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PURPOSE: The main purpose of this study was to investigate the effects of 12 months of rhPTH (1-84) (Natpar®) treatment in a cohort of patients selected according to the indications of hypoparathyroidism guidelines. The use of recombinant human PTH (1-84) [rhPTH (1-84)] is approved as hormonal replacement therapy in patients with hypoparathyroidism not adequately controlled with conventional therapy. METHODS: It is a multicenter, observational, retro-prospective, open label study. Eleven Italian Endocrinological centers, members of Hypoparathyroidism Working Group of the Italian Society of Endocrinology (HypoparaNET) were involved. Main outcome measures were serum and urinary calcium and phosphate concentration, calcium-phosphate product, renal function, oral calcium and vitamin D doses, and clinical manifestations. RESULTS: Fourteen adult subjects, affected by chronic hypoparathyroidism, were treated with rhPTH (1-84) for 12 months. At 12 months of rhPTH (1-84) treatment, 61.5% of patients discontinued calcium supplement and 69.2% calcitriol. Mean albumin-adjusted total serum calcium levels quickly normalized after initiation of rhPTH (1-84) treatment compared to baseline (p = 0.009), remaining in the normal range until 12 months. Rare hypo-hypercalcemia episodes were reported. Renal function was maintained normal and no renal complications were reported. Serum and urinary phosphate and urinary calcium were maintained in the normal range. Mean phosphatemia levels linearly decreased from 3 months up to 12 months compared to baseline (p = 0.014). No severe adverse events were described. CONCLUSIONS: Biochemical and clinical results confirm the efficacy and safety of rhPTH (1-84) therapy, which represents an important option for hypoparathyroid patients unresponsive to conventional therapy.
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Calcio , Hipoparatiroidismo , Adulto , Humanos , Hormona Paratiroidea , Fosfatos/uso terapéutico , Estudios Prospectivos , Resultado del TratamientoRESUMEN
The COVID-19 pandemic has had and is having devastating effects on the health of the population, but also on the economic health of companies and their supply chains. The old paradigms of the commercial and industrial world have been inevitably disrupted: global supply chains have shifted from a system based on efficiency to one oriented towards resilience. To this regard, the present research paper aims at investigating how Supply Chain Resilience will evolve in the new paradigms of the post-COVID business era. In order to contribute to this investigation, a semi-structured questionnaire is developed, through a structured research approach. Future research lines will be based on conducting this questionnaire as a basis for a targeted survey, analysable through association rules.
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We analyzed polymorphism of the ALPL gene in patients with low serum levels of tissue-nonspecific alkaline phosphatase (TNAP). The presence of three or more of the less frequent alleles of ALPL polymorphisms was associated with significantly lower TNAP serum level and higher frequencies of metatarsal fractures, which may help confirm a clinical suspicion of adult hypophosphatasia. INTRODUCTION: Alkaline phosphatases (ALPs) are membrane-bound enzymes that hydrolyze monophosphate esters at a high pH (pH 8-10). Inorganic pyrophosphate, pyridoxal 5-phosphate, the activated form of vitamin B6 (PLP), and phosphoethanolamine (PEA), are natural substrates of ALPs. Hypophosphatasia (HPP, OMIM 146300, 241500, 241510) is a heterogeneous rare metabolic bone disease caused by loss-of-function mutations in the tissue-nonspecific alkaline phosphatase gene (ALPL; MIM 171760) with a deficiency of TNAP. Clinical presentation of HPP in adults demonstrated a wide range of manifestations, many of which are nonspecific. In the present study, we screened the polymorphic genetic variants of ALPL in 56 subjects presenting low serum levels of TNAP and/or other clinical signs of adult HPP in order to evaluate a possible role of polymorphic variants in the diagnosis and management of HPP in adults. METHODS: Genomic DNA was extracted from peripheral blood and ALPL gene was sequenced by PCR-based Sanger technique. RESULTS: Fourteen different polymorphic variants were found in the study population. A lower serum level of TNAP and higher frequencies of metatarsal fractures were observed in patients bearing three or more of the minor frequency alleles (MFAs) of the ALPL polymorphic variants. The presence of some MFAs, mostly as a contemporary presence of three or more of them, was found to be mainly represented in patients having both a significantly lower level of TNAP and a higher level of vitamin B6. CONCLUSION: The genetic analysis and presence of some polymorphic variants may be an instrument to confirm clinical and biochemical data, consider adult HPP, and help clinicians be cautious in the administration of anti-reabsorption drugs.
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Hipofosfatasia , Adulto , Fosfatasa Alcalina/genética , Alelos , Humanos , Hipofosfatasia/genética , Mutación , Fosfato de PiridoxalRESUMEN
Quantum and classical physics can be used for mathematical computations that are hard to tackle by conventional electronics. Very recently, optical Ising machines have been demonstrated for computing the minima of spin Hamiltonians, paving the way to new ultrafast hardware for machine learning. However, the proposed systems are either tricky to scale or involve a limited number of spins. We design and experimentally demonstrate a large-scale optical Ising machine based on a simple setup with a spatial light modulator. By encoding the spin variables in a binary phase modulation of the field, we show that light propagation can be tailored to minimize an Ising Hamiltonian with spin couplings set by input amplitude modulation and a feedback scheme. We realize configurations with thousands of spins that settle in the ground state in a low-temperature ferromagneticlike phase with all-to-all and tunable pairwise interactions. Our results open the route to classical and quantum photonic Ising machines that exploit light spatial degrees of freedom for parallel processing of a vast number of spins with programmable couplings.
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In the past decades, new cancer treatment approaches for children and adolescents have led to a decrease in recurrence rates and an increase in long-term survival. Recent studies have focused on the evaluation of the late effects on bone of pediatric cancer-related treatments, such as chemotherapy, radiation and surgery. Treatment of childhood cancer can impair the attainment of peak bone mass, predisposing to premature onset of low bone mineral density, or causing other bone side-effects, such as bone quality impairment or avascular necrosis of bone. Lower bone mineral density and microarchitectural deterioration can persist during adulthood, thereby increasing fracture risk. Overall, long-term follow-up of childhood cancer survivors is essential to define specific groups at higher risk of long-term bone complications, identify unrecognized long-term adverse effects, and improve patient care. Children and adolescents with a cancer history should be carefully monitored, and patients should be informed of possible late complications of their previous medical treatment. The International Osteoporosis Foundation convened a working group to review the bone complications of pediatric cancer survivors, outlining recommendations for the management of bone health, in order to prevent and treat these complications.
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Neoplasias/patología , Osteoporosis/patología , Osteoporosis/prevención & control , Densidad Ósea , Remodelación Ósea/fisiología , Supervivientes de Cáncer , Niño , Manejo de la Enfermedad , Humanos , Neoplasias/terapia , Osteoporosis/etiologíaRESUMEN
A cause of hypophosphatemia is phosphate wasting disorders. Knowledge concerning mechanisms involved in phosphate wasting disorders has greatly increased in the last decade by the identification of phosphatonins, among them FGF-23. FGF-23 is a primarily bone derived factor decreasing renal tubular reabsorption of phosphate and the synthesis of calcitriol. Currently, pharmacological treatment of these disorders offers limited efficacy and is potentially associated to gastrointestinal, renal, and parathyroid complications; therefore, efforts have been directed toward newer pharmacological strategies that target the FGF-23 pathway. This review focuses on phosphate metabolism, its main regulators, and phosphate wasting disorders in adults, highlighting the main issues related to diagnosis and current and new potential treatments.
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Hipofosfatemia/etiología , Hipofosfatemia/metabolismo , Fosfatos/metabolismo , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/fisiología , Homeostasis/fisiología , Humanos , Hipofosfatemia/diagnóstico , Hipofosfatemia/tratamiento farmacológico , Absorción Intestinal/fisiología , Riñón/metabolismo , Terapia Molecular Dirigida/métodos , Osteomalacia/diagnóstico , Osteomalacia/tratamiento farmacológico , Osteomalacia/etiología , Osteomalacia/metabolismoRESUMEN
Little is known about how leukemia cells alter the bone marrow (BM) niche to facilitate their own growth and evade chemotherapy. Here, we provide evidence that acute myeloid leukemia (AML) blasts remodel the BM niche into a leukemia growth-permissive and normal hematopoiesis-suppressive microenvironment through exosome secretion. Either engrafted AML cells or AML-derived exosomes increased mesenchymal stromal progenitors and blocked osteolineage development and bone formation in vivo. Preconditioning with AML-derived exosomes 'primed' the animals for accelerated AML growth. Conversely, disruption of exosome secretion in AML cells through targeting Rab27a, an important regulator involved in exosome release, significantly delayed leukemia development. In BM stromal cells, AML-derived exosomes induced the expression of DKK1, a suppressor of normal hematopoiesis and osteogenesis, thereby contributing to osteoblast loss. Conversely, treatment with a DKK1 inhibitor delayed AML progression and prolonged survival in AML-engrafted mice. In addition, AML-derived exosomes induced a broad downregulation of hematopoietic stem cell-supporting factors (for example, CXCL12, KITL and IGF1) in BM stromal cells and reduced their ability to support normal hematopoiesis. Altogether, this study uncovers novel features of AML pathogenesis and unveils how AML cells create a self-strengthening leukemic niche that promotes leukemic cell proliferation and survival, while suppressing normal hematopoiesis through exosome secretion.
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Médula Ósea/metabolismo , Médula Ósea/patología , Exosomas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Microambiente Tumoral , Animales , Biomarcadores , Médula Ósea/diagnóstico por imagen , Línea Celular , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Leucemia Mieloide Aguda/diagnóstico por imagen , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Ratones , Ratones Noqueados , Osteoblastos/citología , Osteoblastos/metabolismo , Nicho de Células Madre , Microtomografía por Rayos XRESUMEN
Dysregulation of microRNAs (miRNAs) plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). The Eµ-TCL1 transgenic mouse develops a form of leukemia that is similar to the aggressive type of human B-CLL, and this valuable model has been widely used for testing novel therapeutic approaches. Here, we adopted this model to investigate the potential effects of miR-26a, miR-130an and antimiR-155 in CLL therapy. Improved delivery of miRNA molecules into CLL cells was obtained by developing a novel system based on lipid nanoparticles conjugated with an anti-CD38 monoclonal antibody. This methodology has proven to be highly effective in delivering miRNA molecules into leukemic cells. Short- and long-term experiments showed that miR-26a, miR-130a and anti-miR-155 increased apoptosis after in vitro and in vivo treatment. Of this miRNA panel, miR-26a was the most effective in reducing leukemic cell expansion. Following long-term treatment, apoptosis was readily detectable by analyzing cleavage of PARP and caspase-7. These effects could be directly attributed to miR-26a, as confirmed by significant downregulation of its proven targets, namely cyclin-dependent kinase 6 and Mcl1. The results of this study are relevant to two distinct areas. The first is related to the design of a technical strategy and to the selection of CD38 as a molecular target on CLL cells, both consenting efficient and specific intracellular transfer of miRNA. The original scientific finding inferred from the above approach is that miR-26a can elicit in vivo anti-leukemic activities mediated by increased apoptosis.
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ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Glicoproteínas de Membrana/antagonistas & inhibidores , MicroARNs/uso terapéutico , ADP-Ribosil Ciclasa 1/genética , Animales , Anticuerpos Monoclonales de Origen Murino/química , Caspasa 7/metabolismo , Línea Celular Tumoral , Quinasa 6 Dependiente de la Ciclina/genética , Regulación hacia Abajo , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Lípidos/química , Glicoproteínas de Membrana/genética , Ratones , Ratones Transgénicos , MicroARNs/administración & dosificación , MicroARNs/antagonistas & inhibidores , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Nanopartículas/química , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteínas Proto-Oncogénicas/genéticaRESUMEN
Asparaginase, which depletes asparagine and glutamine, activates amino-acid stress response. Oxidative stress mediated by excessive reactive oxygen species (ROS) causes enhanced mitochondrial permeabilization and subsequent cell apoptosis and is considered as a plausible mechanism for drug-induced hepatotoxicity, a common toxicity of asparaginase in adults with acute lymphoblastic leukemia (ALL). Studies investigating the pharmacogenetics of asparaginase in ALL are limited and focused on asparaginase-induced allergic reaction common in pediatric patients. Here, we sought to determine a potential association between the variant rs4880 in SOD2 gene, a key mitochondrial enzyme that protects cells against ROS, and hepatotoxicity during asparaginase-based therapy in 224 patients enrolled on CALGB-10102, a treatment trial for adults with ALL. We report that the CC genotype of rs4880 is associated with increased hepatotoxicity following asparaginase-based treatment. Thus, rs4880 likely contributes to asparaginase-induced hepatotoxicity, and functional studies investigating this single-nucleotide polymorphism (SNP) are needed to develop therapeutic approaches that mitigate this toxicity.
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Antineoplásicos/efectos adversos , Asparaginasa/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Superóxido Dismutasa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Farmacogenómica , Fenotipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Medición de Riesgo , Factores de Riesgo , Resultado del Tratamiento , Adulto JovenRESUMEN
In this prospective phase 2 clinical trial conducted by Cancer and Leukemia Group B (CALGB, now the Alliance), we studied decitabine as maintenance therapy for younger adults with acute myeloid leukemia (AML) who remained in first complete remission (CR1) following intensive induction and consolidation. Given that decitabine is clinically active in AML and with hypomethylating activity distinct from cytotoxic chemotherapy, we hypothesized that 1 year of maintenance therapy would improve disease-free survival (DFS) for AML patients <60 years, who did not receive allogeneic stem cell transplantation in CR1. After blood count recovery from final consolidation, patients received decitabine at 20 mg/m2 intravenously daily for 4-5 days, every 6 weeks for eight cycles. One hundred and thirty-four patients received decitabine and 85 (63%) had favorable risk AML. The median number of cycles received was 7 (range: 1-8) and the primary reason for discontinuation was relapse. DFS at 1 year and 3 years was 79% and 54%, respectively. These results are similar to the outcomes in the historical control comprising similar patients treated on recent CALGB trials. Thus, maintenance with decitabine provided no benefit overall. Standard use of decitabine maintenance in younger AML patients in CR1 is not warranted. This trial was registered at www.clinicaltrials.gov as NCT00416598.
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Azacitidina/análogos & derivados , Leucemia Mieloide Aguda/tratamiento farmacológico , Quimioterapia de Mantención/métodos , Adolescente , Adulto , Azacitidina/administración & dosificación , Decitabina , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Inducción de Remisión , Tasa de Supervivencia , Adulto JovenRESUMEN
Changes in the enzymatic activity of protein arginine methyltransferase (PRMT) 5 have been associated with cancer; however, the protein's role in acute myeloid leukemia (AML) has not been fully evaluated. Here, we show that increased PRMT5 activity enhanced AML growth in vitro and in vivo while PRMT5 downregulation reduced it. In AML cells, PRMT5 interacted with Sp1 in a transcription repressor complex and silenced miR-29b preferentially via dimethylation of histone 4 arginine residue H4R3. As Sp1 is also a bona fide target of miR-29b, the miR silencing resulted in increased Sp1. This event in turn led to transcription activation of FLT3, a gene that encodes a receptor tyrosine kinase. Inhibition of PRMT5 via sh/siRNA or a first-in-class small-molecule inhibitor (HLCL-61) resulted in significantly increased expression of miR-29b and consequent suppression of Sp1 and FLT3 in AML cells. As a result, significant antileukemic activity was achieved. Collectively, our data support a novel leukemogenic mechanism in AML where PRMT5 mediates both silencing and transcription of genes that participate in a 'yin-yang' functional network supporting leukemia growth. As FLT3 is often mutated in AML and pharmacologic inhibition of PRMT5 appears feasible, the PRMT5-miR-29b-FLT3 network should be further explored as a novel therapeutic target for AML.
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Arginina/química , Metilación de ADN , Epigénesis Genética/genética , Epigenómica , Histonas/química , Leucemia Mieloide Aguda/genética , MicroARNs/genética , Proteína-Arginina N-Metiltransferasas/genética , Animales , Apoptosis , Western Blotting , Proliferación Celular , Inmunoprecipitación de Cromatina , Regulación hacia Abajo , Citometría de Flujo , Regulación Leucémica de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Leucemia Mieloide Aguda/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Activación Transcripcional , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In acute myeloid leukemia (AML), about 25-30% of patients harbor a constitutively active receptor tyrosine kinase (RTK) FLT3 encoded by a FLT3 allele harboring internal tandem duplication (FLT3-ITD) mutation. The presence of FLT3-ITD correlates with poor prognosis in AML and it makes FLT3 an attractive therapeutic target in AML. Unfortunately, to date small-molecule inhibitors of FLT3 have resulted in only partial and transient clinical responses with residual leukemic blasts resistant to FLT3 inhibitors detected in blood or bone marrow. In this study, we investigated whether the RTK Axl is responsible for resistance of FLT3-ITD(+) AML cells to PKC412 and AC220, FLT3 inhibitors currently under clinical trials for FLT3-ITD(+) AML patients. Upon treatment with PKC412 or AC220, phosphorylation of Axl was significantly enhanced in the FLT3-ITD(+) MV4-11 AML cell line and in primary blasts from a FLT3-ITD(+) AML patient. Consistently, a PKC412-resistant AML cell line and PKC412-resistant primary blasts from FLT3-ITD(+) AML patients had significantly higher levels of constitutively phosphorylated Axl and total Axl when compared with a PKC412-sensitive AML cell line and PKC412-sensitive primary blasts from FLT3-ITD(+) AML patients. We also found that resistance of AML cells against the FLT3 inhibitor PKC412 and AC220 was substantially diminished by the inhibition of Axl via a small-molecule inhibitor TP-0903, a soluble receptor Axl fusion protein Axl-Fc or knockdown of Axl gene expression by shRNA. Collectively, our study suggests that Axl is required for resistance of FLT3-ITD(+) AML cells against the FLT3 inhibitor PKC412 and AC220, and that inhibition of Axl activation may overcome resistance to FLT3-targeted therapy in FLT3-ITD(+) AML.
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Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas/fisiología , Proteínas Tirosina Quinasas Receptoras/fisiología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Línea Celular Tumoral , Resistencia a Antineoplásicos , Humanos , Fosforilación , Tirosina Quinasa del Receptor AxlRESUMEN
Current treatments for acute myeloid leukemia (AML) are designed to target rapidly dividing blast populations with limited success in eradicating the functionally distinct leukemia stem cell (LSC) population, which is postulated to be responsible for disease resistance and relapse. We have previously reported high miR-126 expression levels to be associated with a LSC-gene expression profile. Therefore, we hypothesized that miR-126 contributes to 'stemness' and is a viable target for eliminating the LSC in AML. Here we first validate the clinical relevance of miR-126 expression in AML by showing that higher expression of this microRNA (miR) is associated with worse outcome in a large cohort of older (⩾60 years) cytogenetically normal AML patients treated with conventional chemotherapy. We then show that miR-126 overexpression characterizes AML LSC-enriched cell subpopulations and contributes to LSC long-term maintenance and self-renewal. Finally, we demonstrate the feasibility of therapeutic targeting of miR-126 in LSCs with novel targeting nanoparticles containing antagomiR-126 resulting in in vivo reduction of LSCs likely by depletion of the quiescent cell subpopulation. Our findings suggest that by targeting a single miR, that is, miR-126, it is possible to interfere with LSC activity, thereby opening potentially novel therapeutic approaches to treat AML patients.
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Leucemia Mieloide Aguda/terapia , MicroARNs/antagonistas & inhibidores , Nanopartículas/administración & dosificación , Células Madre Neoplásicas/fisiología , Animales , Metilación de ADN , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Antígenos Comunes de Leucocito/antagonistas & inhibidores , Ratones , Ratones Endogámicos C57BL , MicroARNs/fisiología , Células Madre Neoplásicas/efectos de los fármacosRESUMEN
High levels of microRNA-155 (miR-155) are associated with poor outcome in acute myeloid leukemia (AML). In AML, miR-155 is regulated by NF-κB, the activity of which is, in part, controlled by the NEDD8-dependent ubiquitin ligases. We demonstrate that MLN4924, an inhibitor of NEDD8-activating enzyme presently being evaluated in clinical trials, decreases binding of NF-κB to the miR-155 promoter and downregulates miR-155 in AML cells. This results in the upregulation of the miR-155 targets SHIP1, an inhibitor of the PI3K/Akt pathway, and PU.1, a transcription factor important for myeloid differentiation, leading to monocytic differentiation and apoptosis. Consistent with these results, overexpression of miR-155 diminishes MLN4924-induced antileukemic effects. In vivo, MLN4924 reduces miR-155 expression and prolongs the survival of mice engrafted with leukemic cells. Our study demonstrates the potential of miR-155 as a novel therapeutic target in AML via pharmacologic interference with NF-κB-dependent regulatory mechanisms. We show the targeting of this oncogenic microRNA with MLN4924, a compound presently being evaluated in clinical trials in AML. As high miR-155 levels have been consistently associated with aggressive clinical phenotypes, our work opens new avenues for microRNA-targeting therapeutic approaches to leukemia and cancer patients.
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Ciclopentanos/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , MicroARNs/genética , Pirimidinas/farmacología , Secuencias Repetidas en Tándem/genética , Ubiquitinas/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/genética , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Inmunoprecipitación de Cromatina , Resistencia a Antineoplásicos , Femenino , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia Mieloide Aguda/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Monocitos/patología , Proteína NEDD8 , FN-kappa B/genética , FN-kappa B/metabolismo , Regiones Promotoras Genéticas , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Human disorders of phosphate (Pi) handling and skeletal mineralization represent a group of rare bone diseases. One of these disease is tumoral calcinosis (TC). In this study, we present the case of a patient with TC with a new GALNT3 gene mutation. We also performed functional studies using an in vitro cellular model. Genomic DNA was extracted from peripheral blood collected from a teenage Caucasian girl affected by TC, and from her parents. A higher capability to form mineralization nodules in vitro was found in human preosteoblastic cells of mutant when compared to wild-type controls. We found a novel homozygous inactivating splice site mutation in intron I (c.516-2a>g). A higher capability to form mineralization nodules in vitro was found in the mutant cells in human preosteoblastic cells when compared to wild-type controls. Understanding the functional significance and molecular physiology of this novel mutation will help to define the role of FGF23 in the control of Pi homeostasis in normal and in pathological conditions.
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Calcinosis/genética , Hiperostosis Cortical Congénita/genética , Hiperfosfatemia/genética , Mutación , N-Acetilgalactosaminiltransferasas/genética , Osteoblastos/patología , Secuencia de Bases , Técnicas de Cultivo de Célula/métodos , Diferenciación Celular , Niño , Femenino , Factor-23 de Crecimiento de Fibroblastos , Citometría de Flujo , Humanos , Datos de Secuencia Molecular , Linaje , Reacción en Cadena de la Polimerasa , Células Madre/patología , Polipéptido N-AcetilgalactosaminiltransferasaRESUMEN
Alloantibody, not primed T cells, is the major barrier to bone marrow (BM) engraftment in allosensitized mice. We have shown that a single intravenous injection of donor splenocytes, to mimic a blood transfusion, results in high, sustained levels of serum alloantibody sufficient to eliminate donor BM within 3 h, resulting in uniform mortality in lethally irradiated allogeneic recipients. Current studies focused preventing and treating allopriming. Blockade of B cell survival signals with mTACI-Ig pre- and postpriming was ineffective, as was the B cell but not plasma cell depleting anti-CD20 mAb. Germinal center formation inhibition by lymphotoxin-beta receptor-Ig (LßR-Ig) diminished allosensitization, although conditional Prmd1 (Blimp-1) deletion in CD19+ cells was highly effective. By combining anti-CD20 mAb to reduce B cells and LTßR-Ig to diminish the frequency of B cells that could form germinal centers pre- and postpriming, allosensitization was precluded, permitting long-term survival in T- and NK-depleted, irradiated allogeneic recipients, whereas combined therapy postpriming alone was ineffective. As evidence of the critical role of B cells, the proteosomal inhibitor, bortezomib, given unencapsulated or encapsulated, proved ineffective in influencing allosensitization. These data extend our understanding of allopriming and provide a potential therapy for patients at risk for allosensitization and BM graft rejection.
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Trasplante de Células Madre Hematopoyéticas , Isoanticuerpos/biosíntesis , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Antígenos CD19/inmunología , Antígenos CD20/inmunología , Linfocitos B/inmunología , Inmunoglobulina G/inmunología , Receptor beta de Linfotoxina/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Factores de Transcripción/inmunologíaRESUMEN
AIM: Significant strides have been made using endovascular solutions for the treatment of patients with peripheral vascular disease (PAD) and for tissue loss. But the Trans-Atlantic Inter-Society Consensus (TASC) II classification states that surgery still remains the best solution for C and D lesions, though endovascular management of superficial femoral artery (SFA) can improve inflow for distal origin bypass grafts. Our aim was to evaluate the results of combining endovascular treatment of SFA with distal vein bypass in patients with critical limb ischemia (CLI) and great tissue loss or in the cases where the below-knee endoluminal techniques alone were unable to salvage limbs. METHODS: A retrospective study of the combined interventions carried out from January 2006 and June 2013 was performed. Twenty-seven angioplasties or selective stentings of SFA combined with popliteal-distal bypass in 23 patients with stage 4, 5 or 6 Rutherford classification were performed. There were 14 men and 9 women, four were bilateral. Mean age was 71.5 years (55-91); 21 (91.3%) were diabetic, and in these, there was almost always deep debridement of necrotic or infected tissue. In 17 cases (62.9%) SFA angioplasty was performed alone, a self-expendable stent was released in the other 10 (37.1%). Distal bypass originated from distal SFA in 5 cases (18.5%), from above-knee popliteal artery in 8 (29.6%) and from below-knee popliteal artery in 14 (51.8%). Reversed saphenous vein was used for bypass in all cases. The target vessel was the posterior tibial artery in 6 cases, anterior tibial artery in 10 and dorsalis pedis in eleven. Follow-up ranged from 4 months to 6 years (with a mean of 37 months). RESULTS: There were no deaths, but two early graft failures and three major amputations during the perioperative period. Primary patency rate of both the endovascular SFA and the bypass was 81.6% (N.=22) and secondary patency was 88.8% (N.=24). Three years primary and secondary patency rate were, respectively, 74.1% (N.=20) and 81.6% (N.=22). One-year limb salvage rate was 88.8%, at three years was 86.1% and fifteen minor amputations were performed in 13 patients. CONCLUSION: The endovascular treatment of SFA associated with surgical distal vein bypass is a useful and effective strategy in patients with severe lower extremity arterial disease. This strategy allows a good inflow on SFA in selected patients with the opportunity to perform shorter bypass, use of limited autologous conduit and good expectation of patency.
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Angioplastia , Arteria Femoral/cirugía , Isquemia/terapia , Enfermedades Vasculares Periféricas/terapia , Vena Safena/trasplante , Anciano , Anciano de 80 o más Años , Amputación Quirúrgica , Angioplastia/efectos adversos , Angioplastia/instrumentación , Terapia Combinada , Enfermedad Crítica , Femenino , Arteria Femoral/diagnóstico por imagen , Arteria Femoral/fisiopatología , Oclusión de Injerto Vascular/etiología , Oclusión de Injerto Vascular/fisiopatología , Oclusión de Injerto Vascular/cirugía , Humanos , Isquemia/diagnóstico , Isquemia/cirugía , Estimación de Kaplan-Meier , Recuperación del Miembro , Masculino , Persona de Mediana Edad , Enfermedades Vasculares Periféricas/diagnóstico , Enfermedades Vasculares Periféricas/fisiopatología , Enfermedades Vasculares Periféricas/cirugía , Radiografía , Reoperación , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Stents , Factores de Tiempo , Resultado del Tratamiento , Grado de Desobstrucción VascularRESUMEN
PURPOSE: Rare endocrine-metabolic diseases (REMD) represent an important area in the field of medicine and pharmacology. The rare diseases of interest to endocrinologists involve all fields of endocrinology, including rare diseases of the pituitary, thyroid and adrenal glands, paraganglia, ovary and testis, disorders of bone and mineral metabolism, energy and lipid metabolism, water metabolism, and syndromes with possible involvement of multiple endocrine glands, and neuroendocrine tumors. Taking advantage of the constitution of a study group on REMD within the Italian Society of Endocrinology, consisting of basic and clinical scientists, a document on the taxonomy of REMD has been produced. METHODS AND RESULTS: This document has been designed to include mainly REMD manifesting or persisting into adulthood. The taxonomy of REMD of the adult comprises a total of 166 main disorders, 338 including all variants and subtypes, described into 11 tables. CONCLUSIONS: This report provides a complete taxonomy to classify REMD of the adult. In the future, the creation of registries of rare endocrine diseases to collect data on cohorts of patients and the development of common and standardized diagnostic and therapeutic pathways for each rare endocrine disease is advisable. This will help planning and performing intervention studies in larger groups of patients to prove the efficacy, effectiveness, and safety of a specific treatment.
Asunto(s)
Enfermedades del Sistema Endocrino/clasificación , Endocrinología/clasificación , Enfermedades Raras/clasificación , Informe de Investigación , Adulto , Clasificación , Enfermedades del Sistema Endocrino/diagnóstico , Endocrinología/métodos , Femenino , Humanos , Masculino , Enfermedades Raras/diagnósticoRESUMEN
DNMT3B encodes a DNA methyltransferase implicated in aberrant epigenetic changes contributing to leukemogenesis. We tested whether DNMT3B expression, measured by NanoString nCounter assay, associates with outcome, gene and microRNA expression and DNA methylation profiles in 210 older (⩾60 years) adults with primary, cytogenetically normal acute myeloid leukemia (CN-AML). Patients were dichotomized into high versus low expressers using median cut. Outcomes were assessed in the context of known CN-AML prognosticators. Gene and microRNA expression, and DNA methylation profiles were analyzed using microarrays and MethylCap-sequencing, respectively. High DNMT3B expressers had fewer complete remissions (CR; P=0.002) and shorter disease-free (DFS; P=0.02) and overall (OS; P<0.001) survival. In multivariable analyses, high DNMT3B expression remained an independent predictor of lower CR rates (P=0.04) and shorter DFS (P=0.04) and OS (P=0.001). High DNMT3B expression associated with a gene expression profile comprising 363 genes involved in differentiation, proliferation and survival pathways, but with only four differentially expressed microRNAs (miR-133b, miR-148a, miR-122, miR-409-3p) and no differential DNA methylation regions. We conclude that high DNMT3B expression independently associates with adverse outcome in older CN-AML patients. Gene expression analyses suggest that DNMT3B is involved in the modulation of several genes, although the regulatory mechanisms remain to be investigated to devise therapeutic approaches specific for these patients.