Antagonism between salicylate and the cAMP signal controls yeast cell survival and growth recovery from quiescence

Aspirin and its main metabolite salicylate are promising molecules in preventing cancer and metabolic diseases. S. cerevisiae cells have been used to study some of their effects: (i) salicylate induces the reversible inhibition of both glucose transport and the biosyntheses of glucose-derived sugar phosphates, (ii) Aspirin/salicylate causes apoptosis associated with superoxide radical accumulation or early cell necrosis in MnSOD-deficient cells growing in ethanol or in glucose, respectively. So, treatment with (acetyl)-salicylic acid can alter the yeast metabolism and is associated with cell death. We describe here the dramatic effects of salicylate on cellular control of the exit from a quiescence state. The growth recovery of long-term stationary phase cells was strongly inhibited in the presence of salicylate, to a degree proportional to the drug concentration. At high salicylate concentration, growth reactivation was completely repressed and associated with a dramatic loss of cell viability. Strikingly, both of these phenotypes were fully suppressed by increasing the cAMP signal without any variation of the exponential growth rate. Upon nutrient exhaustion, salicylate induced a premature lethal cell cycle arrest in the budded-G2/M phase that cannot be suppressed by PKA activation. We discuss how the dramatic antagonism between cAMP and salicylate could be conserved and impinge common targets in yeast and humans. Targeting quiescence of cancer cells with stem-like properties and their growth recovery from dormancy are major challenges in cancer therapy. If mechanisms underlying cAMP-salicylate antagonism will be defined in our model, this might have significant therapeutic implications

Nutritional Control of Nucleocytoplasmic Localization of cAMP-dependent Protein Kinase Catalytic and Regulatory Subunits in Saccharomyces cerevisiae

In budding yeast, cAMP-dependent protein kinase (PKA) plays a central role in the nutritional control of metabolism, cell cycle, and transcription. This study shows that both the regulatory subunit Bcy1p and the catalytic subunit Tpk1p associated with it are predominantly localized in the nucleus of rapidly growing cells. Activation of nuclear PKA by cAMP leads to fast entry of a significant part of Tpk1p into the cytoplasm, while the regulatory subunit remains nuclear. In contrast to rapidly proliferating cells, both Bcy1p and Tpk1p are distributed over nucleus and cytoplasm in cells growing on a nonfermentable carbon source or in stationary phase cells. These results demonstrate that at least two different mechanisms determine the subcellular localization of PKA; cAMP controls the localization of Tpk1p, and the carbon source determines that of Bcy1p. The N-terminal domain of Bcy1p serves to target it properly during logarithmic and stationary phase. Studies with Bcy1p mutant versions unable to concentrate in the nucleus revealed that cells producing them are less viable in stationary phase than wild type cells, display delayed reproliferation following transfer to fresh growth medium, and, as diploids, exhibit reduced efficiency of sporulation

GPR and seismic surveying in the World War I scenario of Punta Linke (Ortles-Cevedale Group, Italian Alps).

The Ortles-Cevedale Group was the setting of repeated clashes occurring under extreme conditions and at the highest altitudes of all fightings in the Great War (WWI). The research scenario associated with the group is very challenging because modern research faces a series of logistical and climatic obstacles. The gradual retreat of glaciers has unearthed several archaeological remains of WWI such as barracks, barbed wire, military ammunition, weapons and other materials. The study site is the saddle between M. Vioz and Punta Linke, where the Historic War Museum of Pejo, under the direction of the Archaeological Service of the Province of Trento (Soprintendenza per i Beni Culturali, Ufficio Beni Archeologici), started an archaeological excavation in the year 2009 of some of the infrastructure of the cableway station, which also includes a tunnel section in the bedrock. The saddle is placed at the head of Forni Glacier. GPR and seismic imaging was the best survey choice to characterize the glaciological and geo-archaeological context and to find structures or remains within the ice mass. Geophysical imaging spanned two campaigns in the years 2010 and 2011. The ice-rock interface was reconstructed in detail to depths greater than 45-50 m. The surface of the bedrock reveals a complex morphology, with several undulations and two rocky ridges elongated in the NNW-SSE direction. They identified some anomalous reflectors within the ice mass located near the western edge of the saddle of Punta Linke. The interpretation of radar profiles seems to indicate the presence of a tunnel in the ice, whose geometry and position is similar to others excavated in alpine glaciers during the Great War

CDX2 hox gene product in a rat model of esophageal cancer

<p>Abstract</p> <p>Background</p> <p>Barrett's mucosa is the precursor of esophageal adenocarcinoma. The molecular mechanisms behind Barrett's carcinogenesis are largely unknown. Experimental models of longstanding esophageal reflux of duodenal-gastric contents may provide important information on the biological sequence of the Barrett's oncogenesis.</p> <p>Methods</p> <p>The expression of <it>CDX2 </it>hox-gene product was assessed in a rat model of Barrett's carcinogenesis. Seventy-four rats underwent esophago-jejunostomy with gastric preservation. Excluding perisurgical deaths, the animals were sacrificed at various times after the surgical treatment (Group A: <10 weeks; Group B: 10–30 weeks; Group C: >30 weeks).</p> <p>Results</p> <p>No Cdx2 expression was detected in either squamous epithelia of the proximal esophagus or squamous cell carcinomas. <it>De novo </it>Cdx2 expression was consistently documented in the proliferative zone of the squamous epithelium close to reflux ulcers (Group A: 68%; Group B: 64%; Group C: 80%), multilayered epithelium and intestinal metaplasia (Group A: 9%; Group B: 41%; Group C: 60%), and esophageal adenocarcinomas (Group B: 36%; Group C: 35%). A trend for increasing overall Cdx2 expression was documented during the course of the experiment (<it>p </it>= 0.001).</p> <p>Conclusion</p> <p><it>De novo </it>expression of Cdx2 is an early event in the spectrum of the lesions induced by experimental gastro-esophageal reflux and should be considered as a key step in the morphogenesis of esophageal adenocarcinoma.</p

Years of life that could be saved from prevention of hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) causes premature death and loss of life expectancy worldwide. Its primary and secondary prevention can result in a significant number of years of life saved. AIM: To assess how many years of life are lost after HCC diagnosis. METHODS: Data from 5346 patients with first HCC diagnosis were used to estimate lifespan and number of years of life lost after tumour onset, using a semi-parametric extrapolation having as reference an age-, sex- and year-of-onset-matched population derived from national life tables. RESULTS: Between 1986 and 2014, HCC lead to an average of 11.5 years-of-life lost for each patient. The youngest age-quartile group (18-61 years) had the highest number of years-of-life lost, representing approximately 41% of the overall benefit obtainable from prevention. Advancements in HCC management have progressively reduced the number of years-of-life lost from 12.6 years in 1986-1999, to 10.7 in 2000-2006 and 7.4 years in 2007-2014. Currently, an HCC diagnosis when a single tumour <2 cm results in 3.7 years-of-life lost while the diagnosis when a single tumour 65 2 cm or 2/3 nodules still within the Milan criteria, results in 5.0 years-of-life lost, representing the loss of only approximately 5.5% and 7.2%, respectively, of the entire lifespan from birth. CONCLUSIONS: Hepatocellular carcinoma occurrence results in the loss of a considerable number of years-of-life, especially for younger patients. In recent years, the increased possibility of effectively treating this tumour has improved life expectancy, thus reducing years-of-life lost

Post-exercise high-sensitivity troponin T levels in patients with suspected unstable angina

Background Previous studies showed that troponin blood levels may increase after exercise. In this study we assessed whether, among patients admitted with suspected unstable angina, the increase in high-sensitive troponin T (hs-TnT) levels after exercise stress test (EST) might help identify those with obstructive coronary artery disease (CAD) and predict symptom recurrence during short term follow-up. Methods Maximal treadmill EST was performed in 69 consecutive patients admitted to the emergency room with a suspicion of unstable angina (acute chest pain but confirmed normal serum levels of cardiac troponins) was measured before and 4 hours after EST. Coronary angiography was performed in 22 patients (32.8%). Results hs-TnT increased after EST compared to baseline in the whole population (from 0.84\ub10.65 to 1.17\ub10.87 ng/dL, p&lt;0.001). The increase was similar in patients with positive (n = 14) and negative (n = 55) EST (p = 0.72), and was also similar in patients with (n = 12) and without (n = 10) obstructive CAD at angiography (p = 0.91). The achievement of a heart rate at peak EST \ufffd85% of that predicted for age was the variable mainly associated with the post- EST hs-TnT increase at multivariable linear regression analysis (p = 0.005). The change after EST of hs-TnT did not predict the recurrence of symptoms or readmission for chest pain at 6-month follow-up. Conclusions Our data show that hs-TnT increased after EST in patients with suspected unstable angina, which seemed largely independent of most clinical and laboratory variables. Thus, hs-TnT assessed after EST does not seem to be helpful to identify patients with obstructive CAD in this kind of patients

Circulating miR-320b and miR-483-5p levels are associated with COVID-19 in-hospital mortality

none28noThe stratification of mortality risk in COVID-19 patients remains extremely challenging for physicians, especially in older patients. Innovative minimally invasive molecular biomarkers are needed to improve the prediction of mortality risk and better customize patient management. In this study, aimed at identifying circulating miRNAs associated with the risk of COVID-19 in-hospital mortality, we analyzed serum samples of 12 COVID-19 patients by small RNA-seq and validated the findings in an independent cohort of 116 COVID-19 patients by qRT-PCR. Thirty-four significantly deregulated miRNAs, 25 downregulated and 9 upregulated in deceased COVID-19 patients compared to survivors, were identified in the discovery cohort. Based on the highest fold-changes and on the highest expression levels, 5 of these 34 miRNAs were selected for the analysis in the validation cohort. MiR-320b and miR-483-5p were confirmed to be significantly hyper-expressed in deceased patients compared to survived ones. Kaplan-Meier and Cox regression models, adjusted for relevant confounders, confirmed that patients with the 20% highest miR-320b and miR-483-5p serum levels had three-fold increased risk to die during in-hospital stay for COVID-19. In conclusion, high levels of circulating miR-320b and miR-483-5p can be useful as minimally invasive biomarkers to stratify older COVID-19 patients with an increased risk of in-hospital mortality.restrictedGiuliani, Angelica; Matacchione, Giulia; Ramini, Deborah; Di Rosa, Mirko; Bonfigli, Anna Rita; Sabbatinelli, Jacopo; Monsurrò, Vladia; Recchioni, Rina; Marcheselli, Fiorella; Marchegiani, Francesca; Piacenza, Francesco; Cardelli, Maurizio; Galeazzi, Roberta; Pomponio, Giovanni; Ferrarini, Alessia; Gabrielli, Armando; Baroni, Silvia Svegliati; Moretti, Marco; Sarzani, Riccardo; Giordano, Piero; Cherubini, Antonio; Corsonello, Andrea; Antonicelli, Roberto; Procopio, Antonio Domenico; Ferracin, Manuela; Bonafè, Massimiliano; Lattanzio, Fabrizia; Olivieri, FabiolaGiuliani, Angelica; Matacchione, Giulia; Ramini, Deborah; Di Rosa, Mirko; Bonfigli, Anna Rita; Sabbatinelli, Jacopo; Monsurrò, Vladia; Recchioni, Rina; Marcheselli, Fiorella; Marchegiani, Francesca; Piacenza, Francesco; Cardelli, Maurizio; Galeazzi, Roberta; Pomponio, Giovanni; Ferrarini, Alessia; Gabrielli, Armando; Baroni, Silvia Svegliati; Moretti, Marco; Sarzani, Riccardo; Giordano, Piero; Cherubini, Antonio; Corsonello, Andrea; Antonicelli, Roberto; Procopio, Antonio Domenico; Ferracin, Manuela; Bonafè, Massimiliano; Lattanzio, Fabrizia; Olivieri, Fabiol