Clonal hematopoiesis related TET2 loss-of-function impedes IL1ß-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells.

Clonal hematopoiesis (CH) is defined as a single hematopoietic stem/progenitor cell (HSPC) gaining selective advantage over a broader range of HSPCs. When linked to somatic mutations in myeloid malignancy-associated genes, such as TET2-mediated clonal hematopoiesis of indeterminate potential or CHIP, it represents increased risk for hematological malignancies and cardiovascular disease. IL1ß is elevated in patients with CHIP, however, its effect is not well understood. Here we show that IL1ß promotes expansion of pro-inflammatory monocytes/macrophages, coinciding with a failure in the demethylation of lymphoid and erythroid lineage associated enhancers and transcription factor binding sites, in a mouse model of CHIP with hematopoietic-cell-specific deletion of Tet2. DNA-methylation is significantly lost in wild type HSPCs upon IL1ß administration, which is resisted by Tet2-deficient HSPCs, and thus IL1ß enhances the self-renewing ability of Tet2-deficient HSPCs by upregulating genes associated with self-renewal and by resisting demethylation of transcription factor binding sites related to terminal differentiation. Using aged mouse models and human progenitors, we demonstrate that targeting IL1 signaling could represent an early intervention strategy in preleukemic disorders. In summary, our results show that Tet2 is an important mediator of an IL1ß-promoted epigenetic program to maintain the fine balance between self-renewal and lineage differentiation during hematopoiesis.

A new cylindrical borehole detector for radiographic imaging with muons.

Muon radiography is a methodology which enables measuring the mass distribution within large objects. It exploits the abundant flux of cosmic muons and uses detectors with different technologies depending on the application. As the sensitive surface and geometric acceptance are two fundamental parameters for increasing the collection of muons, the optimization of the detectors is very significant. Here we show a potentially innovative detector of size and shape suitable to be inserted inside a borehole, that optimizes the sensitive area and maximizes the angular acceptance thanks to its cylindrical geometry obtained using plastic arc-shaped scintillators. Good spatial resolution is obtained with a reasonable number of channels. The dimensions of the detector make it ideal for use in 25 cm diameter wells. Detailed simulations based on Monte Carlo methods show great cavity detection capability. The detector has been tested in the laboratory, achieving overall excellent performance.

Applications of muon absorption radiography to the fields of archaeology and civil engineering.

Muon radiography, also known as muography, is an imaging technique that provides information on the mass density distribution inside large objects. Muons are naturally produced in the interactions of cosmic rays in the Earth's atmosphere. The physical process exploited by muography is the attenuation of the muon flux, that depends on the thickness and density of matter that muons cross in the course of their trajectory. A particle detector with tracking capability allows the measurement of the muons flux as a function of the muon direction. The comparison of the measured muon flux with the expected one gives information on the distribution of the density of matter, in particular, on the presence of cavities. In this article, the measurement performed at Mt. Echia in Naples (Saracino 2017 Sci. Rep. 7, 1181. (doi:10.1038/s41598-017-01277-3)), will be discussed as a practical example of the possible application of muography in archaeology and civil engineering.This article is part of the Theo Murphy meeting issue 'Cosmic-ray muography'.

Tests of a novel imaging algorithm to localize hidden objects or cavities with muon radiography.

A novel algorithm developed within muon radiography to localize objects or cavities hidden inside large material volumes was recently proposed by some of the authors (Bonechi et al. 2015 J. Instrum. 10, P02003 (doi:10.1088/1748-0221/10/02/P02003)). The algorithm, based on muon back projection, helps to estimate the three-dimensional position and the transverse extension of detected objects without the need for measurements from different points of view, which would be required to make a triangulation. This algorithm can now be tested owing to the availability of real data collected both in laboratory tests and from real-world measurements. The methodology and some test results are presented in this paper.This article is part of the Theo Murphy meeting issue 'Cosmic-ray muography'.

Volcanoes in Italy and the role of muon radiography.

Cosmic-ray muon radiography (muography), an imaging technique that can provide measurements of rock densities within the top few 100 m of a volcanic cone, has now achieved a spatial resolution of the order of 10 m in optimal detection conditions. Muography provides images of the top region of a volcano edifice with a resolution that is considerably better than that typically achieved with other conventional methods (i.e. gravimetric). We expect such precise measurements, to provide us with information on anomalies in the rock density distribution, which can be affected by dense lava conduits, low-density magma supply paths or the compression with the depth of the overlying soil. The MUon RAdiography of VESuvius (MURAVES) project is now in its final phase of construction and deployment. Up to four muon hodoscopes, each with a surface of roughly 1 m2, will be installed on the slope of Vesuvius and take data for at least 12 months. We will use the muographic profiles, combined with data from gravimetric and seismic measurement campaigns, to determine the stratigraphy of the lava plug at the bottom of the Vesuvius crater, in order to infer potential eruption pathways. While the MURAVES project unfolds, others are using emulsion detectors on Stromboli to study the lava conduits at the top of the volcano. These measurements are ongoing: they have completed two measurement campaigns and are now performing the first data analysis.This article is part of the Theo Murphy meeting issue 'Cosmic-ray muography'.

Imaging of underground cavities with cosmic-ray muons from observations at Mt. Echia (Naples).

Muography is an imaging technique based on the measurement of absorption profiles for muons as they pass through rocks and earth. Muons are produced in the interactions of high-energy cosmic rays in the Earth's atmosphere. The technique is conceptually similar to usual X-ray radiography, but with extended capabilities of investigating over much larger thicknesses of matter thanks to the penetrating power of high-energy muons. Over the centuries a complex system of cavities has been excavated in the yellow tuff of Mt. Echia, the site of the earliest settlement of the city of Naples in the 8th century BC. A new generation muon detector designed by us, was installed under a total rock overburden of about 40 metres. A 26 days pilot run provided about 14 millions of muon events. A comparison of the measured and expected muon fluxes improved the knowledge of the average rock density. The observation of known cavities proved the validity of the muographic technique. Hints on the existence of a so far unknown cavity was obtained. The success of the investigation reported here demonstrates the substantial progress of muography in underground imaging and is likely to open new avenues for its widespread utilisation.

Activated Notch counteracts Ikaros tumor suppression in mouse and human T-cell acute lymphoblastic leukemia.

Activating NOTCH1 mutations occur in ~60% of human T-cell acute lymphoblastic leukemias (T-ALLs), and mutations disrupting the transcription factor IKZF1 (IKAROS) occur in ~5% of cases. To investigate the regulatory interplay between these driver genes, we have used a novel transgenic RNA interference mouse model to produce primary T-ALLs driven by reversible Ikaros knockdown. Restoring endogenous Ikaros expression in established T-ALL in vivo acutely represses Notch1 and its oncogenic target genes including Myc, and in multiple primary leukemias causes disease regression. In contrast, leukemias expressing high levels of endogenous or engineered forms of activated intracellular Notch1 (ICN1) resembling those found in human T-ALL rapidly relapse following Ikaros restoration, indicating that ICN1 functionally antagonizes Ikaros in established disease. Furthermore, we find that IKAROS mRNA expression is significantly reduced in a cohort of primary human T-ALL patient samples with activating NOTCH1/FBXW7 mutations, but is upregulated upon acute inhibition of aberrant NOTCH signaling across a panel of human T-ALL cell lines. These results demonstrate for the first time that aberrant NOTCH activity compromises IKAROS function in mouse and human T-ALL, and provide a potential explanation for the relative infrequency of IKAROS gene mutations in human T-ALL.

[Methodological aspects in the evaluation of turn-over and up/down sizing as indicators of work-related stress]. / Aspetti metodologici per la valutazione di turn-over e up/down-sizing quali indicatori di stress da lavoro.

We discuss the methodological aspects related to the evaluation of turn-over and up-down sizing as indicators of work-related stress, in complex organizations like a university hospital. To estimate the active workers population we developed an algorithm which integrated several administrative databases. The indicators were standardized to take into account some potential confounders (age, sex, work seniority) when considering different hospital structures and job mansions. Main advantages of our method include flexibility in the choice of the analysis detail (hospital units, job mansions, a combination of both) and the possibility to describe over-time trends to measure the success of preventive strategies.

[Assessment of job strain and its consequencies in a large public organisation. Findings from the SEMM Study]. / Valutazione del disagio psicosociale ed organizzativo in aziende pubbliche. L'esperienza dello Studio SEMM.

The demand-control model originally developed by Robert Karasek is in Italy the preferred tool to investigate perceived work stress due to work-related organizational constrains. We wish to report the comprehensive results of the SEMM Study, carried on a wide sample of civil servants. N. 5271 women and 2601 men, employed at the Municipality of Milan in the years 1991-1996 were enrolled into the study. The overall participation rate was high in both gender group (75% or more), indicating a good compliance of employees for health prevention programmes carried out in work settings. Each participant, who has given consent, in addition to the medical examinations and biological tests related to the investigation of work exposures, underwent to a structured procedure to measure cardiovascular risk factors, according to the methods developed in the WHO MONICA Project, job strain adopting the Job Content Questionnaire (JCQ), and the Baecke Questionnaire to investigate major quotes of physical activity. In this contest the JCQ has shown an acceptable level of internal and external consistency as well as of acceptance, measured by employees compliance. Psychological job demand and decision latitude can be assessed with two different JCQ revisions available in Italian, which were validated with the contribution of the author, at different complexity, but with comparable results of weighted scores. For a comprehensive assessment of the working conditions social support at work is also of relevance. In the work public sector considered, the JCQ major scores resulted to be valid descriptors of key aspects of the work organization. The concurrent assessment of sick leaves, known marker of burnout, allows to identify work- and individual-related determinants and, in a specific work setting, to give indications for coping actions which may improve workers' integration. In addition, the assessment of cardiovascular risk factors, carried out with standardised and then reliable methods, allow to measure overall global CVD risk and to identify unhealthy behaviours that can be addressed with specific preventive programmes.

[Alcohol consumption, pregnancy and fetal alcohol syndrome: implications in public health and preventive strategies]. / Alcolismo, gravidanza e fetopatia alcolica: implicazioni in Sanità Pubblica e strategie preventive.

Alcohol consumption during pregnancy is a significant public health problem and is an established cause of serious birth defects and developmental delay collectively described as fetal alcohol syndrome (FAS). FAS is caused by congenital alcohol-induced damages and is a cause of mental retardation. It is characterised by facial abnormalities and growth deficiency. Infants affected by the syndrome show intellectual impairment, and difficulties in learning, memory, problem-solving, and attention as well as experiencing additional problems with mental health and social interactions. However, an absence of the characteristic facial defects and growth deficiency may result in a failure to identify children with prenatal alcohol exposure, which can further present as alcohol-related neurodevelopment disorder (ARND) or alcohol-related birth defects (ARBD). Estimates of prevalence of FAS in U.S.A. range between 0.3 to 2.2 per 1,000 live births, but much higher rates occurring in some communities. Harmonisation of the methodology used for epidemiological studies, with research activities that establishes real baseline prevalence of FAS and identification of women who are at highest risk of bearing a FAS-affected child, are an essential prerequisite to prevention. In addition, it is essential to assess different FAS preventive approaches through carefully controlled studies. Universal, selected, and indicated preventive strategies have been identified, targeting different kind of populations. Since FAS and other adverse effects of drinking during pregnancy are theoretically completely preventable, it is vital to make more efforts to improve the application of the most appropriate interventions. Although in Italy alcohol consumption has constantly increased, mainly amongst the young (including women of childbearing age), knowledge on FAS and alcohol-related effects is completely lacking. Because of the high cost for care of individuals with this syndrome, it is essential to apply appropriate interventions to prevent this problem.

[Adaptability of the anti-hepatitis-B vaccine Recombivax HB to the Piazza protocol for the mass vaccination of newborn infants]. / Adattabilità del vaccino anti-epatite B Recombivax HB allo "schema Piazza" per la vaccinazione di massa dei nuovi nati.

27 healthy babies born to HBsAg, antiHBs and antiHBc negative mothers were given three doses of hepatitis B vaccine "Recombivax HB" (5 micrograms/dose/0.5 ml) at 3, 5 and 11 months of age (Piazza's protocol). AntiHBs response was highly satisfactory. Since both in terms of seroconversion rate and of mean antiHBs titre immunogenicity of other hepatitis B vaccines given at 3, 5 and 11 months of age was already demonstrated, it is possible to conclude that Piazza's protocol is valid for all hepatitis B vaccines available in Italy and will certainly facilitate the compulsory hepatitis B vaccination in infants in Italy.

Chronicity rate of hepatitis B virus infection in the families of 60 hepatitis B surface antigen positive chronic carrier children: role of horizontal transmission.

It is known that the 5%-10% of adults infected with hepatitis B virus (HBV) develop a chronic infection and that HBV infection acquired at birth by an hepatitis B surface antigen (HBsAg)/hepatitis B "e" antigen (HBeAg)-positive mother almost invariably leads to chronic infection. Little information is, however, available about the risk of HBV infection acquired in childhood becoming chronic. We have, therefore, studied the chronicity rate of HBV infection in the families of 60 consecutive HBsAg-positive chronic carrier children. Of parents 81.5% and 78.6% of children showed serological evidence of past or ongoing HBV infection. The chronicity rate was significantly higher among children (73.4%) than parents (35.6%). Such a high chronicity rate in these children was not correlated with vertical transmission, since this was reported in only 1.7% of them. It is noteworthy that the chronicity rate of HBV infection was not significantly different between children of HBsAg-positive mothers and those in whom infection must have been horizontally transmitted because their mothers were HBsAg-negative. Although the families studied represent a selected sample and the role of genetic factors could not be excluded, our results seem to show that the most important factor in determining the outcome of infection is the acquisition of hepatitis B during childhood.

A modified immunisation schedule for the hepatitis B vaccine Recombivax HB suitable for mass vaccination in childhood.

Following the demonstration of a fully satisfactory immunogenic activity of a hepatitis B vaccination protocol consisting of three doses of Hevac B Pasteur vaccine given at 3,5 and 11 months of age, it was possible to administer this vaccine at the same times as the vaccinations for diphtheria, tetanus and polio which are mandatory in Italy at those ages. We have also shown that both another plasma-derived vaccine, H-B-VAX (MSD), as well as the DNA-recombinant Engerix B (SK&F) are highly immunogenic when given at the same times as the mandatory childhood vaccinations. In this paper we demonstrate that the same schedule can be used for another hepatitis B vaccine prepared by a DNA-recombinant technique, Recombivax HB (MSD) recently introduced in Italy. In fact two doses of this vaccine, the first given at three months of age and the second two months later, resulted in a 100% seroconversion rate and a mean anti-HBs titre of 440 mUI/ml. Although the date are incomplete since the third dose will be given at 11 months of age, we conclude that this hepatitis B vaccine can also be used in the mass vaccination campaigns of infants in Italy, the first of which was initiated in January 1987 in an hyperendemic area near Naples (HBsAg prevalence about 14%). We underline that this mass vaccination campaign is the first in Europe.

Immunogenicity of a DNA-recombinant hepatitis B vaccine (Engerix B) given at 3, 5 and 11 months of age with a new schedule suitable for mass vaccination programmes.

Following the demonstration of a fully satisfactory immunogenic activity of a hepatitis B vaccination protocol consisting of three doses given at the 3rd and 5th months of age with a booster at 11, it was possible to administer this vaccine at the same times as the vaccinations for diphtheria, tetanus and polio which are mandatory in Italy at those ages. A field trial of this protocol in a hyperendemic area near Naples (prevalence of HBsAg about 14%) started on January 1987. The French vaccine, Hevac B, Pasteur, was used. At this time compliance is 99%, and fully satisfactory results both in terms of seroconversion rate (96.3%) and of mean anti-HBs titre (4,352 mIU/ml) two months after the booster dose have been obtained. In this paper we demonstrate that even for a new hepatitis B vaccine prepared by a DNA-recombinant technique (Engerix B, SK & F) recently introduced in Italy, the same schedule can be used. In fact two doses of this vaccine, the first given at three months of age and the second two months later, resulted in a 100% seroconversion rate and a mean anti-HBs titre of 560 mIU/ml. Two months after the booster given at 11 months of age the mean anti-HBs titre was 12,100.