3,554 research outputs found
Generation of novel therapeutic approaches to selectively target senescent cells in prostate cancer
No full textProstate cancer is the second commonest malignancy in men worldwide and the sixth most typical cause of male mortality1. Patients with metastatic prostate cancer, specifically those with disease progression following primary androgen ablation therapy, are considered refractory to hormonal therapy. The treatment of castration-resistant prostate cancer (CRPC) remains unsatisfactory, and, unfortunately, chemotherapy can only marginally improve patient survival, providing a palliative benefit in this setting.2,3
Besides, immune checkpoint inhibitors and immunotherapies have shown poor efficacy and no increase in overall survival outcomes.4
Hence, there is an urgent need to develop novel effective targeted therapies to enhance the treatment of patients with androgen-resistant diseases.
This project aims to identify novel immune checkpoints in prostate cancer and their exploitation as a novel target for developing drug delivery systems and immunotherapeutic strategies. Starting from bulk-RNA and single-cell data from human patients, we identified a transmembrane protein, Senot2, upregulated in epithelial prostate cancer cells. Senot2 plays immunomodulatory functions, as it can interact with receptors expressed by T and NK cells. Upregulation of Senot2 by cancer cells was found to be even higher upon senescence induction in different in vitro and in vivo models of therapy-induced senescence (TIS) and PTEN-loss-induced cellular senescence (PICS). In cancer, senescence plays both positive and negative roles. On the one hand, senescence inhibits cell growth slowing down tumor development and progression. On the other, the presence and persistence of senescent cells in the tumour may also play tumour-promoting effects such as mitogenic, antiapoptotic and angiogenic activities, mainly through their secreted factors. For this reason, the elimination of senescent cells (senolytic therapy) has been proposed as a strategy to improve the efficacy of currently available chemo-radio or targeted therapy, but the current armamentarium of effective senolytics includes a few compounds with limited selectivity and high toxicity5,6.
Based on our findings, Senot2 represents an exploitable target to remove senescent cancer cells from tumor.7 Moreover, by exploiting co-culture systems, we demonstrated that Senot2 has immunosuppressive effects on T and NK cell-mediated cytotoxicity.
In our study, we also demonstrated the Senot2 immunosuppressive role in the co-culture of cancer cells with T and NK cells-mediated cytotoxicity.
Therefore, Senot2-targeting pharmaceutical strategies may offer a double benefit: to reactivate the immune response and to eliminate senescent cells from the tumor concurrently. We generated senolytic immunoliposomes and CAR-T cells recognizing Senot2 to target senescent prostate tumour cells, and we confirmed their specificity and selectivity in multiple in vitro assays.
Our next goal is to assess their efficacy and safety in preclinical models of prostate cancer.Prostate cancer is the second commonest malignancy in men worldwide and the sixth most typical cause of male mortality1. Patients with metastatic prostate cancer, specifically those with disease progression following primary androgen ablation therapy, are considered refractory to hormonal therapy. The treatment of castration-resistant prostate cancer (CRPC) remains unsatisfactory, and, unfortunately, chemotherapy can only marginally improve patient survival, providing a palliative benefit in this setting.2,3
Besides, immune checkpoint inhibitors and immunotherapies have shown poor efficacy and no increase in overall survival outcomes.4
Hence, there is an urgent need to develop novel effective targeted therapies to enhance the treatment of patients with androgen-resistant diseases.
This project aims to identify novel immune checkpoints in prostate cancer and their exploitation as a novel target for developing drug delivery systems and immunotherapeutic strategies. Starting from bulk-RNA and single-cell data from human patients, we identified a transmembrane protein, Senot2, upregulated in epithelial prostate cancer cells. Senot2 plays immunomodulatory functions, as it can interact with receptors expressed by T and NK cells. Upregulation of Senot2 by cancer cells was found to be even higher upon senescence induction in different in vitro and in vivo models of therapy-induced senescence (TIS) and PTEN-loss-induced cellular senescence (PICS). In cancer, senescence plays both positive and negative roles. On the one hand, senescence inhibits cell growth slowing down tumor development and progression. On the other, the presence and persistence of senescent cells in the tumour may also play tumour-promoting effects such as mitogenic, antiapoptotic and angiogenic activities, mainly through their secreted factors. For this reason, the elimination of senescent cells (senolytic therapy) has been proposed as a strategy to improve the efficacy of currently available chemo-radio or targeted therapy, but the current armamentarium of effective senolytics includes a few compounds with limited selectivity and high toxicity5,6.
Based on our findings, Senot2 represents an exploitable target to remove senescent cancer cells from tumor.7 Moreover, by exploiting co-culture systems, we demonstrated that Senot2 has immunosuppressive effects on T and NK cell-mediated cytotoxicity.
In our study, we also demonstrated the Senot2 immunosuppressive role in the co-culture of cancer cells with T and NK cells-mediated cytotoxicity.
Therefore, Senot2-targeting pharmaceutical strategies may offer a double benefit: to reactivate the immune response and to eliminate senescent cells from the tumor concurrently. We generated senolytic immunoliposomes and CAR-T cells recognizing Senot2 to target senescent prostate tumour cells, and we confirmed their specificity and selectivity in multiple in vitro assays.
Our next goal is to assess their efficacy and safety in preclinical models of prostate cancer
Gli statuti delle fiere di Bolzano in tedesco e in italiano (1792). Ristampa anastatica delle edizioni originali con indici bilingui dei termini giuridici, a cura di Silvia Paialunga, Firenze, Accademia della Crusca, 2022, pp. 335. € 35,00
No full textRecensione a 'Gli statuti delle fiere di Bolzano in tedesco e in italiano (1792). Ristampa anastatica delle edizioni originali con indici bilingui dei termini giuridici, a cura di Silvia Paialunga, Firenze, Accademia della Crusca, 2022, pp. 335. € 35,00
Auditory attention causes visual inattentional blindness
No full textWhen engaged in a visual task, we can fail to detect unexpected events that would otherwise be very noticeable. Here we ask whether a common auditory task, such as that of attending to a verbal stream, can also make us blind to the presence of visual objects that we do not anticipate. In two experiments, 120 observers watched a dynamic display while performing either a visual or an auditory attention task, or both simultaneously. When observers were listening to verbal material, in order to either understand it or remember it (auditory task), their probability of detecting an unexpected visual object was no higher than when they were counting bounces of moving items (visual task), although in the former case the observers' eyes and attention could move around the display freely rather than remaining focused on tracked items. Previous research has shown that attending to verbal material does not affect responses to lights flashing at irregular intervals, suggesting that driving performance is not hampered by listening. The lights, however, were expected. Our data imply that listening to the radio while driving, or to a portable audio player while walking or biking, can impair our reactions to objects or events that we do not expect
Assessment and management of paediatric Head Injuries in the Emergency Department
No full textBackground: Head injuries (HI) are one of the most common causes of morbidity and mortality in the paediatric population in developed countries. Their management places a considerable burden on emergency services, being one of the most common reasons to visit the Emergency Department (ED). The care delivered in the ED covers multiple key aspects to ensure a timely successful recovery and prevent re-injury. Despite evidence supporting the care of paediatric HIs has substantially increased in recent years, many aspects of care still benefit from further research for an optimal management of these patients.
Objectives: To investigate different elements of the journey of paediatric patients with HI in the ED, including: 1. Diagnosis of possible intracranial injuries; 2. Management of concussion; 3. HI prevention.
Methods: This is a collection of eight observational studies with both prospective and retrospective designs, conducted at the paediatric EDs of either Padova Hospital, in Italy, or at the Royal Children’s Hospital Melbourne, in Australia. All the studies included patients presenting to the ED following a head trauma with some project focusing on specific populations (i.e. minor HIs, concussions, and recreational vehicles-related HIs). Data were collected between November 2009 and June 2014, with study periods for each project ranging between nine months and approximately three years.
Results: Key findings are presented for the three research topics listed in the objectives section.
1. Diagnosis of possible intracranial injuries, including the following aspects:
a) Clinical decision rules validation and implementation
We externally validated in 2439 children the Pediatric Emergency Care Applied Research Network (PECARN) rule for computed tomography (CT) scan decision-making in children with minor HI. We found a diagnostic accuracy comparable to the derivation and internal validation cohorts (overall sensitivity 100%, 95% confidence interval (CI) 83.2%-100%; specificity 55%, 95% CI 52.5%-56.6%, and negative predictive value 100%, 95% CI 99.6%-100%).
The PECARN rule was successfully implemented in the paediatric ED of Padova, Italy, showing high adherence (93.5%), unchanged CT rate compared to previous practice (8.4%, 95% CI 6.0%-11.8% vs. 7.3%, 95% CI 4.8%-10.9%), high safety and efficacy (100%, 95% CI 36.8%-100% and 92.3%, 95% CI 89%-95% respectively) and increased medical staff satisfaction compared with the previous minor HI guideline (96% vs. 51%, p<0.0001).
When the PECARN rule was used in clinical practice neither single nor multiple intermediate-risk predictors were significantly associated with ordering a CT scan. Only age younger than three months was found to be significantly associated to the decision to perform a CT (OR 18.1, 95% CI 4.91-66.61).
b) Risks associated with CT – sedation use, practice and adverse events
In our study, sedation for cranial CT scan in children with HI was needed in only 6.3% (95% CI 4.2%-9%), with a higher rate in children < 5 years (OR 22.8 95% CI 6.7-119.1). A Glasgow Coma Scale < 12 was not associated with a lower sedation rate (OR 0.34, 95% CI 0.1-2.2). The most commonly used sedative agent was chloral hydrate in 64.3% of cases. No adverse effects were recorded.
c) Role of an Infrared device as screening tool to reduce CT scan use
We demonstrated the feasibility of use in children (completion of test in 94% of patients after a mean of 4.4±2.9 minutes) of a near-infrared handheld device (Infrascanner) able to detect traumatic intracranial haematomas. Our exploratory analysis showed a specificity of 93% (95% CI 86.5%-96.6%) and a negative predictive value of 100% (95% CI, 81.6%-100%). The use of Infrascanner would have reduced the CT scan rate by 58.8%.
2. Management of concussion.
a) Sport –related concussions. When exploring compliance with and awareness of on-field management and return to play guidelines we found that 42% of children who sustain a sport-related concussion are not managed according to recommended guidelines on the field. Almost all parents (93%) and patients (96%) were unaware of concussion or return to play guidelines from their organization. Overall, 72% were compliant with return to play guidelines provided in the ED before discharge.
b) Post-concussive symptoms. The majority of patients recovered within 2 weeks post-injury. The prevalence of patients with clinically significant post-concussive symptoms was 30% (95% CI, 21%-46%) at 2 and 15% (95% CI 5%-32%) at 3 months post-injury. The health-related quality of life (HRQOL) score at 1 month was significantly worse in patients with clinically significant post-concussive symptoms at 2 weeks compared with asymptomatic or improving subjects (median 68, interquartile range (IQR) 55-89 vs 96, IQR 90-100, p=0.000 for the child report and 71, IQR 55-82 vs 89, IQR 79-95, p=0.002 for the parent report). HRQOL was still worse at 3-months post-injury as per child report (83, IQR 69-92 vs 97, IQR 81-100, p=0.020), but significantly improving compared to the 1-month time point (p=0.031).
3. Prevention of recreational vehicle (RV)-related HIs.
RV-related HIs accounted for 7.5% of all HIs presenting to the ED. The RVs most commonly involved were bicycles (36.3%), push scooters (18.5%) and motorcycles (18.4%). Motorized vehicles were responsible for the most severe HIs. Helmet use was documented in 85.3%, with a positive use in 66.7%.The highest rates of helmet use were recorded for motorcycle riders (83.2%), horse riders (82.9%) and cyclists (65.1%). The CT scan and neurosurgery rate was higher in non-helmeted children compared with children wearing a helmet (37.0% vs. 20.1%, p<0.001 and 5.4% vs. 0.8%, p<0.001 respectively).
Conclusions: 1. The work presented in this thesis provides evidence for the wide implementation of the PECARN rule in clinical practice and supports further research to investigate which rule predictors mostly influence clinicians’ decision-making on CT scan in children at intermediate risk of clinically significant intracranial injury. The use of an infrared device to screen for intracranial haemorrhages and refine the CT scan decision-making seemed promising and should be investigated further. The need of sedation in children undergoing a CT scan for HI was overall quite low and mainly associated to patients’ age. The data provided may help with resource allocation in the ED.
2. Compliance with on-field management and information provided for sport-related concussions in organised sport were not optimal. Education based on return to play guidelines should be routinely provided in the ED for these patients.
The majority of children recovered within two weeks following their concussion. The prevalence of children with clinically significant post-concussive symptoms halved from 2 weeks to 3 months post-injury. Symptomatic children showed a worse HRQOL at 1 and 3 months post-injury.
3. Helmet use and documentation varied by RV with highest usage rates amongst children riding a motorcycle or a horse. Motorized RVs accounted for a small proportion of cases overall, but the majority of intracranial injuries. Helmet use was associated with less severe RV-related HIs and should be encouraged through legislative, social marketing strategies and education in the ED
sj-RData-2-dhj-10.1177_20552076231191967 - Supplemental material for A SuperLearner-enforced approach for the estimation of treatment effect in pediatric trials
No full textSupplemental material, sj-RData-2-dhj-10.1177_20552076231191967 for A SuperLearner-enforced approach for the estimation of treatment effect in pediatric trials by Danila Azzolina, Rosanna Comoretto, Liviana Da Dalt, Silvia Bressan and Dario Gregori in DIGITAL HEALTH</p
sj-docx-1-dhj-10.1177_20552076231191967 - Supplemental material for A SuperLearner-enforced approach for the estimation of treatment effect in pediatric trials
No full textSupplemental material, sj-docx-1-dhj-10.1177_20552076231191967 for A SuperLearner-enforced approach for the estimation of treatment effect in pediatric trials by Danila Azzolina, Rosanna Comoretto, Liviana Da Dalt, Silvia Bressan and Dario Gregori in DIGITAL HEALTH</p
sj-Rmd-4-dhj-10.1177_20552076231191967 - Supplemental material for A SuperLearner-enforced approach for the estimation of treatment effect in pediatric trials
No full textSupplemental material, sj-Rmd-4-dhj-10.1177_20552076231191967 for A SuperLearner-enforced approach for the estimation of treatment effect in pediatric trials by Danila Azzolina, Rosanna Comoretto, Liviana Da Dalt, Silvia Bressan and Dario Gregori in DIGITAL HEALTH</p
cohort study
No full textAbstract not available.Nitaa Eapen, Amit Kochar, Mark D Lyttle, Natalie Phillips, John A Cheek, Jeremy Furyk, Jocelyn Neutze, Silvia Bressan, Amanda Williams, Stephen Hearps, Ed Oakley, Stuart R Dalziel, Meredith L Borlan
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