in an international phase IV trial of 84 patients (ClinicalTrials.gov; NCT01347996). Consecutive serum samples were collected from AML patients in first complete remission (CR) who received cycles of relapse-preventive immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2). Low IL-1ß serum levels before and after the first HDC/IL-2 treatment cycle favorably prognosticated leukemia-free survival and overall survival. Serum levels of IL-1ß were significantly reduced in patients receiving HDC/IL-2. HDC also reduced the formation of IL-1ß from activated human PBMCs in vitro. Additionally, high serum levels of the IL-1 receptor antagonist IL-1RA were associated with favorable outcome, and AML patients with low IL-1ß along with high IL-1RA levels were strikingly protected against leukemic relapse. Our results suggest that strategies to target IL-1ß might impact on relapse risk and survival in AML.
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Interleucina-2 , Leucemia Mieloide Aguda , Humanos , Inmunoterapia , Interleucina-1beta , Leucemia Mieloide Aguda/tratamiento farmacológico , RecurrenciaRESUMEN
The formation of reactive oxygen species (ROS) by the myeloid cell NADPH oxidase NOX2 is critical for the destruction of engulfed microorganisms. However, recent studies imply that ROS, formed by NOX2+ myeloid cells in the malignant microenvironment, exert multiple actions of relevance to the growth and spread of neoplastic cells. By generating ROS, tumor-infiltrating myeloid cells and NOX2+ leukemic myeloid cells may thus (i) compromise the function and viability of adjacent cytotoxic lymphocytes, including natural killer (NK) cells and T cells, (ii) oxidize DNA to trigger cancer-promoting somatic mutations, and (iii) affect the redox balance in cancer cells to control their proliferation and survival. Here, we discuss the impact of NOX2-derived ROS for tumorigenesis, tumor progression, regulation of antitumor immunity, and metastasis. We propose that NOX2 may be a targetable immune checkpoint in cancer.
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Carcinogénesis , Leucemia , Mutación , NADPH Oxidasa 2 , Proteínas de Neoplasias , Especies Reactivas de Oxígeno , Microambiente Tumoral , Animales , Carcinogénesis/genética , Carcinogénesis/inmunología , Carcinogénesis/metabolismo , Humanos , Células Asesinas Naturales/enzimología , Células Asesinas Naturales/inmunología , Leucemia/enzimología , Leucemia/genética , Leucemia/inmunología , Linfocitos Infiltrantes de Tumor/enzimología , Linfocitos Infiltrantes de Tumor/inmunología , Células Mieloides/enzimología , Células Mieloides/inmunología , NADPH Oxidasa 2/genética , NADPH Oxidasa 2/inmunología , NADPH Oxidasa 2/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Proteínas de Neoplasias/metabolismo , Especies Reactivas de Oxígeno/inmunología , Especies Reactivas de Oxígeno/metabolismo , Linfocitos T/enzimología , Linfocitos T/inmunología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
The phosphatidylinositol-4,5-bisphosphate-3 kinase-δ (PI3Kδ) inhibitor idelalisib, used alone or in combination with anti-CD20, is clinically efficacious in B-cell lymphoma and chronic lymphocytic leukemia (CLL) by promoting apoptosis of malignant B cells. PI3K regulates the formation of reactive oxygen species (ROS) by the myeloid NADPH oxidase NOX2, but the role of PI3Kδ in myeloid cell-induced immunosuppression is unexplored. We assessed the effects of idelalisib on the spontaneous and IgG antibody-induced ROS production by human monocytes, on ROS-induced cell death of human natural killer (NK) cells, and on tumor cell clearance in an NK cell-dependent mouse model of metastasis. Idelalisib potently and efficiently inhibited the formation of NOX2-derived ROS from monocytes and rescued NK cells from ROS-induced cell death. Idelalisib also promoted NK cell cytotoxicity against anti-CD20-coated primary human CLL cells and cultured malignant B cells. Experiments using multiple PI3K inhibitors implicated the PI3Kδ isoform in regulating NOX2-induced ROS formation and immunosuppression. In B6 mice, systemic treatment with idelalisib significantly reduced the formation of lung metastases from intravenously injected melanoma cells but did not affect metastasis in B6.129S6-Cybbtm1Din (Nox2 -/-) mice or in NK cell-deficient mice. Our results imply that idelalisib rescues NK cells from NOX2/ROS-dependent immunosuppression and thus exerts antineoplastic efficacy beyond B-cell inhibition.
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Antineoplásicos/farmacología , Células Asesinas Naturales/inmunología , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Melanoma Experimental/tratamiento farmacológico , NADPH Oxidasa 2/genética , Purinas/farmacología , Quinazolinonas/farmacología , Animales , Antígenos CD20/inmunología , Humanos , Terapia de Inmunosupresión , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/patología , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/metabolismo , NADPH Oxidasa 2/inmunología , Metástasis de la Neoplasia , Inhibidores de las Quinasa Fosfoinosítidos-3 , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Large RNA-binding complexes play a central role in gene expression and orchestrate production, function, and turnover of mRNAs. The accuracy and dynamics of RNA-protein interactions within these molecular machines are essential for their function and are mediated by RNA-binding proteins (RBPs). Here, we show that fission yeast whole-cell poly(A)+ RNA-protein crosslinking data provide information on the organization of RNA-protein complexes. To evaluate the relative enrichment of cellular RBPs on poly(A)+ RNA, we combine poly(A)+ RNA interactome capture with a whole-cell extract normalization procedure. This approach yields estimates of in vivo RNA-binding activities that identify subunits within multiprotein complexes that directly contact RNA. As validation, we trace RNA interactions of different functional modules of the 3' end processing machinery and reveal additional contacts. Extending our analysis to different mutants of the RNA exosome complex, we explore how substrate channeling through the complex is affected by mutation. Our data highlight the central role of the RNA helicase Mtl1 in regulation of the complex and provide insights into how different components contribute to engagement of the complex with substrate RNA. In addition, we characterize RNA-binding activities of novel RBPs that have been recurrently detected in the RNA interactomes of multiple species. We find that many of these, including cyclophilins and thioredoxins, are substoichiometric RNA interactors in vivo. Because RBPomes show very good overall agreement between species, we propose that the RNA-binding characteristics we observe in fission yeast are likely to apply to related proteins in higher eukaryotes as well.
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ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo , Schizosaccharomyces/genética , Ciclofilinas/metabolismo , Complejo Multienzimático de Ribonucleasas del Exosoma/genética , Mutación , Subunidades de Proteína/metabolismo , Motivos de Unión al ARN , Proteínas de Unión al ARN/química , Ribosomas/metabolismo , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/química , Transcripción Genética , Factores de Escisión y Poliadenilación de ARNm/metabolismoRESUMEN
OBJECTIVE: To identify the characteristics of retracted publications in rehabilitation and sport sciences journals. DATA SOURCES: The Web of Science, PubMed, and Retraction Watch databases were searched from inception to August 2019. STUDY SELECTION: Retracted publications published in rehabilitation or sport sciences journals, indexed in the Science Citation Index Expanded (SCIE) and Social Sciences Citation Index (SSCI) were included. DATA EXTRACTION: One author extracted the data. Two other authors checked the data. DATA SYNTHESIS: A total of 37 and 52 retracted publications and their retraction notices were identified for rehabilitation and sport sciences, respectively. The majority of retracted publications (68% of all retracted papers in rehabilitation and 54% of all retracted papers in sport sciences) were published in the past decade. Retracted publications in rehabilitation and sport sciences were published in 21 and 22 different journals and originated from 18 and 21 different countries, respectively. The full-text of the retracted publications was available with a retraction watermark or note for 59% of cases in rehabilitation and 58% in sport sciences. The reasons for the retractions were more often attributed to misconduct (79% and 61%) than to honest error (21% and 39%) in rehabilitation and sport sciences, respectively. However, a reason was not stated for 15% of the publications. The median time interval between publication and retraction was 622 days in rehabilitation and 607 days in sport sciences publications. CONCLUSIONS: The total number of retracted publications in rehabilitation and sport sciences journals was small. The retracted publications have been published in a variety of rehabilitation and sport sciences journals and came from different countries across the world. Several retracted publications and retraction notices failed to adhere to The Committee on Publication Ethics guidelines in the handling of full-text (retain with a watermark or note) or stating the underlying reasons for the retraction.
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Publicaciones Periódicas como Asunto/estadística & datos numéricos , Medicina Física y Rehabilitación/estadística & datos numéricos , Retractación de Publicación como Asunto , Medicina Deportiva/estadística & datos numéricos , HumanosRESUMEN
Hyperthermic isolated limb perfusion (ILP) with high-dose melphalan is a treatment option for melanoma patients with metastasis confined to limbs (in-transit metastasis). The therapy entails a complete response (CR) rate of 50-70%. Cellular immunity is proposed to impact on the clinical efficacy of ILP, but the detailed aspects of ILP-induced immune activation remain to be explored. For this study, we explored the potential role of interferon-stimulated gene (ISG) products, including CXCL10, CCL2, PD-L2 and IFN-γ along with expression of their cognate receptors CXCR3, CCR4, CCR5 and PD-1 on lymphocytes, for the clinical efficacy of ILP. Patients with high serum levels of CXCL10, CCL2, PD-L2 and IFN-γ were more likely to achieve CR after ILP. Additionally, the expression of CXCR3, CCR4 and CCR5 on T cells and/or natural killer (NK) cells was enhanced by ILP. Peripheral blood mononuclear cells (PBMCs) secreted high levels of CXCL10, CCL2 and IFN-γ in response to co-culture with melphalan-exposed melanoma cells in vitro. Activated T cells migrated toward supernatants from these co-cultures. Furthermore, melphalan-exposed melanoma cells triggered upregulation of CXCR3, CCR4, CCR5 and PD-1 on co-cultured T cells and/or NK cells. Our results suggest that constituents released from melphalan-exposed melanoma cells stimulate the ISG axis with ensuing formation of chemokines and upregulation of chemokine receptor expression on anti-neoplastic immune cells, which may contribute in ILP-induced tumor regression.
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Hipertermia Inducida , Melanoma , Protocolos de Quimioterapia Combinada Antineoplásica , Quimioterapia del Cáncer por Perfusión Regional , Humanos , Interferones/uso terapéutico , Leucocitos Mononucleares , Melanoma/tratamiento farmacológico , Melfalán/farmacología , Perfusión , Factor de Necrosis Tumoral alfa/uso terapéuticoRESUMEN
Phosphoinositide 3-kinases (PI3Ks) and their downstream proteins constitute a signaling pathway that is involved in both normal cell growth and malignant transformation of cells. Under physiological conditions, PI3K signaling regulates various cellular functions such as apoptosis, survival, proliferation, and growth, depending on the extracellular signals. A deterioration of these extracellular signals caused by mutational damage in oncogenes or growth factor receptors may result in hyperactivation of this signaling cascade, which is recognized as a hallmark of cancer. Although higher activation of PI3K pathway is common in many types of cancer, it has been therapeutically targeted for the first time in chronic lymphocytic leukemia (CLL), demonstrating its significance in B-cell receptor (BCR) signaling and malignant B-cell expansion. The biological activity of the PI3K pathway is not only limited to cancer cells but is also crucial for many components of the tumor microenvironment, as PI3K signaling regulates cytokine responses, and ensures the development and function of immune cells. Therefore, the success or failure of the PI3K inhibition is strongly related to microenvironmental stimuli. In this review, we outline the impacts of PI3K inhibition on the tumor microenvironment with a specific focus on CLL. Acknowledging the effects of PI3K inhibitor-based therapies on the tumor microenvironment in CLL can serve as a rationale for improved drug development, explain treatment-associated adverse events, and suggest novel combinatory treatment strategies in CLL.
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Antineoplásicos/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/inmunología , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Animales , Antineoplásicos/farmacología , Humanos , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Transducción de Señal/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
PURPOSE: To estimate the risk for brain metastases in patients with ovarian cancer using real-world data, and assess whether BRCA mutations increase that risk. METHODS: This retrospective study included 4515 patients diagnosed with ovarian cancer between January 1, 2011, and January 31, 2018, from the Flatiron Health database, a longitudinal, demographically, and geographically diverse database derived from electronic health records in the United States. RESULTS: Forty-six (1%) patients were diagnosed with brain metastases after being diagnosed with ovarian cancer. Of 4515 patients with ovarian cancer, 10% had a known BRCA mutation, 37% had BRCA wildtype (BRCAwt), and the BRCA status of the remaining 51% was unknown/untested. Brain metastases were observed in 3% of patients with BRCA mutations compared with 0.6% of those with BRCAwt. The Kaplan-Meier estimate for the proportion of patients with brain metastases within 5â¯years of diagnosis was 5.7% in the population with BRCA mutations compared with 1.4% in those with BRCAwt (hazard ratio 4.44; 95% confidence interval, 1.97, 10.00; Pâ¯<â¯0.0001). These data demonstrate that patients with a BRCA mutation had a significantly higher risk for brain metastases than those without. CONCLUSION: Despite being a rare manifestation of ovarian cancer, the possibility of developing brain metastases should be considered in these patients, especially in patients with a BRCA mutation. The availability of new therapeutic options that may prolong overall survival and may not cross the blood-brain barrier could also lead to an increase in brain metastases in patients with ovarian cancer.
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Neoplasias Encefálicas/secundario , Genes BRCA1 , Genes BRCA2 , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Anciano , Bases de Datos Factuales , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Mutación , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Mutations leading to constitutive RAS activation contribute in myeloid leukemogenesis. RAS mutations in myeloid cells are accompanied by excessive formation of reactive oxygen species (ROS), but the source of ROS and their role for the initiation and progression of leukemia have not been clearly defined. To determine the role of NOX2-derived ROS in RAS-driven leukemia, double transgenic LSL-KrasG12D × Mx1-Cre mice expressing oncogenic KRAS in hematopoietic cells (M-KrasG12D) were treated with Nα-methyl-histamine (NMH) that targeted the production of NOX2-derived ROS in leukemic cells by agonist activity at histamine H2 receptors. M-KrasG12D mice developed myeloid leukemia comprising mature CD11b+Gr1+ myeloid cells that produced NOX2-derived ROS. Treatment of M-KrasG12D mice with NMH delayed the development of myeloproliferative disease and prolonged survival. In addition, NMH-treated M-KrasG12D mice showed reduction of intracellular ROS along with reduced DNA oxidation and reduced occurence of double-stranded DNA breaks in myeloid cells. The in vivo expansion of leukemia was markedly reduced in triple transgenic mice where KRAS was expressed in hematopoietic cells of animals with genetic NOX2 deficiency (Nox2-/- × LSL-KrasG12D × Mx1-Cre). Treatment with NMH did not alter in vivo expansion of leukemia in these NOX2-deficient transgenic mice. We propose that NOX2-derived ROS may contribute to the progression of KRAS-induced leukemia and that strategies to target NOX2 merit further evaluation in RAS-mutated hematopoietic cancer.
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Hematopoyesis/genética , Trastornos Mieloproliferativos/genética , NADPH Oxidasa 2/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Animales , Proliferación Celular , Transformación Celular Neoplásica/genética , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , Mutación , Trastornos Mieloproliferativos/patología , Estrés Oxidativo/genética , Especies Reactivas de Oxígeno/metabolismo , Análisis de SupervivenciaRESUMEN
Myeloid cell NADPH oxidase isoform 2 (NOX2) generates reactive oxygen species (ROS) that participate in defense against microbial pathogens. Humans with compromised NOX2-mediated ROS formation develop chronic granulomatous disease characterized by recurrent bacterial and fungal infections. Additionally, impaired NOX2 function entails hyperactive lymphocytes and autoimmunity in humans and in murine models. The impact of NOX2 and ROS on cancer development is only partly explored. Recent research published in the Journal of Pathology showed that genetic depletion of any of the NOX2 subunits Cyba, Cybb, Ncf1, Ncf2 and Ncf4 reduced the formation of lung metastases following intravenous injection of murine tumor cells. These findings, together with the role of NOX2 in maintaining self-tolerance, imply that NOX2 is a targetable immune checkpoint in cancer. In particular, the possibility of modulating NOX2 to improve lymphocyte-mediated control of metastatic cells merits further investigation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Asunto(s)
NADPH Oxidasas/genética , Neoplasias , Animales , Autoinmunidad , Granuloma , Humanos , Glicoproteínas de Membrana/genética , Ratones , Especies Reactivas de Oxígeno , Reino UnidoRESUMEN
In patients with acute myeloid leukemia (AML), treatment with histamine dihydrochloride (HDC) and low-dose IL-2 (HDC/IL-2) in the post-chemotherapy phase has been shown to reduce the incidence of leukemic relapse. The clinical benefit of HDC/IL-2 is pronounced in monocytic forms of AML, where the leukemic cells express histamine type 2 receptors (H2R) and the NAPDH oxidase-2 (NOX2). HDC ligates to H2Rs to inhibit NOX2-derived formation of reactive oxygen species, but details regarding the anti-leukemic actions of HDC remain to be elucidated. Here, we report that human NOX2+ myelomonocytic/monocytic AML cell lines showed increased expression of maturation markers along with reduced leukemic cell proliferation after exposure to HDC in vitro. These effects of HDC were absent in corresponding leukemic cells genetically depleted of NOX2 (NOX2-/-). We also observed that exposure to HDC altered the expression of genes involved in differentiation and cell cycle progression in AML cells and that these effects required the presence of NOX2. HDC promoted the differentiation also of primary monocytic, but not non-monocytic, AML cells in vitro. In a xenograft model, immunodeficient NOG mice were inoculated with wild-type or NOX2-/- human monocytic AML cells and treated with HDC in vivo. The administration of HDC reduced the in vivo expansion of NOX2+/+, but not of NOX2-/- human monocytic AML cells. We propose that NOX2 may be a conceivable target in the treatment of monocytic AML.
RESUMEN
Human cytomegalovirus (CMV) infection is reported to promote NK cell differentiation and education. The CMV-induced generation of highly differentiated adaptive-like NK cells has been proposed to affect favorably on the maintenance of remission in patients with acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT). The impact of CMV infection and adaptive-like NK cells on relapse and survival of patients with AML not receiving allo-SCT remains unknown. We assayed CMV IgG serostatus to determine past CMV infection in 81 nontransplanted AML patients who were receiving relapse-prevention immunotherapy comprising histamine dihydrochloride and low-dose interleukin-2 (HDC/IL2; NCT01347996). CMV seropositivity correlated negatively with leukemia-free and overall survival of patients receiving HDC/IL2, but did not correlate with outcomes in a contemporary control cohort. Analysis of outcome after stratification of patients based on concordant or discordant killer immunoglobulin-like receptor (KIR) and HLA genotypes implied that the negative impact of CMV seropositivity was restricted to patients lacking a ligand to inhibitory KIRs (iKIR). Previous CMV infection was also associated with fewer NK cells expressing only nonself iKIRs (NS-iKIR). We propose that CMV-driven NK cell education depletes the population of NS-iKIR NK cells, which in turn reduces the clinical benefit of relapse-preventive immunotherapy in AML. Cancer Immunol Res; 6(9); 1110-9. ©2018 AACR.