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1.
Artigo em Inglês | MEDLINE | ID: mdl-32047037

RESUMO

The prognosis of chronic lymphocytic leukemia (CLL) depends on different markers, including cytogenetic aberrations, oncogenic mutations, and mutational status of the immunoglobulin (Ig) heavy-chain variable (IGHV) gene. The number of IGHV mutations distinguishes mutated (M) CLL with a markedly superior prognosis from unmutated (UM) CLL cases. In addition, B cell antigen receptor (BCR) stereotypes as defined by IGHV usage and complementarity-determining regions (CDRs) classify ∼30% of CLL cases into prognostically important subsets. Subset 2 expresses a BCR with the combination of IGHV3-21-derived heavy chains (HCs) with IGLV3-21-derived light chains (LCs), and is associated with an unfavorable prognosis. Importantly, the subset 2 LC carries a single-point mutation, termed R110, at the junction between the variable and constant LC regions. By analyzing 4 independent clinical cohorts through BCR sequencing and by immunophenotyping with antibodies specifically recognizing wild-type IGLV3-21 and R110-mutated IGLV3-21 (IGLV3-21R110), we show that IGLV3-21R110-expressing CLL represents a distinct subset with poor prognosis independent of IGHV mutations. Compared with other alleles, only IGLV3-21*01 facilitates effective homotypic BCR-BCR interaction that results in autonomous, oncogenic BCR signaling after acquiring R110 as a single-point mutation. Presumably, this mutation acts as a standalone driver that transforms IGLV3-21*01-expressing B cells to develop CLL. Thus, we propose to expand the conventional definition of CLL subset 2 to subset 2L by including all IGLV3-21R110-expressing CLL cases regardless of IGHV mutational status. Moreover, the generation of monoclonal antibodies recognizing IGLV3-21 or mutated IGLV3-21R110 facilitates the recognition of B cells carrying this mutation in CLL patients or healthy donors.

2.
Blood ; 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32006000

RESUMO

CD49d is a remarkable prognostic biomarker of chronic lymphocytic leukemia (CLL). The extensively validated 30% of positive CLL cells cut-off value is able to separate CLL patients into two subgroups with different prognosis, but it does not consider the pattern of CD49d expression. In the present study, we analysed a cohort of 1,630 CLL samples and identified the presence of ~20% of CLL cases (n=313) characterized by a bimodal expression of CD49d, i.e. concomitant presence of a CD49dpos sub-population and a CD49dneg sub-population. At variance with the highly stable CD49d expression observed in CLL patients with a homogeneous pattern of CD49d expression, CD49d bimodal CLL showed a higher level of variability in sequential samples, and an increase in the CD49dpos sub-population over time after therapy. The CD49dpos sub-population from CD49d bimodal CLL displayed higher levels of proliferation compared to the CD49dneg cells, was more highly represented in the bone marrow compared to peripheral blood (PB), and in PB CLL subsets expressing the CXCR4dim/CD5bright phenotype, known to be enriched in proliferative cells. From a clinical standpoint, CLL patients with CD49d bimodal expression, regardless of whether the CD49dpos sub-population exceeded or not the 30% cut-off, experienced a clinical behavior similar to CD49dpos CLL, both in the chemo-immunotherapy (n=1,522) and in the ibrutinib (n=158) settings. Altogether, these results suggest that CD49d can drive disease progression in CLL, and that the pattern of CD49d expression should be also considered to improve the prognostic impact of this biomarker in CLL.

3.
Haematologica ; 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582547

RESUMO

We present a laboratory-based prognostic calculator (designated CRO score) to risk stratify treatment-free survival in early stage (Rai 0) chronic lymphocytic leukemia developed using a training-validation model in a series of 1,879 cases from Italy, the United Kingdom and the United States. By means of regression analysis, we identified five prognostic variables with weighting as follows: deletion of the short arm of chromosome 17 and unmutated immunoglobulin heavy chain gene status, 2 points; deletion of the long arm of chromosome 11, trisomy of chromosome 12, and white blood cell count>32.0x103/microliter, 1 point. Low, intermediate and high-risk categories were established by recursive partitioning in a training cohort of 478 cases, and then validated in four independent cohorts of 144/395/540/322 cases, as well as in the composite validation cohort. Concordance indices were 0.75 in the training cohort and ranged from 0.63 to 0.74 in the four validation cohorts (0.69 in the composite validation cohort). These findings advocate potential application of our novel prognostic calculator to better stratify early-stage chronic lymphocytic leukemia, and aid case selection in risk-adapted treatment for early disease. Furthermore, they support immunocytogenetic analysis in Rai 0 chronic lymphocytic leukemia being performed at the time of diagnosis to aid prognosis and treatment, particularly in today's chemo-free era.

6.
Cell Death Differ ; 26(11): 2493, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30728458

RESUMO

Since publication of the article, the authors were notified by ATCC that the cell line HCC1395 (ATCC® CRL-2324™ Lot 62235652) suffered a "low level of cell line cross-contamination" with another cell line.

9.
Methods Mol Biol ; 1881: 101-112, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30350200

RESUMO

The integrin heterodimer CD49d/CD29 (a.k.a. Very Late Antigen-4, VLA-4) mediates cell-cell and cell-matrix interaction through the binding of its ligands VCAM-1 and fibronectin. VLA-4 can be present on the cell surface at different conformation states that affect the binding affinity for the ligands. In chronic lymphocytic leukemia (CLL), higher VLA-4 levels, as determined by measuring the expression of CD49d chain by flow cytometry, have been demonstrated to associate with a worse prognosis, in keeping with the role of VLA-4 as key molecule favoring CLL cell localization in protective niches of bone marrow and lymph nodes. Given the emerging clinical relevance of VLA-4 evaluation in CLL, both in the setting of the conventional chemo-immunotherapy and the novel drugs targeting the BCR pathway, here we describe the flow cytometric approaches followed by us to quantify the CD49d expression levels and the VLA-4 activation status in CLL cells.


Assuntos
Citometria de Fluxo/métodos , Integrina alfa4/análise , Integrina alfa4beta1/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Fibronectinas/metabolismo , Citometria de Fluxo/instrumentação , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Linfócitos/metabolismo , Linfócitos/patologia , Molécula 1 de Adesão de Célula Vascular/metabolismo
11.
BMC Infect Dis ; 18(1): 428, 2018 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-30153797

RESUMO

BACKGROUND: Chronic diseases, chiefly cancers and circulatory system diseases (CSDs), have become the leading non-AIDS-related causes of death among HIV-infected people, as in the general population. After our previous report of an excess mortality for several non-AIDS-defining cancers, we now aim to assess whether people with AIDS (PWA) experience also an increased mortality for CSDs and diabetes mellitus (DM), as compared to the non-AIDS general population (non-PWA). METHODS: A nationwide, population-based, retrospective cohort study was conducted including 5285 Italians, aged 15-74 years, who were diagnosed with AIDS between 2006 and 2011. Multiple cause-of-death (MCoD) data, i.e. all conditions reported in death certificates, were retrieved through record-linkage with the National Register of Causes of Death up to 2011. Using MCoD data, sex- and age-standardized mortality ratios (SMRs) with 95% confidence intervals (CIs) were calculated by dividing the observed number of PWA reporting a specific disease among MCoD to the expected number, estimated on the basis of mortality rates (based on MCoD) of non-PWA. RESULTS: Among 1229 deceased PWA, CSDs were mentioned in 201 (16.4%) certificates and DM in 46 (3.7%) certificates among the various causes of death. These values corresponded to a 13-fold higher mortality related to CSDs (95% CI 10.8-14.4) and DM (95% CI: 9.5-17.4) as compared to 952,019 deceased non-PWA. Among CSDs, statistically significant excess mortality emerged for hypertension (23 deaths, SMR = 6.3, 95% CI: 4.0-9.4), ischemic heart diseases (39 deaths, SMR = 6.1, 95% CI: 4.4-8.4), other forms of heart diseases (88 deaths, SMR = 13.4, 95% CI: 10.8-16.5), and cerebrovascular diseases (42 deaths, SMR = 13.4, 95% CI: 9.7-18.2). The SMRs were particularly elevated among PWA aged < 50 years and those infected through drug injection. CONCLUSIONS: The use of MCoD data disclosed the fairly high mortality excess related to several CSDs and DM among Italian PWA as compared to non-PWA. Study findings also indicate to start preventive strategies for such diseases at a younger age among AIDS patients than in the general population and with focus on drug users.


Assuntos
Síndrome de Imunodeficiência Adquirida/mortalidade , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus/mortalidade , Síndrome de Imunodeficiência Adquirida/complicações , Adolescente , Adulto , Idoso , Doenças Cardiovasculares/complicações , Causas de Morte , Transtornos Cerebrovasculares/complicações , Transtornos Cerebrovasculares/mortalidade , Estudos de Coortes , Angiopatias Diabéticas/complicações , Angiopatias Diabéticas/mortalidade , Feminino , Infecções por HIV/complicações , Infecções por HIV/mortalidade , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
12.
Cell Death Differ ; 25(12): 2165-2180, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29666469

RESUMO

Inactivation of p53 contributes significantly to the dismal prognosis of breast tumors, most notably triple-negative breast cancers (TNBCs). How the relief from p53 tumor suppressive functions results in tumor cell aggressive behavior is only partially elucidated. In an attempt to shed light on the implication of microRNAs in this context, we discovered a new signaling axis involving p53, miR-30a and ZEB2. By an in silico approach we identified miR-30a as a putative p53 target and observed that in breast tumors reduced miR-30a expression correlated with p53 inactivation, lymph node positivity and poor prognosis. We demonstrate that p53 binds the MIR30A promoter and induces the transcription of both miRNA strands 5p and 3p. Both miR-30a-5p and -3p showed the capacity of targeting ZEB2, a transcription factor involved in epithelial-mesenchymal transition (EMT), tumor cell migration and drug resistance. Intriguingly, we found that p53 does restrain ZEB2 expression via miR-30a. Finally, we provide evidence that the new p53/miR-30a/ZEB2 axis controls tumor cell invasion and distal spreading and impinges upon miR-200c expression. Overall, this study highlights the existence of a novel axis linking p53 to EMT via miR-30a, and adds support to the notion that miRNAs represent key elements of the complex network whereby p53 inactivation affects TNBC clinical behavior.


Assuntos
MicroRNAs/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Proteína Supressora de Tumor p53/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Pessoa de Meia-Idade
13.
Nutrition ; 53: 43-48, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29655776

RESUMO

OBJECTIVES: The components of a diet can modulate inflammation and may have an effect on the development of Hodgkin's lymphoma (HL). Little is known about the inflammatory potential of diet in relation to HL. METHODS: Data from an Italian multicenter case-control study that was conducted between 1992 and 2008 were used to estimate the relation between a dietary inflammatory index (DII®) and the risk of HL. The data included 179 cases with incident, histologically confirmed HL and 186 control cases who were hospitalized for acute non-neoplastic diseases. The DII was computed on the basis of a validated, 78-item, food-frequency questionnaire. Logistic regression models were used to estimate odds ratios that were adjusted for age, sex, total energy intake, center, body mass index, years of education, tobacco use, and alcohol consumption. RESULTS: No significant association was observed between an increasing DII and the risk of HL when used either as a continuous or categorical variable. The multivariate odds ratio for the highest versus the lowest DII tertile was 1.20 (95% confidence interval: 0.71-2.04). Similarly, no positive association was observed when analyses were carried out by different strata of selected covariates. CONCLUSIONS: These results do not support the hypothesis that the inflammatory potential of a diet plays a major role in the development of HL.


Assuntos
Dieta/efeitos adversos , Doença de Hodgkin/epidemiologia , Inflamação/epidemiologia , Adulto , Estudos de Casos e Controles , Causalidade , Comorbidade , Feminino , Humanos , Itália/epidemiologia , Masculino , Fatores de Risco
14.
J Exp Med ; 215(2): 681-697, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29301866

RESUMO

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors.


Assuntos
Integrina alfa4beta1/metabolismo , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Adesão Celular/efeitos dos fármacos , Humanos , Imunoglobulina M/metabolismo , Estimativa de Kaplan-Meier , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Linfonodos/patologia , Linfocitose/metabolismo , Linfocitose/patologia , Análise Multivariada , Fosfatidilinositol 3-Quinases/metabolismo , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptores de Antígenos de Linfócitos B/metabolismo
15.
Clin Cancer Res ; 24(1): 120-129, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29066507

RESUMO

Purpose: Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types, and pharmacologic inhibition of the PI3K/mTOR pathway has shown activity in lymphoma patients. Here, we extensively characterized the in vitro and in vivo activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models.Experimental Design: This study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on in vivo models and primary cells, proteomics and gene-expression profiling, and comparison with other signaling inhibitors.Results: PQR309 had in vitro antilymphoma activity as single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab. Sensitivity to PQR309 was associated with specific baseline gene-expression features, such as high expression of transcripts coding for the BCR pathway. Combining proteomics and RNA profiling, we identified the different contribution of PQR309-induced protein phosphorylation and gene expression changes to the drug mechanism of action. Gene-expression signatures induced by PQR309 and by other signaling inhibitors largely overlapped. PQR309 showed activity in cells with primary or secondary resistance to idelalisib.Conclusions: On the basis of these results, PQR309 appeared as a novel and promising compound that is worth developing in the lymphoma setting. Clin Cancer Res; 24(1); 120-9. ©2017 AACR.


Assuntos
Antineoplásicos/farmacologia , Linfoma/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Humanos , Linfoma/tratamento farmacológico , Linfoma/genética , Linfoma/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Purinas , Quinazolinonas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Eur J Cancer Prev ; 27(2): 180-183, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-27479542

RESUMO

The aim of this study is to evaluate the association between metabolic disorders and the risk of nasopharyngeal carcinoma, considering different histological subtypes. Between 1992 and 2008, we carried out a multicentre case-control study in Italy. One-hundred and ninety-seven White patients with histologically confirmed nasopharyngeal carcinoma were enrolled as cases. The control group included 592 cancer-free patients, frequency matched by study centre, area of residence, sex, age and period of interview. Odds ratios (OR) and corresponding 95% confidence intervals (CI), for nasopharyngeal carcinoma according to obesity and self-reported history of other metabolic disorders, were calculated through logistic regression models adjusted for matching variables and tobacco smoking and drinking habits. Obesity (OR=1.44; 95% CI: 0.88-2.36), diabetes mellitus (OR=0.91; 95% CI: 0.42-1.98), hypertension (OR=0.79; 95% CI: 0.48-1.32), hypercholesterolaemia (OR=1.41; 95% CI: 0.84-2.35) and metabolic syndrome (i.e. at least three among the four previously cited metabolic disorders; OR=1.11; 95% CI: 0.86-1.43) were not significantly associated with the overall risk of nasopharyngeal carcinoma. However, the associations observed for diabetes mellitus, hypercholesterolaemia and metabolic syndrome were stronger among differentiated nasopharyngeal carcinomas than among undifferentiated ones. In particular, 21.7% of differentiated nasopharyngeal carcinoma cases and 7.8% of controls reported a history of metabolic syndrome (OR=3.37; 95% CI: 1.05-10.81). The results of the study indicated no overall association between metabolic disorders and nasopharyngeal carcinoma. Nonetheless, although the small sample size calls for caution in interpretation, metabolic disorders could increase the risk of differentiated nasopharyngeal carcinoma. This finding further supports a different aetiology of the two histological subtypes.


Assuntos
Diabetes Mellitus/epidemiologia , Hipercolesterolemia/epidemiologia , Síndrome Metabólica/epidemiologia , Carcinoma Nasofaríngeo/epidemiologia , Neoplasias Nasofaríngeas/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Incidência , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco
19.
Br J Nutr ; 117(10): 1456-1462, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28606221

RESUMO

The dietary inflammatory indexTM (DII) has been shown to correlate with concentrations of several inflammatory markers and a variety of chronic disease endpoints, including cancers of various anatomic sites. We investigated whether the DII was associated with the risk for death among women with breast cancer (BrCa). This retrospective cohort study included 1453 women with BrCa, diagnosed between 1990 and 1994, and previously enrolled in a case-control study in northern Italy. With a median follow-up of 12·6 years, we observed 503 deaths, among which 398 were due to BrCa. The usual diet was assessed at BrCa diagnosis using a validated FFQ. DII scores were calculated using thirty-one foods/nutrients. Hazard ratios (HR) of death from all causes or from BrCa, with corresponding 95 % CI, were calculated using the Cox models, adjusted for age at diagnosis, tumour stage, oestrogen/progesterone receptor status and other potential confounders. The median DII score of the study women was -1·23, with a relatively narrow range (interquartile range -2·24 to -0·11), indicating a mainly anti-inflammatory diet. There was no difference in survival according to DII tertiles, neither considering all-cause mortality (HRtertile III v. I 1·00; 95 % CI 0·78, 1·28) nor BrCa-specific mortality (HRtertile III v. I 0·97; 95 % CI 0·73, 1·27). Study findings did not suggest an association between the inflammatory potential of diet, measured by the DII, and the survival of BrCa women. However, further studies are needed in populations reporting higher DII scores and a broader range of variability in the scores.


Assuntos
Neoplasias da Mama/epidemiologia , Dieta/efeitos adversos , Inflamação/etiologia , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Itália/epidemiologia , Pessoa de Meia-Idade , Estudos Retrospectivos
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