Charting differentially methylated regions in cancer with Rocker-meth

Matteo Benelli et al. present Rocker-meth, a new Hidden Markov Model (HMM)-based method, to robustly identify differentially methylated regions (DMRs). They use Rocker-meth to analyse more than 6000 methylation profiles across 14 cancer types, providing a catalog of tumor-specific and shared DMRs

The archaeal elongation factor EF-2 induces the release of aIF6 from 50S ribosomal subunit

The translation factor IF6 is a protein of about 25 kDa shared by the Archaea and the Eukarya but absent in Bacteria. It acts as a ribosome anti-association factor that binds to the large subunit preventing the joining to the small subunit. It must be released from the large ribosomal subunit to permit its entry to the translation cycle. In Eukarya, this process occurs by the coordinated action of the GTPase Efl1 and the docking protein SBDS. Archaea do not possess a homolog of the former factor while they have a homolog of SBDS. In the past, we have determined the function and ribosomal localization of the archaeal (Sulfolobus solfataricus) IF6 homolog (aIF6) highlighting its similarity to the eukaryotic counterpart. Here, we analyzed the mechanism of aIF6 release from the large ribosomal subunit. We found that, similarly to the Eukarya, the detachment of aIF6 from the 50S subunit requires a GTPase activity which involves the archaeal elongation factor 2 (aEF-2). However, the release of aIF6 from the 50S subunits does not require the archaeal homolog of SBDS, being on the contrary inhibited by its presence. Molecular modeling, using published structural data of closely related homologous proteins, elucidated the mechanistic interplay between the aIF6, aSBDS, and aEF2 on the ribosome surface. The results suggest that a conformational rearrangement of aEF2, upon GTP hydrolysis, promotes aIF6 ejection. On the other hand, aSBDS and aEF2 share the same binding site, whose occupation by SBDS prevents aEF2 binding, thereby inhibiting aIF6 release

Socio-economic disparities in the appropriateness of diabetes care in an Italian region: findings of AEQUITAS study

Background: To evaluate socio-economic disparities in diabetes prevalence and care in Marches (a region of central Italy) in 2003-2010 through a cross-sectional study. Methods: The databases of 52 general practitioners were mined for people with diabetes (age ≥20 years). These data were linked with records from other regional administrative databases. Healthcare disparities, specifically potentially preventable hospitalizations (PPH) related to diabetes and its complications, were analysed using participants’ gender, age, and education data and the Italian Deprivation Index. Crude, age-specific and gender-specific diabetes prevalence was estimated for each year of observation. A time-trend analysis was performed. Admissions that might have been prevented according to Agency for Healthcare Research and Quality criteria were used to calculate the PPH rate for each level of social condition indicators. Rate ratios and 95% confidence intervals were estimated with a multiple Poisson regression model. Results: The search found 6,494 participants with diabetes mellitus aged ≥20 years. Disease prevalence ranged from 5.4% (2003) to 7.8% (2010), with a significant 0.31% positive trend. Those aged ≤44 years were at significantly higher risk of PPH than older people. A significant PPH excess was found among people living in socio-economically disadvantaged areas. Education and gender did not significantly affect PPH. Conclusion. People with diabetes seem to use primary care services appropriately irrespective of socio-economic status. Outpatient services are not equally distributed on the regional territory; this may increase disease severity and/or the risk of diabetes complications and affect appropriateness of diabetes care

Case report: A novel patient presenting TRIM32-related limb-girdle muscular dystrophy

Limb-girdle muscular dystrophy autosomal recessive 8 (LGMDR8) is a rare clinical manifestation caused by the presence of biallelic variants in the TRIM32 gene. We present the clinical, molecular, histopathological, and muscle magnetic resonance findings of a novel 63-years-old LGMDR8 patient of Italian origins, who went undiagnosed for 24 years. Clinical exome sequencing identified two TRIM32 missense variants, c.1181G > A p.(Arg394His) and c.1781G > A p.(Ser594Asp), located in the NHL1 and NHL4 structural domains, respectively, of the TRIM32 protein. We conducted a literature review of the clinical and instrumental data associated to the so far known 26 TRIM32 variants, carried biallelically by 53 LGMDR8 patients reported to date in 20 papers. Our proband's variants were previously identified only in three independent LGMDR8 patients in homozygosis, therefore our case is the first in literature to be described as compound heterozygous for such variants. Our report also provides additional data in support of their pathogenicity, since p.(Arg394His) is currently classified as a variant of uncertain significance, while p.(Ser594Asp) as likely pathogenic. Taken together, these findings might be useful to improve both the genetic counseling and the diagnostic accuracy of this rare neuromuscular condition

Solid Organ Transplantation During COVID-19 Pandemic: An International Web-based Survey on Resources’ Allocation

Background. Solid organ transplants (SOTs) are life-saving interventions, recently challenged by coronavirus disease 2019 (COVID-19). SOTs require a multistep process, which can be affected by COVID-19 at several phases. Methods. SOT-specialists, COVID-19-specialists, and medical ethicists designed an international survey according to CHERRIES guidelines. Personal opinions about continuing SOTs, safe managing of donors and recipients, as well as equity of resources' allocation were investigated. The survey was sent by e-mail. Multiple approaches were used (corresponding authors from Scopus, websites of scientific societies, COVID-19 webinars). After the descriptive analysis, univariate and multivariate ordinal regression analysis was performed. Results. There were 1819 complete answers from 71 countries. The response rate was 49%. Data were stratified according to region, macrospecialty, and organ of interest. Answers were analyzed using univariate- multivariate ordinal regression analysis and thematic analysis. Overall, 20% of the responders thought SOTs should not stop (continue transplant without restriction); over 70% suggested SOTs should selectively stop, and almost 10% indicated they should completely stop. Furthermore, 82% agreed to shift resources from transplant to COVID-19 temporarily. Briefly, main reason for not stopping was that if the transplant will not proceed, the organ will be wasted. Focusing on SOT from living donors, 61% stated that activity should be restricted only to "urgent"cases. At the multivariate analysis, factors identified in favor of continuing transplant were Italy, ethicist, partially disagreeing on the equity question, a high number of COVID-19- related deaths on the day of the answer, a high IHDI country. Factors predicting to stop SOTs were Europe except-Italy, public university hospital, and strongly agreeing on the equity question. Conclusions. In conclusion, the majority of responders suggested that transplant activity should be continued through the implementation of isolation measures and the adoption of the COVID-19-free pathways. Differences between professional categories are less strong than supposed

Identification and development of epigenetic tumor biomarkers through computational biology approaches

DNA-methylation alterations are common in cancer and display unique characteristics that make them ideal markers for tumor quantification and classification. In this study, we discuss the development and testing of a computational framework exploiting minimal DNA-methylation signatures composed by a few dozen informative DNA-methylation sites to quantify and classify tumor signals in tissue and cell-free DNA samples. Extensive analyses of multiple independent and heterogenous datasets including >7,200 samples demonstrate the capability of the framework to provide precise estimations of tumor content and to enable accurate classification of tumor type and molecular subtype. To evaluate its applicability in the clinical context, we designed an informed assay incorporating the minimal signatures for breast cancer. Using both artificial samples and clinical serial cell-free DNA samples from patients with metastatic breast cancer, we show that our approach provides accurate estimations of tumor content, sensitive detection of tumor signal and the ability to capture clinically relevant molecular subtype in patients’ circulation. This study provides evidence that an extremely parsimonious approach can be used to develop cost-effective and highly-scalable DNA-methylation assays that could support and facilitate the implementation of precision oncology in clinical practice

Information System and Systems Thinking: A Compulsory Marriage?

Information systems play a fundamental role in enterprise management and development. Moving from MRP to ERP and from CAD to PLM, the amount of information stored in the enterprises' computers increased exponentially. Nowadays enterprises face a double-faced risk: on one side they have increasing difficulties in the management of large amount of information and sometimes they lose the access to important data; on the other side the availability of large amount of information allows for unconstrained modification of product development process and sometimes it promotes solutions which do not preserve the enterprises' core competences. Both problems could be solved by experts trained to manage complex data in complex systems. The evolution of information systems from MRP to ERP and from CAD to PLM may require a new approach based on a holistic view or, in engineering words, on system thinking. The paper deals with such hypothesis: the adoption of system thinking approach in product development process and the skills required to people involved in the proces

Firm-level Drivers of Export Performance and External Competitiveness in Italy

This paper provides an in-depth study on the main firm-level drivers of external competitiveness during the recent crisis in Italy. We contribute to the debate on the Italian international position by presenting evidence based on a unique sample survey database (the MET dataset). Overall, our results confirm the high degree of heterogeneity of the Italian corporate sector and the well-known differences between internationalised and domestic companies in terms of performance as well as structure and behaviour. In particular, the data highlight not only the correlation between internationalisation and innovative activities but also a positive change of attitude of Italian firms towards these strategies. Our analysis shows that, whilst structural factors play a key role for external competitiveness (size, location, industry, etc.), other critical firm-level aspects, especially those related to strategic profiles, technological capabilities, and ‘proactive’ behaviour, trigger superior performances. To this extent, our policy suggestions focus on the need to sustain and foster innovative activities to improve aggregate competitiveness

Shear modulus reduction and damping ratios curves joined with engineering geological units in Italy

Abstract Numerical simulations of seismic site response require the characterization of the nonlinear behaviour of shallow subsoil. When extensive evaluations are of concern, as in the case of seismic microzonation studies, funding problems prevent from the systematic use of laboratory tests to provide detailed evaluations. For this purpose, 485 shear modulus reduction, G\G0(γ) and damping ratio, D(γ) curves were collected from multiple literature sources available in Italy. Each curve was associated with the related engineering geological units considered in seismic microzonation studies. A statistical analysis of the data was carried out with the aim of shedding light on the significant difference between the laboratory classification of samples and the macroscopic/engineering geological one, provided during seismic microzonation studies. Since the engineering geological classification plays a prominent role in extensive site response evaluations, the outcomes of the present work may be of help at least when preliminary seismic response estimates are of concern. The dataset provides reference information that can serve as key data for large-scale hazard assessments worldwide