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1.
Blood ; 144(8): 853-866, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-38820588

RESUMEN

ABSTRACT: In this last decade, a deeper understanding of the pathophysiology of hereditary red cell disorders and the development of novel classes of pharmacologic agents have provided novel therapeutic approaches to thalassemias, sickle cell disease (SCD), and other red cell disorders. Here, we analyze and discuss the novel therapeutic options according to their targets, taking into consideration the complex process of erythroid differentiation, maturation, and survival of erythrocytes in the peripheral circulation. We focus on active clinical exploratory and confirmatory trials on thalassemias, SCD, and other red cell disorders. Beside ß-thalassemia and SCD, we found that the development of new therapeutic strategies has allowed for the design of clinic studies for hereditary red cell disorders still lacking valuable therapeutic alternative such as α-thalassemias, congenital dyserythropoietic anemia, or Diamond-Blackfan anemia. In addition, reduction of heme synthesis, which can be achieved by the repurposed antipsychotic drug bitopertin, might affect not only hematological disorders but multiorgan diseases such as erythropoietic protoporphyria. Finally, our review highlights the current state of therapeutic scenarios, in which multiple indications targeting different red cell disorders are being considered for a single agent. This is a welcome change that will hopefully expand therapeutic option for patients affected by thalassemias, SCD, and other red cell disorders.


Asunto(s)
Anemia de Células Falciformes , Talasemia , Humanos , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/complicaciones , Talasemia/tratamiento farmacológico , Talasemia/terapia , Eritrocitos/metabolismo , Eritrocitos/patología
2.
Haematologica ; 109(6): 1918-1932, 2024 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-38105727

RESUMEN

Inflammatory vasculopathy is critical in sickle cell disease (SCD)-associated organ damage. An imbalance between pro-inflammatory and pro-resolving mechanisms in response to different triggers such as hypoxia/reoxygenation or infections has been proposed to contribute to the progression of SCD. Administration of specialized pro-resolving lipid mediators may provide an effective therapeutic strategy to target inflammatory vasculopathy and to modulate inflammatory response. Epeleuton (15 hydroxy eicosapentaenoic acid ethyl ester) is a novel, orally administered, second-generation ω-3 fatty acid with a favorable clinical safety profile. In this study we show that epeleuton re-programs the lipidomic pattern of target organs for SCD towards a pro-resolving pattern. This protects against systemic and local inflammatory responses and improves red cell features, resulting in reduced hemolysis and sickling compared with that in vehicle-treated SCD mice. In addition, epeleuton prevents hypoxia/reoxygenation-induced activation of nuclear factor-κB with downregulation of the NLRP3 inflammasome in lung, kidney, and liver. This was associated with downregulation of markers of vascular activation in epeleuton-treated SCD mice when compared to vehicle-treated animals. Collectively our data support the potential therapeutic utility of epeleuton and provide the rationale for the design of clinical trials to evaluate the efficacy of epeleuton in patients with SCD.


Asunto(s)
Anemia de Células Falciformes , Modelos Animales de Enfermedad , Daño por Reperfusión , Animales , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/metabolismo , Anemia de Células Falciformes/patología , Anemia de Células Falciformes/complicaciones , Ratones , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/farmacología , Ácidos Grasos Omega-3/farmacología , Humanos , Masculino , Hipoxia/metabolismo , Hipoxia/tratamiento farmacológico
4.
Eur J Clin Invest ; 48(2): e12870, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29235098

RESUMEN

BACKGROUND: The liver hormone hepcidin regulates iron homoeostasis that is often altered in hepatocellular carcinoma (HCC). Epigenetic phenomena control gene expression through a dynamic fashion; therefore, considering the plasticity of both iron homoeostasis and epigenetic mechanisms and their role in liver carcinogenesis, we investigated whether hepcidin gene (HAMP) expression is modulated by DNA methylation, thus affecting iron status in human HCC. MATERIALS AND METHODS: Thirty-two patients affected by nonviral HCC were enrolled, and their main clinical and biochemical characteristics were obtained. Neoplastic and homologous non-neoplastic liver tissues were analysed for HAMP promoter DNA methylation, for HAMP gene expression and for iron content. An in vitro demethylation assay with a human hepatocarcinoma cell line was performed to evaluate the role of DNA methylation on HAMP transcriptional repression. RESULTS: Gene expression and DNA methylation analyses on tissues showed that HAMP was transcriptionally repressed in HCC tissues consensually with a promoter hypermethylation. Furthermore, patients with HCC had low serum hepcidin concentrations, and HCC tissues had relative iron depletion as compared to non-neoplastic liver tissues. The cell culture model showed the functional role of DNA hypermethylation by downregulating HAMP gene expression. Through a quantitative methylation analysis on HCC tissues, we then proved that methylation at definite CpG sites within consensus sequences for specific transcription factors is possibly the mechanism underlying HAMP repression. CONCLUSIONS: This study highlights a novel role for HAMP downregulation through DNA promoter hypermethylation and emphasises the significance of epigenetics in the regulation of iron metabolism in HCC.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Metilación de ADN/fisiología , Hepcidinas/metabolismo , Neoplasias Hepáticas/metabolismo , Regiones Promotoras Genéticas/fisiología , Anciano , Análisis de Varianza , Proteínas de Transporte de Catión/metabolismo , Regulación hacia Abajo/fisiología , Femenino , Expresión Génica/fisiología , Hepcidinas/genética , Humanos , Deficiencias de Hierro , Masculino , Proteínas de la Membrana/metabolismo , Serina Endopeptidasas/metabolismo , Transcripción Genética/fisiología
6.
Transfusion ; 58(9): 2192-2201, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29984534

RESUMEN

BACKGROUND: The desire for pregnancy in sickle cell disease (SCD) women has become a true challenge for hematologists, requiring a multidisciplinary approach. Erythrocytapheresis (ECP) is an important therapeutic tool in SCD, but only limited data on starting time and the effects of ECP during pregnancy are available. STUDY DESIGN AND METHODS: This is a double-center retrospective cross-sectional study on a total of 46 single pregnancies in SCD women from January 2008 to June 2017. ECP was started at 10.7 ± 5.2 weeks of gestation, and prophylactic enoxaparin (4,000 U daily) was introduced due to the reported high prevalence of thromboembolic events in pregnant SCD women. RESULTS: The alloimmunization ratio was 2.1 per 1,000 and the alloimmunization rate was 5.6%. In early ECP-treated SCD women, no severe vaso-occlusive crisis, sepsis or severe infection, or preeclampsia or eclampsia were observed. We found normal umbilical arterial impedance during pregnancy, suggesting an optimal uteroplacental function in early ECP-treated SCD women. This was also supported by the improvement in newborn birthweights compared to previous studies. In our cohort, three SCD women were started later on ECP (20-25 weeks), and gestation ended with late fetal loss. Placenta pathology documented SCD-related damage and erythroblasts in placental vessels, indicating fetal hypoxia. CONCLUSIONS: Collectively, our data generate a rationale to support a larger clinical trial of early ECP program in SCD pregnancy.


Asunto(s)
Anemia de Células Falciformes/terapia , Citaféresis , Complicaciones Hematológicas del Embarazo/prevención & control , Complicaciones Hematológicas del Embarazo/terapia , Tromboembolia/prevención & control , Aborto Espontáneo/epidemiología , Aborto Espontáneo/etiología , Adulto , Anticoagulantes/uso terapéutico , Peso al Nacer , Estudios Transversales , Citaféresis/métodos , Enoxaparina/uso terapéutico , Femenino , Muerte Fetal/etiología , Hipoxia Fetal/epidemiología , Hipoxia Fetal/etiología , Hipoxia Fetal/prevención & control , Edad Gestacional , Humanos , Recién Nacido , Placenta/fisiopatología , Embarazo , Complicaciones Hematológicas del Embarazo/epidemiología , Resultado del Embarazo , Estudios Retrospectivos , Mortinato , Tromboembolia/epidemiología , Factores de Tiempo , Resultado del Tratamiento
10.
Orphanet J Rare Dis ; 19(1): 22, 2024 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-38254184

RESUMEN

Pain is an hallmark of sickle-cell-related acute clinical manifestations as part of acute vaso-occlusive crisis (VOC). In SCD pain has different origins such as vascular or neuropathic pain, which requires multimodal analgesia. This is based on the administration of drugs with different pharmacological mechanisms of action, maximizing analgesia and minimizing their adverse events and the risk of drug-addition in patients experiencing acute-recurrent pain events as in SCD. Ketorolac is a potent non-narcotic analgesic, being relatively safe and effective during pain-management in children and adults. Up to now, there is a lack of safety information on continuous infusion ketorolac as used to control acute pain in patients with SCD, and the benefits/risks ratio needs to be investigated. Here, we report for the first time the safety profile of ketorolac in the special population of patients with SCD. We confirmed that ketorolac in combination with tramadol, an opioid like molecule, is effective in pain control of adult patients with SCD experiencing acute severe VOCs defined by pain visual analog scale. Our study shows that short term (72 h) continuous infusion of ketorolac plus tramadol is not associated with adverse events such as liver or kidney acute disfunction or abnormalities in coagulation parameters during patients' hospitalization and within 30 days after patients discharge. This is extremely important for patients with SCD, who should have access to multimodal therapy to control recurrent acute pain crisis in order to limit central sensitization a fearsome issue of undertreated recurrent acute pain and of chronic pain.


Asunto(s)
Dolor Agudo , Analgesia , Anemia de Células Falciformes , Hemoglobinopatías , Tramadol , Adulto , Niño , Humanos , Ketorolaco/uso terapéutico , Dolor Agudo/tratamiento farmacológico , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico
11.
Diagnostics (Basel) ; 12(11)2022 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-36428852

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent of coronavirus disease 2019 (COVID-19), in which coagulation abnormalities and endothelial dysfunction play a key pathogenic role. Tissue factor (TF) expression is triggered by endothelial dysfunction. Activated factor VII-antithrombin (FVIIa-AT) complex reflects indirectly FVIIa-TF interaction and has been proposed as a potential biomarker of prothrombotic diathesis. FVIIa-AT plasma concentration was measured in 40 patients (30 males and 10 females; 64.8 ± 12.3 years) admitted with SARS-CoV-2 pneumonia during the first pandemic wave in Italy. Two sex- and age-matched cohorts without COVID-19, with or without signs of systemic inflammation, were used to compare FVIIa-AT data. The FVIIa-AT plasma levels in COVID-19 patients were higher than those in non-COVID-19 subjects, either with or without inflammation, while no difference was observed among non-COVID-19 subjects. The association between COVID-19 and FVIIa-AT levels remained significant after adjustment for sex, age, C-reactive protein, renal function, fibrinogen, prothrombin time and activated partial thromboplastin time. Our results indicate that SARS-CoV-2 infection, at least during the first pandemic wave, was characterized by high FVIIa-AT levels, which may suggest an enhanced FVIIa-TF interaction in COVID-19, potentially consistent with SARS-CoV-2-induced endotheliopathy.

12.
Front Oncol ; 10: 596040, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33585212

RESUMEN

BACKGROUND: Mechanisms underlying hepatocellular carcinoma (HCC) development are largely unknown. The role of trace elements and proteins regulating metal ions homeostasis, i.e. metallothioneins (MTs), recently gained an increased interest. Object of the study was to investigate the role of promoter DNA methylation in MTs transcriptional regulation and the possible prognostic significance of serum trace elements in HCC. METHODS: Forty-nine HCC patients were enrolled and clinically characterized. Cu, Se, and Zn contents were measured by Inductively Coupled Plasma Mass Spectrometry in the serum and, for a subset of 27 patients, in HCC and homologous non-neoplastic liver (N) tissues. MT1G and MT1H gene expression in hepatic tissues was assessed by Real-Time RT-PCR and the specific promoter DNA methylation by Bisulfite-Amplicon Sequencing. RESULTS: Patients with Cu serum concentration above the 80th percentile had a significantly decreased survival rate (P < 0.001) with a marked increased hazard ratio for mortality (HR 6.88 with 95% CI 2.60-18.23, P < 0.001). Se and Zn levels were significantly lower in HCC as compared to N tissues (P < 0.0001). MT1G and MT1H gene expression was significantly down-regulated in HCC as compared to N tissues (P < 0.05). MTs promoter was hypermethylated in 9 out of the 19 HCC tissues showing MTs down-regulation and methylation levels of three specific CpGs paralleled to an increased mortality rate among the 23 patients analyzed (P = 0.015). CONCLUSIONS: MT1G and MT1H act as potential tumor suppressor genes regulated through promoter DNA methylation and, together with serum Cu concentrations, be related to survival rate in HCC.

13.
Mediterr J Hematol Infect Dis ; 11(1): e2019002, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30671208

RESUMEN

Sickle cell disease (SCD; ORPHA232; OMIM # 603903) is a chronic and invalidating disorder distributed worldwide, with high morbidity and mortality. Given the disease complexity and the multiplicity of pathophysiological targets, development of new therapeutic options is critical, despite the positive effects of hydroxyurea (HU), for many years the only approved drug for SCD. New therapeutic strategies might be divided into (1) pathophysiology-related novel therapies and (2) innovations in curative therapeutic options such as hematopoietic stem cell transplantation and gene therapy. The pathophysiology related novel therapies are: a) Agents which reduce sickling or prevent sickle red cell dehydration; b) Agents targeting SCD vasculopathy and sickle cell-endothelial adhesive events; c) Anti-oxidant agents. This review highlights new therapeutic strategies in SCD and discusses future developments, research implications, and possible innovative clinical trials.

15.
Front Genet ; 8: 229, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29375619

RESUMEN

Colon cancer is one of the most frequent solid tumor and simultaneous diagnosis of primary colon cancer and liver metastases occurs in about one fourth of cases. The current knowledge on epigenetic signatures, especially those related to hydroxymethylation in primary cancer tissue, synchronous metastasis, and blood circulating cells is lacking. This study aimed to investigate both methylcytosine (mCyt) and hydroxymethylcytosine (hmCyt) status in the DNA of individual patients from colon cancer tissue, synchronous liver metastases, and in cancer-free colon and liver tissues and leukocytes. Patients undergoing curative surgery (n = 16) were enrolled and their laboratory and clinical history data collected. The contents of mCyt and hmCyt were determined by a liquid chromatography/mass spectrometry (LC/MS/MS) method in DNA extracted from primary colon cancer, synchronous hepatic metastatic tissues and homologous cancer-free tissues, i.e., colon and liver tissues as well as leukocytes. The mCyt and hmCyt levels were compared between cancerous and cancer-free tissues, and correlations between leukocytes and colon/liver tissues for both the mCyt and hmCyt levels were evaluated. The mCyt levels were similar in primary colon cancer and liver metastasis tissues (4.69 ± 0.37% vs. 4.77 ± 0.38%, respectively, p = 0.535), and both primary and metastatic tissues were hypomethylated compared to cancer-free colon (4.98 ± 0.26%). The difference in the mCyt content between cancerous and cancer-free colon tissues was significantly lower in primary colon cancer (p = 0.004), but not in liver metastasis (p = 0.148). The hmCyt content was similar in primary colon cancer compared to liver metastasis (0.035%, C.I. 0.024-0.052% versus 0.035%, C.I. 0.021-0.058%, respectively, p = 0.905) and markedly depleted compared to the cancer-free colon (0.081%, C.I. 0.055-0.119%) with a statistically significant difference (p < 0.05) for both comparisons. The mCyt levels showed a borderline correlation between leukocytes and colon cancer tissue (Pearson's correlation coefficient = 0.51, p = 0.052) while no correlations were detected for the hmCyt levels. In conclusion, primary colon cancer and synchronous liver metastasis tissues showed a similar epigenetic status but were significantly hypomethylated and hypohydroxymethylated as compared to homologous cancer-free colon tissues.

16.
PLoS One ; 11(12): e0167534, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27936032

RESUMEN

Polymorphisms within one-carbon metabolism genes have been largely studied in relation to cancer risk for the function of this pathway in nucleotide synthesis and DNA methylation. Aims of this study were to explore the possible link among several common functional gene polymorphisms within one-carbon metabolism and survival rate in primary liver cancers, i.e., hepatocellular carcinoma and cholangiocarcinoma, and to assess the additional effect of global DNA methylation on survival rate and mortality risk. Forty-seven primary liver cancer patients were genotyped for ten polymorphisms: DHFR 19bp ins/del, TS 2rpt-3rpt, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, BHMT 716 A>G, TC II 776C>G. Methylation was determined in peripheral blood mononuclear cells (PBMCs) DNA as methylcytosine (mCyt) content using LC/MS/MS. Among the polymorphisms analysed, the RFC1 80G>A (rs1051266) influenced the survival rate in primary liver cancers. The RFC1 80AA was associated to a significantly reduced survival rate (22.2%) as compared to both GG and GA genotypes (61.5% and 76% respectively, p = 0.005). When the cancer patients were stratified according to the mCyt median value as high (>5.34%) or low (≤5.34%), the concomitant presence of AA genotype and low mCyt level led to a significantly worse survival rate as compared to the G allele carriership (p<0.0001) with a higher Hazard Ratio (HR = 6.62, p = 0.001). The subjects carrying the AA genotype in association with high mCyt did not show a significant difference in survival rate as compared with the G allele carriers (p = 0.919). The RFC1 80G>A polymorphism influenced the survival rate, and the presence of RFC1 80AA genotype with low global methylation in PBMCs DNA was associated with poorer prognosis and higher mortality risk, therefore highlighting novel molecular signatures potentially helpful to define prognostic markers for primary liver cancers.


Asunto(s)
Carbono/metabolismo , Metilación de ADN , Predisposición Genética a la Enfermedad/genética , Neoplasias Hepáticas/genética , Polimorfismo de Nucleótido Simple , Proteína Portadora de Folato Reducido/genética , Anciano , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidad , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/mortalidad , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Estimación de Kaplan-Meier , Leucocitos Mononucleares/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Tasa de Supervivencia
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