UHRF1 coordinates DNA methylation and histone post-translational modifications in colon cancer .

In Colorectal cancer (CRC) genetic and epigenetic alterations are tightly connected, although these interactions on the patient\u2019s outcome are not clearly understood. A peculiar subclass of sporadic CRC tumors, is characterized by Microsatellite instability (MSI), due to hyper-methylated promoter of MHL1 gene and subsequent inactivation of the mismatch repair (MMR) mechanism, and the hypermethylation of CpG islands phenotype (CIMP), mediated by the hyper-methylation of promoter regions of several tumor suppressor genes (TSGs). This subclass carries a good prognosis and presents an inverse correlation with genomic and chromosome instability (CIN), together with a higher levels of DNA methylation at global level, compared to other CRCs. Among the epigenetic alterations, DNA methylation and histone modifications rearrangements are extremely important steps during tumorigenesis. UHRF1 is a key master epigenetic regulator that couples the maintenance of DNA methylation through the cell cycle with the histone-modification pattern. It monoubiquitinates H3K18/23 enabling the correct localization and activation of DNMT1 on the specific sites. UHRF1 is overexpressed in several cancer types mediating the hypermethylation of promoter regions of the TSGs and coordinating their heterochromatic silencing. Relying on the idea that UHRF1 could play a crucial role in the modulation of DNA methylation changes, the overall aim of this PhD thesis was to evaluate the role of UHRF1 in the coordination of DNA methylation and histone post-translational modifications both at genome-wide and at locus specific level in CRCs. Unexpectedly, we found that in CRC tissues UHRF1 was higher in tumors with microsatellite instability (MSI CRC), which have a better prognosis, compared to the stable ones (MSS CRC). MSI tumors were also characterized by higher levels of DNA methylation compared to the MSS. The UHRF1 knock-down in a MSI CRC cell line (RKO cells) induced an overall decrease in DNA methylation (RRB-seq analysis, pyrosequencing and MS-MLPA) both at global level and at gene promoters without affecting DNMTs levels, as observed by WB and RNA-seq analysis. ChIP experiments showed that UHRF1 depletion reduces DNMT1 binding to both repetitive elements (LINE-1) and specific gene promoters (MLH1, CDH1), decreasing H3K9me3 and increasing H3K4me3 on those hypo-methylated loci. RNA-seq data analysis showed that UHRF1 loss interferes with several important pathways, among others cell cycle, growth and proliferation. SILAC LC-MS/MS analysis showed that in RKO cells, UHRF1 loss decreases the overall presence of H3K23ub (\ubb 30%) and H3K18ub (\ubb 8%). These results, together with the published findings, led us to hypothesize a model in which the loss of UHRF1 directly impairs the DNA methylation maintenance by reducing H3K18/K23ub and consequently DNMT1 activity and, indirectly, impairs the binding of Suv39H1, the histone methyl transferase (HMT) responsible for H3K9me3, to both genome-wide and promoter specific loci. These changes led to a severe chromatin rearrangement of heterochromatic signatures toward a more open and transcriptionally accessible structure, probably due to the disruption of the axis UHRF1-H3ub-DNMT1-HMTs. Our molecular data, together with the analysis performed on CRC samples, led us to speculate that the better prognosis correlated with MSI-CRC model, could reside in the UHRF1-high levels that result in a sort of protective condition for the genome integrity, maintaining the global DNA methylation level closer to the normal mucosae, and probably counteracting the hyper-methylation of TSGs

The self motor evaluation/assessment in professional training of learning support teachers

One of the most significant experiences of SISS on the motor –training plan, which allowed in some cases the implementation of activity of research-action, was the motor- sports laboratory. The activity of laboratory in the motor- sports field and the motor subjects, along with specific training, represents in the SSIS (Specialization School Teaching Secondary) area an innovative element. This also gave a strong contribute to the definition of a new professional profile of the teacher that has in it those transversal skills needed to promote a new teaching, finding the necessary balances between the cognitive moment and the applicative and operative one

Evaluating the integration of the sensory-motor abilities to facilitate teaching-learning processes: a comparison between Italian and Indian models of teaching through the use of VMI test

Nowadays a great number of evidences seems to prove that the movement plays a central role in the integrationof different mental processes. The visual-motor feedback may be considered the first sensorial integration of thedevelopment. The importance of an effective support to the pre-adolescent development of the sensory-motorintegration ability seems one of most important aim that every school system should follow. The aim of thisresearch is to investigate and monitor on international scale if the current Italian and Indian schools systems canadequately support the development of the student’s sensory-motor integration ability. According to the datashowed in this paper, it is clear that the scores obtained by the Italian and Indian students are lower than theinternational mean. However if a wider analysis based on a larger and more representative sample of the twoCountries should confirm the output of this research, it will be clear that the two school systems cannoteffectively support the development of the visual-motor integration abilities of the students. If the trend showedin this work should be confirmed by future and more precise researches, it will be necessary an accurate analysisaimed to identify the possible reasons of this phenomenon and the possible school support, since without them, awhole generation of students will risk to reduce the cultural level of the two nations and to be not competitive onan international level

Physical education and sport in the Campania region

The didactic of physical activities in the school, while exercising the individual technical skills, never loses sight of the unity of knowledge and invites the child to reflect on his actions, on his mental and physical changes, but also on his knowledge. For this reason, the school is differs from sports federations and associations, and it must rise to the role of leadership in the sport education. After these necessary preambles, it seems now particularly interesting to introduce the scenario laid out by ISTAT (Italian Statistics Institute) survey \u201c100 statistics to understand the country we live in\u201d. The ISTAT analysis shows how Campania is the region after Sicily with the highest percentage of people with a sedentary lifestyle. It seems that in Campania, the primary school fails in its leadership role with regard to the sports education and the motor practices and in supporting non-sedentary lifestyles. In fact, in Campania the sport practice is very low and the level of giving up is particularly high. This discussion starts from this point and should be considered as a pilot study to evaluate a possible contributory cause of the status here outlined, i.e. the perception that teachers have of their own basic and technical skills in the motor field. It is not forbidden to think that, if this survey shows a widespread perception of lack of ability, this will adversely affect the motor teaching and be at least partly responsible for the situation described herein. Therefore the aim of this research is to monitor the level of the basic skills and of the motor teaching skills of primary school teachers in the region Campania, and the way they perceive the movement, highlighting any possible critical factor

Transcatheter Aortic Valve Implantation (TAVI) Planning with Dual-Layer Spectral CT Using Virtual Monoenergetic Image (VMI) Reconstructions and 20 mL of Contrast Media

Transcatheter aortic valve implantation (TAVI) is a less invasive alternative to surgical implantation and its implementation is progressively increasing worldwide. We routinely perform pre-procedural aortic angiography CT to assess aortic dimensions and vascular anatomy. This study aims to evaluate the image quality of CTA for TAVI planning using dual-layer spectral CT, with virtual monoenergetic image reconstructions at 40 keV. Thirty-one patients underwent a CTA protocol with the injection of 20 mL of contrast media. Image quality was assessed by measuring the mean density in Hounsfield Units (HU), the signal-to-noise ratio, and the contrast-to-noise ratio in VMI reconstructions. Additionally, a blinded subjective analysis was conducted by two observers. The results showed significant enhancement at all sampled vascular levels with a gradual decrease in HU from proximal to distal regions. Favourable subjective ratings were given for all parameters, with greater variability in the evaluation of iliac axes. A significant negative correlation (p < 0.05) was observed between BMI and CA at all vascular levels, indicating reduced contrast enhancement with increasing BMI. Spectral CT, along with reducing iodine load, allows for obtaining high-quality images without a significant increase in noise. The reduction in iodine load can have positive implications in clinical practice, improving patient safety and resource efficiency

Theoretical Investigations of the Effects of J-Aggregation on the Linear and Nonlinear Optical Properties of E-4-(4-Dimethylaminostyryl)-1-methylpyridinium [DAMS + ]

J-type aggregation of organic chromophores into inorganic host matrixes provides a useful route toward materials showing strong second-order nonlinear optical (NLO) response. The increased NLO response of J-aggregates is related to the peculiar arrangement of the NLO-phores into the host matrix, which produces the appearance of a narrow and intense band in the material electronic absorption spectrum, red-shifted with respect to the main absorption band of the isolated NLO-phore. A theoretical investigation, based on DFT, TDDFT, and ZINDO calculations on the relationship between the structural features of various or oligomeric aggregates and their linear and nonlinear optical properties shows that the appearance of a new red-shifted absorption band, typical of J-aggregation, is associated with interchromophoric transitions of charge-transfer character, due to the splitting of HOMO and LUMO levels. The intensity of this latter band increases by increasing the number of NLO-phores in a model of oligomeric arrangement of J-aggregates. The calculated quadratic hyperpolarizabilities for the mostly responsive J-type trimeric aggregates of [DAMS + ] are found to largely exceed that of three isolated NLO-phores, confirming a cooperative NLO strong contribution due to J-aggregation. Finally, our DFT and TDDFT calculations on eclipsed or with opposite dipole dimeric H-aggregates of [DAMS + ] show a splitting of HOMO and LUMO levels, which gives place to interchromophoric transitions of chargetransfer character but blue-shifted, as observed experimentally

The Games for Older Adults Active Life (GOAL) Project for People With Mild Cognitive Impairment and Vascular Cognitive Impairment: A Study Protocol for a Randomized Controlled Trial

Background: People living with Mild Cognitive Impairment (MCI) and Vascular Cognitive Impairment (VCI) are persons who do not fulfill a diagnosis of dementia, but who have a high risk of progressing to a dementia disorder. The most recent guidelines to counteract cognitive decline in MCI/VCI subjects suggest a multidimensional and multi-domain interventions combining cognitive, physical, and social activities. The purpose of this study is to test an innovative service that provides a multi-dimensional tele-rehabilitation program through a user-friendly web application. The latter has been developed through a participatory design involving MCI specialists, patients, and their caregivers. Particularly, the proposed tele-rehabilitation program includes cognitive, physical, and caregiver-supported social activities. The goal is to promote and preserve an active life style and counteract cognitive decline in people living with MCI/VCI.Methods:The study is a randomized controlled trial. Sixty subjects will be randomly assigned to the experimental group, who will receive the tele-rehabilitation program, or the control group, who will not receive any treatment. The trial protocol comprises three steps of assessment for the experimental group: at the baseline (T_0), after tele-rehabilitation program (T_1) and at follow-up after 12-months (T_2). Differently, the control group will be assessed twice: at the baseline and at 12-months follow-up. Both the experimental and the control group will be assessed with a multidimensional evaluation battery, including cognitive functioning, behavioral, functional, and quality of life measures. The tele-rehabilitation program lasts 8 weeks and includes cognitive exercises 3 days a week, physical activities 2 days a week, and social activities once a week. In addition, group will be given an actigraph (GENEActiv, Activisinghts Ltd., Cambridgshire, UK) to track physical and sleep activity.Discussion:Results of this study will inform on the efficacy of the proposed tele-rehabilitation to prevent or delay further cognitive decline in MCI/VCI subjects. The expected outcome is to counteract cognitive decline and improve both physical functioning and quality of life.Ethics and Dissemination:The study is approved by the Local Ethics Committee and registered in https://clinicaltrials.gov (NCT03383549). Dissemination will include submission to a peer-reviewed journal, patients, and healthcare magazines and congress presentations.Trial Registration: ClinicalTrials.gov ID: NCT03383549 (registration date: 26/dec/2017)Trial Funding: Bando FAS Salute 2014 Regione ToscanaVersion Identifier: ver 5—16/11/201

Sudden Unexpected Deaths and Vaccinations during the First Two Years of Life in Italy: A Case Series Study

Background The signal of an association between vaccination in the second year of life with a hexavalent vaccine and sudden unexpected deaths (SUD) in the two days following vaccination was reported in Germany in 2003. A study to establish whether the immunisation with hexavalent vaccines increased the short term risk of SUD in infants was conducted in Italy. Methodology/Principal Findings The reference population comprises around 3 million infants vaccinated in Italy in the study period 1999–2004 (1.5 million received hexavalent vaccines). Events of SUD in infants aged 1–23 months were identified through the death certificates. Vaccination history was retrieved from immunisation registries. Association between immunisation and death was assessed adopting a case series design focusing on the risk periods 0–1, 0–7, and 0–14 days after immunisation. Among the 604 infants who died of SUD, 244 (40%) had received at least one vaccination. Four deaths occurred within two days from vaccination with the hexavalent vaccines (RR = 1.5; 95% CI 0.6 to 4.2). The RRs for the risk periods 0–7 and 0–14 were 2.0 (95% CI 1.2 to 3.5) and 1.5 (95% CI 0.9 to 2.4). The increased risk was limited to the first dose (RR = 2.2; 95% CI 1.1 to 4.4), whereas no increase was observed for the second and third doses combined. Conclusions The RRs of SUD for any vaccines and any risk periods, even when greater than 1, were almost an order of magnitude lower than the estimates in Germany. The limited increase in RRs found in Italy appears confined to the first dose and may be partly explained by a residual uncontrolled confounding effect of age

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients