Serine 249 phosphorylation and Pin1-induced isomerization activate mutant p53 R249S gain-of-function and promote cross-talk with JAK/STAT1 signalling in hepatocellular carcinoma

Evidences from basic and clinical studies clearly established that mutations of the tumour suppressor TP53 contribute to carcinogenesis. Unlike the majority of tumour suppressors, the TP53 gene is often found to undergo missense mutations, with a strong dominance in the DNA-binding domain. Mutant p53 proteins contribute to carcinogenesis by losing tumour suppressor activities, by exerting dominant negative effects over the wild-type allele and by acquiring gain-of-function properties. These oncogenic activities enforce tumour growth, EMT, metastasis and chemoresistance. It has been clearly demonstrated that mutations on p53 are not sufficient to drive tumorigenesis per se but mutant p53 needs to be activated by specific oncogenic signalling produced by a pro-tumorigenic cellular background to be active as an oncogene. Moreover, understanding what are the environmental factors that account for the selection of specific p53 mutant forms in different tumours is critical to identify novel determinants of carcinogenesis and to find new putative targets for cancer therapy. Among the frequently mutated residues in p53, Arginine 249 is replaced in about 65% of cases with a Serine (mutp53 R249S). Since Arginine 249 regulates the secondary structure of p53 loops 2 and 3, its substitution is responsible for a local distortion of the molecule, which reaches a dynamic equilibrium between a native and a native-like conformation. Although mutp53 R249S displays an overall low frequency in tumours bearing missense mutations in p53, it is detected in up to 90% of hepatocellular carcinomas (HCC) occurring in populations exposed to HBV infections and aflatoxin B1 food-contamination, which represent two major risk factors for the HCC in the east of Asia and sub-Saharan Africa. In these areas, since R249S mutation occurs early in the pathway leading to HCC, it is considered an early biomarker of hepatocarcinogenesis. Interestingly, R249S mutation is associated to a bad prognosis and to the expression of a stem cell-associated gene signature. Although in vitro studies show that mutant p53 R249S is able to promote the proliferation of HCC cell lines and that the co-expression with the HBV-oncogene HBx provides further oncogenic properties, a specific mechanism of gain of function is still missing. In this thesis, it is shown that mutation of the Arginine 249 introduces a residue phosphorylated in liver and breast cancer cells, and that the Dual-specificity Tyrosine regulated kinase 2, DYRK2, is the main kinase for Serine 249 phosphorylation. Moreover, it is provided evidence that Serine 249 phosphorylation creates a new binding site for Pin1, which is responsible for the distorted conformation of mutant p53 R249S. Cancer cells depleted of mutp53 R249S show an impairment in their proliferation, which is unleashed by Pin1 activity over mutant p53. By analyzing the transcription profile of Mahlavu cells upon knocking down of mutp53 R249S, it has been identified the JAK/STAT pathway as molecular axis which sustains the mutant p53 R249S activity. This study unveils a novel post-translational modification signalling converging in mutant p53 R249S required for the gain-of-function of the protein and suggests a possible opportunity for therapeutic intervention

Health-related quality of life in patients with Gilles de la Tourette syndrome at the transition between adolescence and adulthood

Gilles de la Tourette syndrome (GTS) is a neurodevelopmental condition characterised by tics and comorbid behavioural problems, affecting predominantly male patients. Tic severity typically fluctuates over time, with a consistent pattern showing improvement after adolescence in a considerable proportion of patients. Both tics and behavioural co-morbidities have been shown to have the potential to affect patients’ health-related quality of life (HR-QoL) in children and adults with persisting symptoms. In this study, we present the results of the first investigation of HR-QoL in patients with Gilles de la Tourette syndrome at the transition between adolescence and adulthood using a disease-specific HR-QoL measure, the Gilles de la Tourette Syndrome-Quality of Life-Children and Adolescents scale. Our results showed that patients with GTS and more severe co-morbid anxiety symptoms reported lower HR-QoL across all domains, highlighting the impact of anxiety on patient’s well-being at a critical stage of development. Routine screening for anxiety symptoms is recommended in all patients with GTS seen at transition clinics from paediatric to adult care, to implement effective behavioural and pharmacological interventions as appropriate

El Amadís de Gaula y la novela caballeresca. Continuaciones e imitaciones del Amadís. El Palmerín de Olivia y la fortuna de los libros de caballerías

oai:riviste.dlls.univr.it:article/10Traducción española realizada por Stefano Neri de dos ensayos del hispanista Carmelo Samonà (1926-1990). Los trabajos, publicados por primera vez en 1972, han sido escogidos por su especial interés en el estudio del Amadís y de los libros de caballerías y por ser, hoy en día, de difícil acceso.Traducción española realizada por Stefano Neri de dos ensayos del hispanista Carmelo Samonà (1926-1990). Los trabajos, publicados por primera vez en 1972, han sido escogidos por su especial interés en el estudio del Amadís y de los libros de caballerías y por ser, hoy en día, de difícil acceso

Glucocorticoid receptor signalling activates YAP in breast cancer

The Hippo pathway is an oncosuppressor signalling cascade that plays a major role in the control of cell growth, tissue homoeostasis and organ size. Dysregulation of the Hippo pathway leads to aberrant activation of the transcription co-activator YAP (Yes-associated protein) that contributes to tumorigenesis in several tissues. Here we identify glucocorticoids (GCs) as hormonal activators of YAP. Stimulation of glucocorticoid receptor (GR) leads to increase of YAP protein levels, nuclear accumulation and transcriptional activity in vitro and in vivo. Mechanistically, we find that GCs increase expression and deposition of fibronectin leading to the focal adhesion-Src pathway stimulation, cytoskeleton-dependent YAP activation and expansion of chemoresistant cancer stem cells. GR activation correlates with YAP activity in human breast cancer and predicts bad prognosis in the basal-like subtype. Our results unveil a novel mechanism of YAP activation in cancer and open the possibility to target GR to prevent cancer stem cells self-renewal and chemoresistance

Frequency-dependent tuning of the human vestibular "sixth sense" by transcranial oscillatory currents

Objective: The vestibular cortex is a multisensory associative region that, in neuroimaging investigations, is activated by slow-frequency (1-2 Hz) galvanic stimulation of peripheral receptors. We aimed to directly activate the vestibular cortex with biophysically modeled transcranial oscillatory current stimulation (tACS) in the same frequency range. Methods: Thirty healthy subjects and one rare patient with chronic bilateral vestibular deafferentation underwent, in a randomized, double-blind, controlled trial, to tACS at slow (1 or 2 Hz) or higher (10 Hz) frequency and sham stimulations, over the Parieto-Insular Vestibular Cortex (PIVC), while standing on a stabilometric platform. Subjective symptoms of motion sickness were scored by Simulator Sickness Questionnaire and subjects' postural sways were monitored on the platform. Results: tACS at 1 and 2 Hz induced symptoms of motion sickness, oscillopsia and postural instability, that were supported by posturographic sway recordings. Both 10 Hz-tACS and sham stimulation on the vestibular cortex did not affect vestibular function. As these effects persisted in a rare patient with bilateral peripheral vestibular areflexia documented by the absence of the Vestibular-Ocular Reflex, the possibility of a current spread toward peripheral afferents is unlikely. Conversely, the 10 Hz-tACS significantly reduced his chronic vestibular symptoms in this patient. Conclusions: Weak electrical oscillations in a frequency range corresponding to the physiological cortical activity of the vestibular system may generate motion sickness and postural sways, both in healthy subjects and in the case of bilateral vestibular deafferentation. Significance: This should be taken into account as a new side effect of tACS in future studies addressing cognitive functions. Higher frequencies of stimulation applied to the vestibular cortex may represent a new interventional option to reduce motion sickness in different scenarios

Computed Tomography Structured Reporting in the Staging of Lymphoma: A Delphi Consensus Proposal

Abstract Structured reporting (SR) in radiology is becoming increasingly necessary and has been recognized recently by major scientific societies. This study aims to build structured CT-based reports for lymphoma patients during the staging phase to improve communication between radiologists, members of multidisciplinary teams, and patients. A panel of expert radiologists, members of the Italian Society of Medical and Interventional Radiology (SIRM), was established. A modified Delphi process was used to develop the SR and to assess a level of agreement for all report sections. The Cronbach's alpha (Cα) correlation coefficient was used to assess internal consistency for each section and to measure quality analysis according to the average inter-item correlation. The final SR version was divided into four sections: (a) Patient Clinical Data, (b) Clinical Evaluation, (c) Imaging Protocol, and (d) Report, including n = 13 items in the "Patient Clinical Data" section, n = 8 items in the "Clinical Evaluation" section, n = 9 items in the "Imaging Protocol" section, and n = 32 items in the "Report" section. Overall, 62 items were included in the final version of the SR. A dedicated section of significant images was added as part of the report. In the first Delphi round, all sections received more than a good rating (≥3). The overall mean score of the experts and the sum of score for structured report were 4.4 (range 1-5) and 1524 (mean value of 101.6 and standard deviation of 11.8). The Cα correlation coefficient was 0.89 in the first round. In the second Delphi round, all sections received more than an excellent rating (≥4). The overall mean score of the experts and the sum of scores for structured report were 4.9 (range 3-5) and 1694 (mean value of 112.9 and standard deviation of 4.0). The Cα correlation coefficient was 0.87 in this round. The highest overall means value, highest sum of scores of the panelists, and smallest standard deviation values of the evaluations in this round reflect the increase of the internal consistency and agreement among experts in the second round compared to first round. The accurate statement of imaging data given to referring physicians is critical for patient care; the information contained affects both the decision-making process and the subsequent treatment. The radiology report is the most important source of clinical imaging information. It conveys critical information about the patient's health and the radiologist's interpretation of medical findings. It also communicates information to the referring physicians and records this information for future clinical and research use. The present SR was generated based on a multi-round consensus-building Delphi exercise and uses standardized terminology and structures, in order to adhere to diagnostic/therapeutic recommendations and facilitate enrolment in clinical trials, to reduce any ambiguity that may arise from non-conventional language, and to enable better communication between radiologists and clinicians

Hypomelanosis of Ito with a trisomy 2 mosaicism: a case report

Introduction: Hypomelanosis of Ito is a rare neurocutaneous disorder, characterized by streaks and swirls of hypopigmentation following the lines of Blaschko that may be associated to systemic abnormalities involving the central nervous system and musculoskeletal system. Despite the preponderance of reported sporadic hypomelanosis of Ito, few reports of familial hypomelanosis of Ito have been described. Case presentation: A 6-month-old Caucasian girl presented with unilateral areas of hypomelanosis distributed on the left half of her body and her father presented with similar mosaic hypopigmented lesions on his upper chest. Whereas both blood karyotypes obtained from peripheral lymphocyte cultures were normal, a 16% trisomy 2 mosaicism was found in cultured skinfibroblasts derived from a hypopigmented skin area of her father. Conclusions: Familial cases of hypomelanosis of Ito are very rare and can occur in patients without systemic involvement. Hypomelanosis of Ito constitutes a non-specific diagnostic definition including different clinical entities with a wide phenotypic variability, either sporadic or familial. Unfortunately, a large number of cases remain misdiagnosed due to both diagnostic challenges and controversial issues on cutaneous biopsies in the pediatric population

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

Evolving trends in the management of acute appendicitis during COVID-19 waves. The ACIE appy II study

Background: In 2020, ACIE Appy study showed that COVID-19 pandemic heavily affected the management of patients with acute appendicitis (AA) worldwide, with an increased rate of non-operative management (NOM) strategies and a trend toward open surgery due to concern of virus transmission by laparoscopy and controversial recommendations on this issue. The aim of this study was to survey again the same group of surgeons to assess if any difference in management attitudes of AA had occurred in the later stages of the outbreak. Methods: From August 15 to September 30, 2021, an online questionnaire was sent to all 709 participants of the ACIE Appy study. The questionnaire included questions on personal protective equipment (PPE), local policies and screening for SARS-CoV-2 infection, NOM, surgical approach and disease presentations in 2021. The results were compared with the results from the previous study. Results: A total of 476 answers were collected (response rate 67.1%). Screening policies were significatively improved with most patients screened regardless of symptoms (89.5% vs. 37.4%) with PCR and antigenic test as the preferred test (74.1% vs. 26.3%). More patients tested positive before surgery and commercial systems were the preferred ones to filter smoke plumes during laparoscopy. Laparoscopic appendicectomy was the first option in the treatment of AA, with a declined use of NOM. Conclusion: Management of AA has improved in the last waves of pandemic. Increased evidence regarding SARS-COV-2 infection along with a timely healthcare systems response has been translated into tailored attitudes and a better care for patients with AA worldwide