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3.
Thromb Res ; 140 Suppl 1: S196, 2016 Apr.
Article in English | MEDLINE | ID: mdl-27161742

ABSTRACT

INTRODUCTION: Ibrutinib treatment in patients with chronic lymphatic leukemia (LLC) is associated with bleeding-related adverse events. About 50% of treated patients display minor bleedings and about 5% major bleedings. A defect of platelet function has been hypothesized and inhibition of signaling by glycoprotein (GP) VI, which is the receptor for collagen, has been previously described. Ibrutinib-associated bleedings and platelet dysfunction may be relevant in the context of aged patients, who are often under antithrombotic treatments. AIM: Aim of this study is to investigate and characterize the effect of ibrutinib on platelet function in vitro in patients with CLL. MATERIALS AND METHODS: Nine patients recruited in ongoing ibrutinib clinical trials were studied. Assessment of spontaneous bleeding was performed using the WHO bleeding scale. The following tests were performed before and after initiation of treatment with ibrutinib: 1) Light transmission aggregometry (LTA) using platelet-rich-plasma (ADP 2-4µM, PAR1-AP 25 µM, Collagen 10 ug /mL, arachidonic acid 1 mM, ristocetin 0.6-1.2mg/mL) 2) Measurement of vWF antigen and ristocetin cofactor activities by chemiluminescent immunoassay. RESULTS: I) Five patients displayed grade 1 bleeding (cutaneous bleeding) and one patient grade 2 bleeding (rectal bleeding) (66.7%) after initiation of ibrutinib treatment. II) Eight patients displayed abnormalities of the aggregation by 10 ug/ml collagen after initiation of ibrutinib treatment. At high collagen concentration, only significant prolongation of the lag phase was measured (60.4±10.6sec vs basal 38.4±17sec), whereas the maximal aggregation was not impaired (67.9±21.4% vs basal 85.5±5.8%). Compared to previous reports, these results confirmed an impairment of collagen induced aggregation, but at these concentrations only the lag phase was affected. III) Five patients displayed a significant improvement of the aggregation by 2 uM (91.25±5.26% vs basal 39.3±24.62%) and 4 uM (91±2.83% vs basal 65.42±19.43%) ADP after initiation of ibrutinib treatment. IV) vWF antigen and ristocetin cofactor activity were measured in 3 patients. In all patients vWF levels were higher at the onset of the disease (169±38%) and reduced up to normal values under Ibrutinib treatment (111.4±47%). CONCLUSIONS: Ibrutinib treatment in LLC patients causes a mild bleeding phenotype most probably due to platelet dysfunction. In this study, collagen induced aggregation resulted impaired, whereas the aggregation by PAR1-AP, ristocetin and arachidonic acid was not affected. On the contrary, the aggregation by ADP was improved upon ibrutinib treatment. The levels of vonWillebrand factor are significantly higher in LLC patients before treatment and were normalized by ibrutinib.

4.
Leukemia ; 29(1): 86-95, 2015 Jan.
Article in English | MEDLINE | ID: mdl-24732594

ABSTRACT

Deregulation of the miR-15a/16-1 cluster has a key role in the pathogenesis of chronic lymphocytic leukemia (CLL), a clinically heterogeneous disease with indolent and aggressive forms. The miR-15a/16-1 locus is located at 13q14, the most frequently deleted region in CLL. Starting from functional investigations of a rare SNP upstream the miR cluster, we identified a novel allele-specific mechanism that exploits a cryptic activator region to recruit the RNA polymerase III for miR-15a/16-1 transcription. This regulation of the miR-15a/16- locus is independent of the DLEU2 host gene, which is often transcribed monoallellically by RPII. We found that normally one allele of miR-15a/16-1 is transcribed by RNAPII, the other one by RNAPIII. In our subset of CLL patients harboring 13q14 deletions, exclusive RNA polymerase III (RPIII)-driven transcription of the miR-15a/16-1 was the consequence of loss of the RPII-regulated allele and correlated with high expression of the poor prognostic marker ZAP70 (P=0.019). Thus, our findings point to a novel biological process, characterized by double allele-specific transcriptional regulation of the miR-15a/16-1 locus by alternative mechanisms. Differential usage of these mechanisms may distinguish at onset aggressive from indolent forms of CLL. This provides a basis for the clinical heterogeneity of the CLL patients carrying 13q14 deletions.


Subject(s)
Alleles , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , MicroRNAs/genetics , Transcription, Genetic , Base Sequence , Biomarkers, Tumor/genetics , Cell Line, Tumor , Chromatin Immunoprecipitation , DNA/genetics , DNA Copy Number Variations , Humans , Molecular Sequence Data , Polymorphism, Single Nucleotide , Real-Time Polymerase Chain Reaction
5.
Mini Rev Med Chem ; 11(6): 508-18, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21561405

ABSTRACT

Over the last few years, several new agents have been under evaluation in preclinical studies and clinical trials, showing promise in treating chronic lymphocytic leukemia (CLL). Among these agents, monoclonal antibodies (mAbs) such as rituximab and alemtuzumab have changed the natural course of the disease. Nowadays there are several new promising monoclonal antibodies under investigation against the CD20, CD23, CD37 and CD40 molecules. Application of newer monoclonal antibodies represents an area of ongoing clinical research in CLL.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Antibodies, Monoclonal/immunology , Antigens, CD/chemistry , Antigens, CD/metabolism , Antigens, CD20/chemistry , Antigens, CD20/metabolism , Antigens, Neoplasm/chemistry , Antigens, Neoplasm/metabolism , Antineoplastic Agents/immunology , CD40 Antigens/antagonists & inhibitors , CD40 Antigens/metabolism , CD52 Antigen , Glycoproteins/antagonists & inhibitors , Glycoproteins/metabolism , Humans , Receptors, IgE/antagonists & inhibitors , Receptors, IgE/metabolism , Tetraspanins
6.
Curr Med Chem ; 17(29): 3358-76, 2010.
Article in English | MEDLINE | ID: mdl-20712568

ABSTRACT

Different intervention trials have been so far conducted and others are ongoing to evaluate the effect of increased intake of n-3 polyunsaturated fatty acids (PUFAs) in the prevention of several disorders affecting lungs and airways. They have been focused on chronic obstructive pulmonary disease, acute respiratory distress syndrome, acute lung injury, pulmonary fibrosis, alteration of lung function in cystic fibrosis, as well as asthma and cachexia in lung cancer patients. Their outcomes are not always consistent, but, if beneficial effects were observed, they have been related mainly to the anti-inflammatory action of n-3 PUFAs. On the contrary, trials investigating their effects on the development and progression of lung cancer are still not available. This in spite of the huge number of equivalent studies performed on other kind of cancers (breast, colon and prostate cancer), which share with lung cancer the highest incidence in Western countries and an elevated sensitivity to chemoprevention. Contrasting results were also obtained by the few epidemiological studies available on lung cancer. However, different experimental studies, performed in vivo and in vitro, provided strong indications of the anti-tumor action of n-3 PUFAs against lung cancer, and identified molecular mechanisms for their action. In this review our effort will concentrate in critically reviewing the current evidence for the beneficial effect of n-3 PUFAs in inflammatory and neoplastic disorders of lungs and airways, and in identifying possible molecular mechanisms underlying their effects.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Anticarcinogenic Agents/therapeutic use , Fatty Acids, Omega-3/therapeutic use , Lung Diseases/prevention & control , Lung Neoplasms/prevention & control , Acute Lung Injury/metabolism , Acute Lung Injury/pathology , Acute Lung Injury/prevention & control , Asthma/metabolism , Asthma/pathology , Asthma/prevention & control , Dietary Supplements , Fatty Acids, Omega-6/therapeutic use , Humans , Lung Diseases/metabolism , Lung Diseases/pathology , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/pathology , Pulmonary Disease, Chronic Obstructive/prevention & control , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/prevention & control
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