Prevalence and Prognostic Role of IDH Mutations in Acute Myeloid Leukemia: Results of the GIMEMA AML1516 Protocol

IDH1/2 mutations are common in acute myeloid leukemia (AML) and represent a therapeutic target. The GIMEMA AML1516 observational protocol was designed to study the prevalence of IDH1/2 mutations and associations with clinico-biological parameters in a cohort of Italian AML patients. We analyzed a cohort of 284 AML consecutive patients at diagnosis, 139 females and 145 males, of a median age of 65 years (range: 19–86). Of these, 38 (14%) harbored IDH1 and 51 (18%) IDH2 mutations. IDH1/2 mutations were significantly associated with WHO PS >2 (p < 0.001) and non-complex karyotype (p = 0.021) when compared to IDH1/2-WT. Furthermore, patients with IDH1 mutations were more frequently NPM1-mutated (p = 0.007) and had a higher platelet count (p = 0.036). At relapse, IDH1/2 mutations were detected in 6 (25%) patients. As per the outcome, 60.5% of IDH1/2-mutated patients achieved complete remission; overall survival and event-free survival at 2 years were 44.5% and 36.1%, respectively: these rates were similar to IDH1/2-WT. In IDH1/2-mutated patients, high WBC proved to be an independent prognostic factor for survival. In conclusion, the GIMEMA AML1516 confirms that IDH1/2 mutations are frequently detected at diagnosis and underlines the importance of recognizing IDH1/2-mutated cases up-front to offer the most appropriate therapeutic strategy, given the availability of IDH1/2 inhibitors

Hypogammaglobulinemia and risk of severe infection in kidney transplant recipients

Background Recent data have outlined a link between hypogammaglobulinemia (HGG) and infection risk and suggested that HGG correction may decrease post‐transplant infections. Methods We analyzed the risk factors of HGG and the relationship between HGG and the risk of severe infection in a cohort of 318 kidney transplant recipients (KTR) who were transplanted between 2003 and 2013. Immunoglobulin (Ig) concentration was measured prospectively at day 15 (D15), month 6 (M6), month 12 (M12), and month 24 (M24) post transplant. Results The prevalence of IgG HGG was 56% and 36.8% at D15 and M6, respectively. Age was the sole identified risk factors for D15 IgG HGG (odds ratio [OR] 1.02, P = 0.019). Risk factors for M6 IgG HGG were the presence of D15 IgG HGG (OR 6.41, P < 0.001) and treatment of acute rejection (OR 2.63, P = 0.014). Most infections occurred between D15 and M6 post transplant. Only age (hazard ratio 1.03, P < 0.001) was identified as a risk factor of infection between D15 and M6 post transplant. Survival free of infection (overall infections and bacterial or viral infections) did not differ significantly between patients with or without D15 IgG HGG. Only septicemia occurring between M6 and M12 post transplant was more frequently observed in patients with HGG. The low prevalence of severe HGG (<400 mg/dL) did not allow conclusions on the infectious risk associated with this patient subgroup. Conclusions This study does not support the existence of a strong link between post‐transplant HGG and the risk of severe infections in KTR. Correction of HGG to minimize the risk of severe infections in KTR is thus questionable and needs to be reevaluated in prospective studies

Whole-Blood Flow-Cytometric Analysis of Antigen-Specific CD4 T-Cell Cytokine Profiles Distinguishes Active Tuberculosis from Non-Active States

T-cell based IFN-γ release assays do not permit distinction of active tuberculosis (TB) from successfully treated disease or latent M. tuberculosis infection. We postulated that IFN-γ and IL-2 cytokine profiles of antigen-specific T cells measured by flow-cytometry ex vivo might correlate with TB disease activity in vivo. Tuberculin (PPD), ESAT-6 and CFP-10 were used as stimuli to determine antigen-specific cytokine profiles in CD4 T cells from 24 patients with active TB and 28 patients with successfully treated TB using flow-cytometry. Moreover, 25 individuals with immunity consistent with latent M. tuberculosis infection and BCG-vaccination, respectively, were recruited. Although the frequency of cytokine secreting PPD reactive CD4 T cells was higher in patients with active TB compared to patients with treated TB (median 0.81% vs. 0.39% of CD4 T cells, p = 0.02), the overlap in frequencies precluded distinction between the groups on an individual basis. When assessing cytokine profiles, PPD specific CD4 T cells secreting both IFN-γ and IL-2 predominated in treated TB, latent infection and BCG-vaccination, whilst in active TB the cytokine profile was shifted towards cells secreting IFN-γ only (p<0.0001). Cytokine profiles of ESAT-6 or CFP-10 reactive CD4 T cells did not differ between the groups. Receiver operator characteristics (ROC) analysis revealed that frequencies of PPD specific IFN-γ/IL-2 dual-positive T cells below 56% were an accurate marker for active TB (specificity 100%, sensitivity 70%) enabling effective discrimination from non-active states. In conclusion, a frequency lower than 56% IFN-γ/IL-2 dual positive PPD-specific circulating CD4 T-cells is strongly indicative of active TB

Association of Mitochondrial DNA Variations with Lung Cancer Risk in a Han Chinese Population from Southwestern China

Mitochondrial DNA (mtDNA) is particularly susceptible to oxidative damage and mutation due to the high rate of reactive oxygen species (ROS) production and limited DNA-repair capacity in mitochondrial. Previous studies demonstrated that the increased mtDNA copy number for compensation for damage, which was associated with cigarette smoking, has been found to be associated with lung cancer risk among heavy smokers. Given that the common and “non-pathological” mtDNA variations determine differences in oxidative phosphorylation performance and ROS production, an important determinant of lung cancer risk, we hypothesize that the mtDNA variations may play roles in lung cancer risk. To test this hypothesis, we conducted a case-control study to compare the frequencies of mtDNA haplogroups and an 822 bp mtDNA deletion between 422 lung cancer patients and 504 controls. Multivariate logistic regression analysis revealed that haplogroups D and F were related to individual lung cancer resistance (OR = 0.465, 95%CI = 0.329–0.656, p<0.001; and OR = 0.622, 95%CI = 0.425–0.909, p = 0.014, respectively), while haplogroups G and M7 might be risk factors for lung cancer (OR = 3.924, 95%CI = 1.757–6.689, p<0.001; and OR = 2.037, 95%CI = 1.253–3.312, p = 0.004, respectively). Additionally, multivariate logistic regression analysis revealed that cigarette smoking was a risk factor for the 822 bp mtDNA deletion. Furthermore, the increased frequencies of the mtDNA deletion in male cigarette smoking subjects of combined cases and controls with haplogroup D indicated that the haplogroup D might be susceptible to DNA damage from external ROS caused by heavy cigarette smoking

La renovación de la palabra en el bicentenario de la Argentina : los colores de la mirada lingüística

El libro reúne trabajos en los que se exponen resultados de investigaciones presentadas por investigadores de Argentina, Chile, Brasil, España, Italia y Alemania en el XII Congreso de la Sociedad Argentina de Lingüística (SAL), Bicentenario: la renovación de la palabra, realizado en Mendoza, Argentina, entre el 6 y el 9 de abril de 2010. Las temáticas abordadas en los 167 capítulos muestran las grandes líneas de investigación que se desarrollan fundamentalmente en nuestro país, pero también en los otros países mencionados arriba, y señalan además las áreas que recién se inician, con poca tradición en nuestro país y que deberían fomentarse. Los trabajos aquí publicados se enmarcan dentro de las siguientes disciplinas y/o campos de investigación: Fonología, Sintaxis, Semántica y Pragmática, Lingüística Cognitiva, Análisis del Discurso, Psicolingüística, Adquisición de la Lengua, Sociolingüística y Dialectología, Didáctica de la lengua, Lingüística Aplicada, Lingüística Computacional, Historia de la Lengua y la Lingüística, Lenguas Aborígenes, Filosofía del Lenguaje, Lexicología y Terminología

Activated T lymphocytes instruct monocytes to differentiate into inflammatory dendritic cells in a feedback control of human Th1/Th2 responses

Le cellule dendritiche (DCs) rappresentano una popolazione di cellule eterogenea con diversa origine, fenotipo e funzione che svolge un ruolo chiave nell' induzione, coordinazione e mantenimento delle risposte immunitarie adattative. La maggior parte delle conoscenze riguardanti le DCs sono state acquisite grazie ad esperimenti eseguiti con DCs fatte differenziare in vitro da monociti trattati con diverse combinazioni di citochine; in particolare è ormai noto che i monociti umani differenziano a DCs se coltivati con il fattore di stimolazione di colonie granulocita rie/macrofagiche(GM-CSF) e interleuchina (IL)-4. Tuttavia, la possibilità che i monociti rappresentino i precursori di DCs umane tissutali in condizioni fisiologiche rimane un' ipotesi controversa. Inoltre, non è stato ancora definitivamente stabilito quale sia la popolazione cellulare responsabile della sintesi delle citochine necessarie al differenziamento di monociti in vitro ed in che modo il loro rilascio venga regolato in vivo. In questa tesi viene dimostrato come, in seguito ad attivazione specifica, i linfociti T sono in grado di rilasciare citochine che a loro volta inducono il differenziamento in DCs sia di monociti presentanti l' antigene che di monociti circolanti. In base alla polarizzazione funzionale dei linfociti T attivati, i monociti differenziano in DCs con diverso fenotipo e funzionalità. I monociti esposti alle citochine rilasciate da linfociti T helper (Th) 1 e Th0 differenziano in DCs caratterizzate da una ridotta capacità di captazione e presentazione dell' antigene. Inoltre, queste DCs mostrano una capacità limitata nellâ'indurre una polarizzazione in senso Th1 delle cellule T naive, bensì sono in grado di attivare cellule T naive secernenti IL-10, dimostrando in questo modo un potenziale tollerogenico. Al contrario, DCs derivate da monociti che risentono di citochine rilasciate da linfociti Th2 sono cellule presentanti l' antigene (APC) caratterizzate da una marcata capacità di polarizzazione in senso Th1. Partendo dalla considerazione che i monociti vengono reclutati insieme ai linfociti in siti di infiammazione cronica, i risultati ottenuti in questo lavoro suggeriscono che, in ambienti caratterizzati da un rilascio prevalente di citochine associate a cellule Th1, Th0 o Th2, possono essere generate DCs funzionalmente differenti tra loro. Poiché le capacità dimostrate da queste DCs come cellule presentanti l' antigene hanno conseguenze funzionali opposte, è stato proposto un modello in vitro in grado di riprodurre il contributo delle DCs infiammatorie, derivate da monociti, nella regolazione della risposta immunitaria in atto.Dendritic cells (DCs) are a heterogeneous population of cells with different origin, phenotype and function that share the crucial role of inducing, coordinating and maintaining adaptive immune responses. Most of the knowledge on human DCs relies on experiments performed with DCs differentiated in vitro from monocytes treated with diverse cocktails of recombinant cytokines; in particular it is well established that human monocytes differentiate into DCs when cultured with granulocyte-macrophage colony-stimulating factor and interleukin (IL)-4. However, the possibility that monocytes represent precursors for tissue human DCs under physiological conditions remains controversial. Moreover, it is not completely established which cell population synthesizes the cytokines required for monocyte differentiation in vitro and how their secretion is regulated in vivo. In this thesis is shown that, on specific activation, T lymphocytes are capable of secreting cytokines, which in turn induce the differentiation into DCs of antigen-presenting and bystander monocytes. Depending on the functional polarization of the activated T lymphocytes, monocytes differentiate into DCs with diverse phenotype and functionality. Monocytes exposed to cytokines released by T helper (Th) 1 and Th0 lymphocytes differentiate into DCs with a reduced antigen uptake and antigen presentation capacity. Moreover, these DCs show a limited capacity to induce Th1 polarization of naive T cells but are capable of priming IL-10-secreting T cells, thus displaying tolerogenic potential. Conversely, DCs derived from monocytes sensing cytokines released by Th2 lymphocytes are antigen-presenting-cell (APC) endowed with a marked Th1 polarization capacity. Starting from the point that monocytes are co-recruited with lymphocytes in chronic inflammation sites, the results obtained in this work suggest that functionally different DCs can be generated in environments characterized by the prevalent release of Th1-, Th0-, or Th2-associated cytokines. Because the APC capacities of these DCs showed opposite functional consequences, it has been proposed an in vitro model that can reproduce a contribution in the regulation of the ongoing immune response by monocyte-derived inflammatory DCs

Protocollo tecnico per la valutazione degli apparecchi acustici a conduzione aerea

SIGLEITItal