Genetic and epigenetic alterations as serum markers for cancer detection

Several studies have shown that epigenetic mechanisms, as microRNAs (miRs) expression and gene methylation are involved in cancer, by regulating cell proliferation, apoptosis and angiogenesis. Accordingly, epigenetic changes occur from early stages and accumulate during cancer progression, by contributing to cancer development and progression. The present work includes three papers presenting novel genetic and epigenetic changes that could contribute to the identification of new non-invasive cancer biomarkers. The aim of first work was to compare the status of KRAS mutation and SEPT9 methylation between the primary tumors and matched plasma samples in patients affected by colorectal cancer (CRC). KRAS mutations and SEPT9 promoter methylation were present in 34.1% (29/85) and in 95.3% (81/85) of the primary tumour tissue samples. Patients presented with both genetic and epigenetic alterations in tissue specimens (31.8%, 27/85) were considered for further analyses on cfDNA. The median methylation rate in tumour tissues and plasma samples was 64.5% (12.2\u201399.8%) and 14.5% (0\u201345.5%), respectively. The median KRAS mutation load (for matched mutations) was 33.6% (1.2- 86%) in tissues and 4% (0-17%) in plasma samples. A statistically significant correlation was found between tissue and plasma SEPT9 methylation rate (r=0.41, p=0.035), whereas no association was found between tissue and plasma KRAS mutation load (r=0.09, p=0.651). These data show a discrepancy in epigenetic versus genetic alterations detectable in cfDNA as markers for tumour detection. Many factors could affect the mutant cfDNA analysis including the sensitivity of the detection method and the presence of tumour clonal heterogeneity. The second line of research has focused on patients affected by epithelial ovarian cancer (EOC). Serum levels of miR-199a and miR-125b were found to be significantly higher in EOC patients compared to healthy controls (p=0.007 and p=0.002, respectively). A statistically significant correlation was found between miR-199a and miR-125b expression levels (r=0.38, p=0.03). The ROC curve analysis revealed that HE4 had a significantly higher area under the curve (AUC: 0.90) when compared to CA125 (AUC: 0.85), miR-199a (AUC: 0.70) and miR-125b (AUC: 0.67). Despite the low specificity, mainly in pre-menopausal women, CA125 and HE4 seem to have better diagnostic performance compared to miRs investigated in our study. The third line of research has focused on investigate in human endometrial cancer (EC) the expression of miR-186, miR-222, miR-223, miR-204. Serum levels of miR-186, miR-222 and miR-223 resulted significantly up-regulated in patients compared to healthy controls (p=0.004, p=0.002 and p<0.0001). Contrarily, miR-204 resulted significantly down-regulated in EC patients compared to healthy controls (p<0.0001). A positive significant correlation was observed between miR-186 and both miR-222 (r=0.71, p<0.0001) and miR-223 (r=0.64, p<0.0001) as well also between miR-222 and miR-223 (r=0.57, p<0.0001). The AUCs for the selected miRs ranged from 0.70 to 0.87, significantly higher than for CA125 (0.59). Our results confirm that these miRs are implicated in EC and hold promise as a novel blood-based biomarker for the diagnosis. In conclusion, our results indicate that circulating nucleic acids are a potentially promising source of tumor-specific biomarkers in patients affected by different solid cancer

Neoclassical realism and Italy's military behaviour, 1946–2010: a combined dyad/nation analysis

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Comparison of plasma lipids changes after middle-distance running in euglycemic and diabetic subjects

Background: Although regular performance of aerobic physical exercise is pivotal for preserving or improving health and fitness, scarce information is available on plasma lipids changes after middle-distance running in euglycemic and diabetic subjects. Methods: Eleven male euglycemic amateur runners (mean age 41\ub16 years) and 9 male diabetic amateur runners (4 with type 1 and 5 with type 2 diabetes; mean age 55\ub114 years) participated to a 21.1-km running trial. All subjects belonged to an amateur running team, regularly engaged in amateur running. Blood was collected before the start of the trial and immediately after. The lipid profile, encompassing measurement of total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), was assayed with Roche Cobas 6000. Results: All athletes successfully completed the 21.1-km running trial, with running pace comprised between 9.6\u201312.8 km/h. In both categories of subjects the values of LDL-C significantly decreased by approximately 6% after the run, whilst HDL-C and triglycerides significantly increased by 6\u20139% and 30\u201336%, respectively. The post-run variations of all lipoprotein fractions after the running trial were virtually identical in diabetic and euglycemic subjects. Conclusions: The results of this study show for the first time that middle-distance running elicits acute favorable changes of lipid profile both in euglycemic and diabetic subjects. This form of endurance exercise shall hence be further fostered for purposes of public health promotion and improvement

NEARCHOS. Networked Archaeological Open Science: Advances in Archaeology Through Field Analytics and Scientific Community Sharing

The full release and circulation of excavation results often takes decades, thus slowing down progress in archaeology to a degree not in keeping with other scientific fields. The nonconformity of released data for digital processing also requires vast and costly data input and adaptation. Archaeology should face the cognitive challenges posed by digital environments, changing in scope and rhythm. We advocate the adoption of a synergy between recording techniques, field analytics, and a collaborative approach to create a new epistemological perspective, one in which research questions are constantly redefined through real-time, collaborative analysis of data as they are collected and/or searched for in an excavation. Since new questions are defined in science discourse after previous results have been disseminated and discussed within the scientific community, sharing evidence in remote with colleagues, both in the process of field collection and subsequent study, will be a key innovative feature, allowing a complex and real-time distant interaction with the scholarly community and leading to more rapid improvements in research agendas and queries

Healthcare Service Quality Evaluation in a Community-Oriented Primary Care Center, Italy

Community-oriented primary care (COPC) is an inclusive healthcare approach that combines individual care with a population-based outlook, striving to offer effective and equitable services. This study concentrates on assessing the perceived quality of a "Casa della Comunita" (CdC) implemented by the Romagna Local Health Authority, which embraces the COPC model. Through the examination of user experiences, the study aims to comprehend the influence of the CdC's care delivery model on the community's perception of service quality. From 13-18 March 2023, paper questionnaires were distributed by trained healthcare professionals and volunteers. The cross-sectional study enrolled participants aged 18 or older, capable of understanding written Italian, and willing to take part voluntarily. A total of 741 questionnaires were collected, resulting in an overall acceptance rate of 85.6%. Among the respondents, 37.9% were female, with an average age of 55.4 &amp; PLUSMN; 16.2 years. While the respondents generally held a positive view of the quality, the results displayed varying levels of satisfaction across the different areas. Multivariate analysis revealed significant associations between factors such as gender, employment status, financial resources, education level, and distance from the healthcare center with the perceived quality of the facility in terms of accessibility, environment, staff, continuity of care, and overall satisfaction. The study yielded valuable insights, identifying strengths and areas for improvement and underscoring the importance of ongoing monitoring studies to enhance patient satisfaction continuously

Effects of antiangiogenetic drugs on microcirculation and macrocirculation in patients with advanced-stage renal cancer

Adverse cardiovascular effects, including hypertension, were described in patients with different cancers treated with tyrosine kinase inhibitors (TKI). The mechanism of TKI-related hypertension is still debated. The aim of this work was to study the effects of TKI on blood pressure (BP), searching for a relationship with possible causative factors in patients with metastatic renal cell carcinoma. We included 29 patients in a prospective, observational study; 22 were treated with a first-line drug (sunitinib), while seven participated in the second-line treatment (axitinib or cabozantinib). Patients were investigated at the beginning of antiangiogenic therapy (T0) and at one (T1), three (T2), and six months (T3) after treatment. Patients were evaluated by office blood pressure (BP) and ultrasonography to measure flow-mediated dilatation (FMD), and carotid artery distensibility (cDC) by echocardiography and nailfold capillaroscopy. Plasma endothelin-1 (p-ET-1), urine nitrates, and proteins were also measured. At T1, systolic BP, along with U proteins and p-ET-1, increased significantly. In patients with a clinically significant increase in BP (defined as either the need for an antihypertensive drug or systolic blood pressure (SBP) T1\u207bT0 6510 and/or SBP 65140 mmHg and/or diastolic blood pressure (DBP) T1\u207bT0 655 and/or DBP 6590 mmHg), the urine nitrate concentration was lower at T0, whereas there were no differences in the p-ET-1 and U proteins. Seventeen participants showed changes in the capillaroscopic pattern at T1 with no association with BP increases. There were no differences in the FMD, cDC, and echocardiographic parameters. Our findings are consistent with those of previous studies about BP increases by TKI, and suggest a role of nitric oxide in BP maintenance in this population

PEG-capped, lanthanide doped GdF3 nanoparticles: luminescent and T-2 contrast agents for optical and MRI multimodal imaging

A facile method for the synthesis of water dispersible Er3+/Yb3+ and Tm3+/Yb3+ doped upconverting GdF3 nanoparticles is reported. Strong upconversion emissions are observed in the red (for Er/Yb doped) and near-infrared (for Tm/Yb doped) regions upon laser excitation at 980 nm. The PEG coating ensures a good dispersion of the system in water and reduces the radiationless de-excitation of the excited states of the Er3+ and Tm3+ ions by water molecules. The r(2) relaxivity values are quite high with respect to the common T-2-relaxing agents (22.6 +/- 3.4 mM(-1) s(-1) and 15.8 +/- 3.4 mM(-1) s(-1) for the Tm/Yb and Er/Yb doped samples, respectively), suggesting that the present NPs can be interesting as T-2 weighted contrast agents for proton MRI purpose. Preliminary experiments conducted in vitro, in stem cell cultures, and in vivo, after subcutaneous injection of the lanthanide-doped GdF3 NPs, indicate scarce toxic effects. After an intravenous injection in mice, the GdF3 NPs localize mainly in the liver. The present results indicate that the present Er3+/Yb3+ and Tm3+/Yb3+ doped GdF3 NPs are suitable candidates to be efficiently used as bimodal probes for both in vitro and in vivo optical and magnetic resonance imaging

Genetic and epigenetic alteration as serum markers for cancer detection

Several studies have shown that epigenetic mechanisms, as microRNAs (miRs) expression and gene methylation are involved in cancer, by regulating cell proliferation, apoptosis and angiogenesis. Accordingly, epigenetic changes occur from early stages and accumulate during cancer progression, by contributing to cancer development and progression. Since tumour specific genetic and epigenetic alterations can be detected not only in cancer tissues but also in circulating serum or plasma cell-free DNA (cfDNA), this method is considered promising for improving non-invasive cancer detection and monitoring. The present work includes three papers presenting novel genetic and epigenetic changes that could contribute to the identification of new non-invasive cancer biomarkers. The aim of first work was to compare the status of KRAS mutation and SEPT9 methylation between the primary tumors and matched plasma samples in patients affected by colorectal cancer (CRC). KRAS mutations and SEPT9 promoter methylation were present in 34.1% (29/85) and in 95.3% (81/85) of the primary tumour tissue samples. Patients presented with both genetic and epigenetic alterations in tissue specimens (31.8%, 27/85) were considered for further analyses on cfDNA. In 4 primary tumours with KRAS mutations, identical mutations were not observed in the corresponding plasma samples. The median methylation rate in tumour tissues and plasma samples was 64.5% (12.2\u201399.8%) and 14.5% (0\u201345.5%), respectively. The median KRAS mutation load (for matched mutations) was 33.6% (1.2-86%) in tissues and 4% (0-17%) in plasma samples. A statistically significant correlation was found between tissue and plasma SEPT9 methylation rate (r=0.41, p=0.035), whereas no association was found between tissue and plasma KRAS mutation load (r=0.09, p=0.651). These data show a discrepancy in epigenetic versus genetic alterations detectable in cfDNA as markers for tumour detection. Many factors could affect the mutant cfDNA analysis including the sensitivity of the detection method and the presence of tumour clonal heterogeneity. The second line of research has focused on patients affected by epithelial ovarian cancer (EOC). Serum levels of miR-199a and miR-125b were found to be significantly higher in EOC patients compared to healthy controls (p=0.007 and p=0.002, respectively). A statistically significant correlation was found between miR-199a and miR-125b expression levels (r=0.38, p=0.03). The ROC curve analysis of the diagnostic performance on healthy controls and EOC patients revealed that HE4 had a significantly higher area under the curve (AUC: 0.90) when compared to CA125 (AUC: 0.85), miR-199a (AUC: 0.70) and miR-125b (AUC: 0.67). Despite the low specificity, mainly in pre-menopausal women, CA125 and HE4 seem to have better diagnostic performance compared to miRs investigated in our study. The third line of research has focused on investigate in human endometrial cancer (EC) the expression of miR-186, miR-222, miR-223, miR-204. Serum levels of miR-186, miR-222 and miR-223 resulted significantly up-regulated in patients compared to healthy controls (p=0.004, p=0.002 and p&lt;0.0001). Contrarily, miR-204 resulted significantly down-regulated in EC patients compared to healthy controls (p&lt;0.0001). A positive significant correlation was observed between miR-186 and both miR-222 (r=0.71, p&lt;0.0001) and miR-223 (r=0.64, p&lt;0.0001) as well also between miR-222 and miR-223 (r=0.57, p&lt;0.0001). The AUCs for the selected miRs ranged from 0.70 to 0.87, significantly higher than for CA125 (0.59). Our results confirm that these miRs are implicated in EC and hold promise as a novel blood-based biomarker for the diagnosis. In conclusion, our results indicate that circulating nucleic acids are a potentially promising source of tumor-specific biomarkers in patients affected by different solid cancer. Accordingly, we have demonstrated that some circulating tumour-specific biomarkers can be detected at any time during the course of the disease and once detected indicate that a tumour is probably present. The biggest challenge remains to standardize the methodologies including sample storage and DNA or miRs extraction to translate the quantitation of circulating epigenetic biomarkers into a clinical routine for cancer diagnosis and prognosis prediction