90 research outputs found
Thrombin mutants with altered enzymatic activity have an impaired mitogenic effect on mouse fibroblasts and are inefficient modulators of stellation of rat cortical astrocytes
AbstractWe produced recombinant human thrombin mutants to investigate the correlation between the thrombin enzyme and mitogenic activity. Single amino acid substitutions were introduced in the catalytic triad (H43N, D99N, S205A, S205T), in the oxy-anion binding site (G203A) and in the anion binding exosite-1 region (R73E). Proteins were produced as prethrombin-2 mutants secreted in the culture medium of DXB11-derived cell lines. All mutants were activated by ecarin to the corresponding thrombin mutants; the enzymatic activity was assayed on a chromogenic substrate and on the procoagulant substrate fibrinogen. Mutations S205A and G203A completely abolished the enzyme activity. Mutations H43N, D99N and S205T dramatically impaired the enzyme activity toward both substrates. The R73E mutation dissociated the amidolytic activity and the clotting activity of the protein. The ability of thrombin mutants to induce proliferation was investigated in NIH3T3 mouse fibroblasts and rat cortical astrocytes. The ability of the thrombin mutants to revert astrocyte stellation was also studied. The mitogenic activity and the effect on the astrocyte stellation of the thrombin mutants correlated with their enzymatic activity. Furthermore the receptor occupancy by the inactive S205A mutant prevented the thrombin effects providing strong evidence that a proteolytically activated receptor is involved in cellular responses to thrombin
Targeting the Diuretic Hormone Receptor to Control the Cotton Leafworm,<i>Spodoptera littoralis</i>
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Diclofenac-Induced Apoptosis in the Neuroblastoma Cell Line SH-SY5Y: Possible Involvement of the Mitochondrial Superoxide Dismutase
Diclofenac, a nonsteroidal anti-inflammatory drug, induces apoptosis on the neuroblastoma cell line SH-SY5Y through a mitochondrial dysfunction, affecting some antioxidant mechanisms. Indeed, the time- and dose-dependent increase of apoptosis is associated to an early enhancement of the reactive oxygen species (ROS). Mitochondrial superoxide dismutase (SOD2) plays a crucial role in the defence against ROS, thus protecting against several apoptotic stimuli. Diclofenac decreased the protein levels and the enzymatic activity of SOD2, without any significant impairment of the corresponding mRNA levels in the SH-SY5Y extracts. When cells were incubated with an archaeal exogenous thioredoxin, an attenuation of the diclofenac-induced apoptosis was observed, together with an increase of SOD2 protein levels. Furthermore, diclofenac impaired the mitochondrial membrane potential, leading to a release of cytochrome c. These data suggest that mitochondria are involved in the diclofenac-induced apoptosis of SH-SY5Y cells and point to a possible role of SOD2 in this process
Association between mode of breast cancer detection and diagnosis delay
abstract We investigated the association between mode of breast cancer (Bca) detection and diagnosis delay in a case-series of primary, histologically confirmed Bca patients from Southern Italy. Nine hundred and fifty nine women diagnosed with incident, primary Bca were recruited in two southern Italian regions. We grouped the mode of detection into two categories: Self-Detection (S-D) and Mammography (MG). Diagnosis delay was defined as the time between detection and a histologically confirmed diagnosis of invasive Bca. 20.9% detected Bca with MG while 79.1% had S-D Bca. Women who detected Bca themselves (S-D) were more likely to delay breast cancer diagnosis than women who were diagnosed by a mammography (MG) (OR: 2.0; 95% CI: 1.39â2.87); when considering the model adjusted for health system-related characteristics, the risk increased (OR: 2.13; 95% CI: 1.47â3.09). Our study indicates a disadvantage in terms of diagnostic delay for women who were admitted and treated in community hospitals compared to women admitted and treated in breast health services
A web-delivered group intervention supporting parental sensitivity and self-efficacy: an Italian pilot study
Background: Stable parent-infant relationships and adequate ordinary care significantly support childrenâs development since the very early stages of life. Principal models of intervention sustain parental skills and foster quality of parent-infant interactions since the early infancy. Standardized programs, with a well-defined focus, of short duration, based on specific methods and techniques, represent an effective tool in supporting parental effort. The present pilot study provides a description and an initial evaluation of the brief online âCon i Genitoriâ (CiG) Intervention, aimed to enhance parental sensitivity, self-efficacy and reduce stress in parents of typically-developed children aging 0-6 years.
Methods: The intervention involved parents of typically-developed children aging 0-6 years. Four interactive group sessions, based on well-known empirically-based programsâ assumptions were delivered. Participants were asked to complete questionnaires at baseline (T0) and after CiG (T1). The assessment included the Tool to measure Parenting Self-Efficacy (TOPSE; Kendall Bloomfield, 2005), Parenting Stress Index-SF for parental distress (PSI; Abidin, 1996), Emotional Regulation Checklist for childrenâs emotional regulation (ERC; Shields Cicchetti et al., 1997) and Social Provision Scale for social support (SPS; Cutrona and Russell, 1987). A weekly âad-hocâ questionnaire evaluated parental sensitivity. Moreover, a semi-structured interview measured participantsâ satisfaction and acceptability with the intervention one month after its end.
Results: Twelve parents completed all the sessions of the CiG (10 mothers, 2 fathers with mean age = 42.7; SD= 6.3). Children mean age was 3.9 (SD=1.9), 58.3% male. Our results showed statistically significant decrease in parental distress and increased social support after attending CiG. No statistically significant variations were detected considering parental self-efficacy.
Conclusions: Our findings confirm the potential value of online-delivered interventions targeting parenthood in infancy, supporting parent-infant relationship and positive parenting from early infancy in a public health community approach. Online delivered programs constitute an important resource for addressing unmet parent mental health needs, which may be particularly widespread following the COVID-19 pandemic, representing a valuable alternative to traditional face-to-face interventions targeting parental wellbeing in infancy
Association of Upfront Peptide Receptor Radionuclide Therapy With Progression-Free Survival Among Patients With Enteropancreatic Neuroendocrine Tumors
open57noIMPORTANCE Data about the optimal timing for the initiation of peptide receptor radionuclide
therapy (PRRT) for advanced, well-differentiated enteropancreatic neuroendocrine tumors
are lacking.
OBJECTIVE To evaluate the association of upfront PRRT vs upfront chemotherapy or targeted
therapy with progression-free survival (PFS) among patients with advanced enteropancreatic
neuroendocrine tumors who experienced disease progression after treatment with somatostatin
analogues (SSAs).
DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study analyzed the
clinical records from 25 Italian oncology centers for patients aged 18 years or older who had
unresectable, locally advanced or metastatic, well-differentiated, grades 1 to 3 enteropancreatic
neuroendocrine tumors and received either PRRT or chemotherapy or targeted therapy after
experiencing disease progression after treatment with SSAs between January 24, 2000, and July 1,
2020. Propensity score matching was done to minimize the selection bias.
EXPOSURES Upfront PRRT or upfront chemotherapy or targeted therapy.
MAIN OUTCOMES AND MEASURES The main outcome was the difference in PFS among patients
who received upfront PRRT vs among those who received upfront chemotherapy or targeted
therapy. A secondary outcome was the difference in overall survival between these groups. Hazard
ratios (HRs) were fitted in a multivariable Cox proportional hazards regression model to adjust for
relevant factors associated with PFS and were corrected for interaction with these factors.
RESULTS Of 508 evaluated patients (mean ([SD] age, 55.7 [0.5] years; 278 [54.7%] were male), 329
(64.8%) received upfront PRRT and 179 (35.2%) received upfront chemotherapy or targeted
therapy. The matched group included 222 patients (124 [55.9%] male; mean [SD] age, 56.1 [0.8]
years), with 111 in each treatment group. Median PFS was longer in the PRRT group than in the
chemotherapy or targeted therapy group in the unmatched (2.5 years [95%CI, 2.3-3.0 years] vs 0.7
years [95%CI, 0.5-1.0 years]; HR, 0.35 [95%CI, 0.28-0.44; P < .001]) and matched (2.2 years [95%
CI, 1.8-2.8 years] vs 0.6 years [95%CI, 0.4-1.0 years]; HR, 0.37 [95%CI, 0.27-0.51; P < .001])
populations. No significant differences were shown in median overall survival between the PRRT and chemotherapy or targeted therapy groups in the unmatched (12.0 years [95%CI, 10.7-14.1 years] vs
11.6 years [95%CI, 9.1-13.4 years]; HR, 0.81 [95%CI, 0.62-1.06; P = .11]) and matched (12.2 years [95%
CI, 9.1-14.2 years] vs 11.5 years [95%CI, 9.2-17.9 years]; HR, 0.83 [95%CI, 0.56-1.24; P = .36])
populations. The use of upfront PRRT was independently associated with improved PFS (HR, 0.37;
95%CI, 0.26-0.51; P < .001) in multivariable analysis. After adjustment of values for interaction,
upfront PRRT was associated with longer PFS regardless of tumor functional status (functioning:
adjusted HR [aHR], 0.39 [95%CI, 0.27-0.57]; nonfunctioning: aHR, 0.29 [95%CI, 0.16-0.56]), grade
of 1 to 2 (grade 1: aHR, 0.21 [95%CI, 0.12-0.34]; grade 2: aHR, 0.52 [95%CI, 0.29-0.73]), and site of
tumor origin (pancreatic: aHR, 0.41 [95%CI, 0.24-0.61]; intestinal: aHR, 0.19 [95%CI, 0.11-0.43])
(P < .001 for all). Conversely, the advantage was not retained in grade 3 tumors (aHR, 0.31; 95%CI,
0.12-1.37; P = .13) or in tumors with a Ki-67 proliferation index greater than 10% (aHR, 0.73; 95%CI,
0.29-1.43; P = .31).
CONCLUSIONS AND RELEVANCE In this cohort study, treatment with upfront PRRT in patients
with enteropancreatic neuroendocrine tumors who had experienced disease progression with SSA
treatment was associated with significantly improved survival outcomes compared with upfront
chemotherapy or targeted therapy. Further research is needed to investigate the correct strategy,
timing, and optimal specific sequence of these therapeutic options.openPusceddu, Sara; Prinzi, Natalie; Tafuto, Salvatore; Ibrahim, Toni; Filice, Angelina; Brizzi, Maria Pia; Panzuto, Francesco; Baldari, Sergio; Grana, Chiara M.; Campana, Davide; DavĂŹ, Maria Vittoria; Giuffrida, Dario; Zatelli, Maria Chiara; Partelli, Stefano; Razzore, Paola; Marconcini, Riccardo; Massironi, Sara; Gelsomino, Fabio; Faggiano, Antongiulio; Giannetta, Elisa; Bajetta, Emilio; Grimaldi, Franco; Cives, Mauro; Cirillo, Fernando; Perfetti, Vittorio; Corti, Francesca; Ricci, Claudio; Giacomelli, Luca; Porcu, Luca; Di Maio, Massimo; Seregni, Ettore; Maccauro, Marco; Lastoria, Secondo; Bongiovanni, Alberto; Versari, Annibale; Persano, Irene; Rinzivillo, Maria; Pignata, Salvatore Antonio; Rocca, Paola Anna; Lamberti, Giuseppe; Cingarlini, Sara; Puliafito, Ivana; Ambrosio, Maria Rosaria; Zanata, Isabella; Bracigliano, Alessandra; Severi, Stefano; Spada, Francesca; Andreasi, Valentina; Modica, Roberta; Scalorbi, Federica; Milione, Massimo; Sabella, Giovanna; Coppa, Jorgelina; Casadei, Riccardo; Di Bartolomeo, Maria; Falconi, Massimo; de Braud, FilippoPusceddu, Sara; Prinzi, Natalie; Tafuto, Salvatore; Ibrahim, Toni; Filice, Angelina; Brizzi, Maria Pia; Panzuto, Francesco; Baldari, Sergio; Grana, Chiara M.; Campana, Davide; DavĂŹ, Maria Vittoria; Giuffrida, Dario; Zatelli, Maria Chiara; Partelli, Stefano; Razzore, Paola; Marconcini, Riccardo; Massironi, Sara; Gelsomino, Fabio; Faggiano, Antongiulio; Giannetta, Elisa; Bajetta, Emilio; Grimaldi, Franco; Cives, Mauro; Cirillo, Fernando; Perfetti, Vittorio; Corti, Francesca; Ricci, Claudio; Giacomelli, Luca; Porcu, Luca; Di Maio, Massimo; Seregni, Ettore; Maccauro, Marco; Lastoria, Secondo; Bongiovanni, Alberto; Versari, Annibale; Persano, Irene; Rinzivillo, Maria; Pignata, Salvatore Antonio; Rocca, Paola Anna; Lamberti, Giuseppe; Cingarlini, Sara; Puliafito, Ivana; Ambrosio, Maria Rosaria; Zanata, Isabella; Bracigliano, Alessandra; Severi, Stefano; Spada, Francesca; Andreasi, Valentina; Modica, Roberta; Scalorbi, Federica; Milione, Massimo; Sabella, Giovanna; Coppa, Jorgelina; Casadei, Riccardo; Di Bartolomeo, Maria; Falconi, Massimo; de Braud, Filipp
Innovative approaches to active and healthy ageing: Campania experience to improve the adoption of innovative good practices
The demographic projections on the
European population predict that people aged over
60 will increase by about two million/year in the next
decades. Since 2012, the Campania Reference Site of
the European Innovation Partnership on Active and
Healthy Ageing supports the innovation of the
Regional Health System, to face up demographic
changes and sustainability. Campania Reference Site
provides the opportunity to connect loco-regional
stakeholders in social and health care services
(universities, healthcare providers, social services,
local communities and municipalities), with
international organizations, in order to adopt and
scale up innovative solutions and approaches. This
paper describes the building process of Campania
Reference Site and the main results achieved, that
have been allowing it to become a hub for open
innovation in the field of active and healthy aging at
regional, national and international level
Genetic determinants in a critical domain of ns5a correlate with hepatocellular carcinoma in cirrhotic patients infected with hcv genotype 1b
HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domainâ1 interacts with cellular proteins inducing proâoncogenic pathways. Thus, we explore genetic variations in NS5A domainâ1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotypeâ1b infected DAAânaĂŻve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, p = 0.01), T122M (8.8% vs. 0.0%, p < 0.001), M133I (20.6% vs. 3.9%, p < 0.001), and Q181E (11.8% vs. 0.6%, p < 0.001). By multivariable analysis, the presence of >1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7â82.3); p < 0.001). Focusing on HCCâgroup, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4â6.2) log IU/mL vs. 5.3 (4.4â5.6) log IU/mL, p = 0.02) and lower ALT (35 (30â71) vs. 83 (48â108) U/L, p = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cellâcycle regulation (p53, p85âPIK3, and ÎČâ catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCVâmediated oncogenesis. The role of these NS5A domainâ1 mutations in triggering proâoncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation
The evaluation turn in the higher education system: lessons from Italy
This article explores how new public management policy ideas and technologies circulating in the globalised education space have been re-contextualised in the re-design of the Italian Higher Education System. In doing so, it uses the governmentality studies as a sensitising framework to problematise what we term here as
the âcalculative and instrumental turnâ in the evaluation of Higher Education. The work reflects on the complex assemblage of forms of knowledge, technical means and collective and individual subjects through which the evaluation of the Italian universities unfolds in its current form. The attempt is to highlight the
changes produced in how Higher Education and its ethical subjects are thought and their qualities are conceived and appraised. The article presents some conclusive remarks on some of the paradoxical risks of the Evaluation turn, namely contractualisation, depoliticisation and fabrication, but also insists
on its reflexivity potential, interpreting the current developments as a missed opportunity
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