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Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged >= 80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged >= 80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged >= 80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency >= 0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged >= 80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged >= 80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged >= 80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.

Long non-coding RNAs (lncRNAs), an emerging group of gene expression regulators in normal and cancer cells, are defined as endogenous RNAs consisting of more than 200 nucleotides and lacking an ope...

We studied the impact of driver mutations of JAK2, CALR, (calreticulin gene) or MPL on clinical course, leukemic transformation, and survival of patients with primary myelofibrosis (PMF). Of the 617 subjects studied, 399 (64.7%) carried JAK2 (V617F), 140 (22.7%) had a CALR exon 9 indel, 25 (4.0%) carried an MPL (W515) mutation, and 53 (8.6%) had nonmutated JAK2, CALR, and MPL (so-called triple-negative PMF). Patients with CALR mutation had a lower risk of developing anemia, thrombocytopenia, and marked leukocytosis compared with other subtypes. They also had a lower risk of thrombosis compared with patients carrying JAK2 (V617F). At the opposite, triple-negative patients had higher incidence of leukemic transformation compared with either CALR-mutant or JAK2-mutant patients. Median overall survival was 17.7 years in CALR-mutant, 9.2 years in JAK2-mutant, 9.1 years in MPL-mutant, and 3.2 years in triple-negative patients. In multivariate analysis corrected for age, CALR-mutant patients had better overall survival than either JAK2-mutant or triple-negative patients. The impact of genetic lesions on survival was independent of current prognostic scoring systems. These observations indicate that driver mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials.

The settlement of Gorgo del Ciliegio (Sansepolcro-Arezzo) is situated on an ancient terrace on the left bank of the Afra Creek, at about 400 metres above sea level, near-by the tuscan-emilian Appennines divide. During the six last years (2001 -2006) an area of approximately 178 square meters was investigated, resulting in the fi ndings of a living fl oor with several structures (pole holes, combustion structures, pits of different typology), including a small food oven of particular interest. The pottery retrieved from the deposit is represented by cylindrical, troncoconic and globular vessels, among which milk boilers are present, carinated shapes (bowls, cups) and some sherds decorated in the Appennine styles, which has allowed for the attribution of the site to an early phase of the Middle Bronze 3 (BM3). The Middle Bronze Age people settled on a preserved portion of an alluvial surface (T1a) standing about 10 meters higher than the coeval active channel of the Afra Creek, whose deposits are bounded by the surface T2. This location ensured a relative protection from fl oods being, at the same time, close to a large water source. Sedimentological features of the alluvial gravels bounded on top by T1a and T2 surfaces, suggest a significantly different fl uvial style during the late Holocene compared to the modern Afra Creek. Before (e.g. T1a deposits) and during (e.g. T2 deposits) the human occupation at this site, the Afra Creek was characterized by a relatively wide (about 150 meters) valley with multiple shallow channels inside, fi lled by gravels. This style can be observed in some modern creeks of the Upper Tiber River basin, indicating local condition of channel overfilling. On the whole this ancient style contrasts with the modern one in which a few tens meter wide Afra Creek is deeply entrenched in the bedrock and still affected by erosive processes. Despite the different valley morphology attained during the late Holocene, the terracing of the Afra Creek recorded at the site, attests to successive readjustment of the river profile to repeated perturbation of base level possibly due to the active tectonic setting of the Upper Tiber River valley. The preliminary results of the archeozoological study demonstrate that the inhabitants of Gorgo del Ciliegio were involved in the rearing of mostly sheep-goats and pigs and cattle in the second place, and in the hunting of deer and roe-deer; domestic dogs were present on the site. Such a pattern and the geographic location of the site, might suggest that Gorgo del Ciliegio community mostly practised mobile pastoralism and the dogs may have been kept to assist with herding the animals. Preliminary pollen analysis of the archaeological soil, reveals a scarcity and a bad preservation of the pollen grains possibly due to a highly acidic environment. Nevertheless, few grains of Urticaceae point to local anthropic impact on the vegetation cover, fully consistent with the settlement activity.

We studied the impact of driver mutations of JAK2, CALR, (calreticulin gene) or MPL on clinical course, leukemic transformation, and survival of patients with primary myelofibrosis (PMF). Of the 617 subjects studied, 399 (64.7%) carried JAK2 (V617F), 140 (22.7%) had a CALR exon 9 indel, 25 (4.0%) carried an MPL (W515) mutation, and 53 (8.6%) had nonmutated JAK2, CALR, and MPL (so-called triple-negative PMF). Patients with CALR mutation had a lower risk of developing anemia, thrombocytopenia, and marked leukocytosis compared with other subtypes. They also had a lower risk of thrombosis compared with patients carrying JAK2 (V617F). At the opposite, triple-negative patients had higher incidence of leukemic transformation compared with either CALR-mutant or JAK2-mutant patients. Median overall survival was 17.7 years in CALR-mutant, 9.2 years in JAK2-mutant, 9.1 years in MPL-mutant, and 3.2 years in triple-negative patients. In multivariate analysis corrected for age, CALR-mutant patients had better overall survival than either JAK2-mutant or triple-negative patients. The impact of genetic lesions on survival was independent of current prognostic scoring systems. These observations indicate that driver mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials.

Primary myelofibrosis (PMF) is a Philadelphia-negative (Ph-) myeloproliferative disorder, showing abnormal CD34+ progenitor cell trafficking, splenomegaly, marrow fibrosis leading to extensive extramedullary haematopoiesis, and abnormal neoangiogenesis in either the bone marrow or the spleen. Monocytes expressing the angiopoietin-2 receptor (Tie2) have been shown to support abnormal angiogenic processes in solid tumors through a paracrine action that takes place in proximity to the vessels. In this study we investigated the frequency of Tie2 expressing monocytes in the spleen tissue samples of patients with PMF, and healthy subjects (CTRLs), and evaluated their possible role in favouring spleen angiogenesis. We show by confocal microscopy that in the spleen tissue of patients with PMF, but not of CTRLs, the most of the CD14+ cells are Tie2+ and are close to vessels; by flow cytometry, we found that Tie2 expressing monocytes were Tie2+CD14lowCD16brightCDL62-CCR2- (TEMs) and their frequency was higher (p = 0.008) in spleen tissue-derived mononuclear cells (MNCs) of patients with PMF than in spleen tissue-derived MNCs from CTRLs undergoing splenectomy for abdominal trauma. By in vitro angiogenesis assay we evidenced that conditioned medium of immunomagnetically selected spleen tissue derived CD14+ cells of patients with PMF induced a denser tube like net than that of CTRLs; in addition, CD14+Tie2+ cells sorted from spleen tissue derived single cell suspension of patients with PMF show a higher expression of genes involved in angiogenesis than that found in CTRLs. Our results document the enrichment of Tie2+ monocytes expressing angiogenic genes in the spleen of patients with PMF, suggesting a role for these cells in starting/maintaining the pathological angiogenesis in this organ.