Sexuality education in Italy 2016-2020: a national survey investigating coverage, content and evaluation of school-based educational activities

Comprehensive sexuality education is an important means of promoting sexual well-being amongst young people and is key to preventing sexually transmitted infections (STIs). However, sexuality education is not currently included in the formal curriculum in Italian schools. The aim of this study was to develop an inventory of schoolbased sexuality education (SBSE) activities carried out by external providers and implemented in Italy from 2016 to 2020. A desk review and survey were carried out. In the desk review online documents on STI prevention were analysed. The survey investigated the providers, objectives, content and methods used to implement SBSE activities in secondary schools. Findings revealed a highly heterogeneous situation in terms of geographical coverage, service providers, objectives and evaluation. Some SBSE activities were classified as adopting a comprehensive approach to sexuality education, while the majority focused on STI prevention, and many were single-session activities. Although most activities were said to have been evaluated no results were available. The data showed that SBSE is not systematically and equally delivered across Italy. Action is needed to provide young people with evidence-based, age-appropriate and accurate education about sexual and reproductive health and wellbeing

Mutant p53 proteins counteract autophagic mechanism sensitizing cancer cells to mTOR inhibition

Mutations in TP53 gene play a pivotal role in tumorigenesis and cancer development. Here, we report that gain-of-function mutant p53 proteins inhibit the autophagic pathway favoring antiapoptotic effects as well as proliferation of pancreas and breast cancer cells. We found that mutant p53 significantly counteracts the formation of autophagic vesicles and their fusion with lysosomes throughout the repression of some key autophagy-related proteins and enzymes as BECN1 (and P-BECN1), DRAM1, ATG12, SESN1/2 and P-AMPK with the concomitant stimulation of mTOR signaling. As a paradigm of this mechanism, we show that atg12 gene repression was mediated by the recruitment of the p50 NF-\u3baB/mutant p53 protein complex onto the atg12 promoter. Either mutant p53 or p50 NF-\u3baB depletion downregulates atg12 gene expression. We further correlated the low expression levels of autophagic genes (atg12, becn1, sesn1, and dram1) with a reduced relapse free survival (RFS) and distant metastasis free survival (DMFS) of breast cancer patients carrying TP53 gene mutations conferring a prognostic value to this mutant p53-and autophagy-related signature. Interestingly, the mutant p53-driven mTOR stimulation sensitized cancer cells to the treatment with the mTOR inhibitor everolimus. All these results reveal a novel mechanism through which mutant p53 proteins promote cancer cell proliferation with the concomitant inhibition of autophagy

Lenalidomide-based induction and maintenance in elderly newly diagnosed multiple myeloma patients: updated results of the EMN01 randomized trial

In the EMN01 trial, the addition of an alkylator (melphalan or cyclophosphamide) to lenalidomide-steroid induction has been prospectively evaluated in transplant-ineligible multiple myeloma patients. After induction, patients were randomly assigned to maintenance treatment with lenalidomide alone or with prednisone continuously. This analysis (median follow-up of 71 months) focused on maintenance treatment and on subgroup analyses according to the International Myeloma Working Group Frailty Score. 217 patients in lenalidomide-dexamethasone, 217 in melphalan-prednisone-lenalidomide and 220 in cyclophosphamide-prednisone-lenalidomide arms were evaluable. 284 (43%) patients were fit, 205 (31%) intermediate-fit and 165 (25%) frail. After induction, 402 patients were eligible for maintenance, (lenalidomide arm: 204; lenalidomide-prednisone: 198). After a median duration of maintenance of 22.0 months, progression-free survival from start of maintenance was 22.2 months with lenalidomide-prednisone vs 18.6 months with lenalidomide (HR 0.85,p=0.14), with no differences across frailty subgroups. The most frequent grade ≥3 toxicity was neutropenia (10% of lenalidomide-prednisone and 21% of lenalidomide patients; p=0.001). Grade ≥3 non-hematologic adverse events were rare (<15%). In fit patients, melphalan-prednisone-lenalidomide significantly prolonged progression-free survival compared to cyclophosphamide-prednisone-lenalidomide (HR 0.72,p=0.05) and lenalidomide-dexamethasone (HR 0.72, p=0.04). Likewise, a trend towards a better overall survival was noted for melphalan-prednisone-lenalidomide and cyclophosphamide-prednisone-lenalidomide, as compared to lenalidomide-dexamethasone. No differences were observed in intermediate-fit and frail patients. This analysis showed positive outcomes of maintenance with lenalidomide-based regimens, with a good safety profile. For the first time, we showed that fit patients benefit from a triplet full-dose regimen, while intermediate-fit and frail patients from gentler regimens. ClinicalTrials.gov registration number: NCT01093196

MATRix-RICE therapy and autologous haematopoietic stem-cell transplantation in diffuse large B-cell lymphoma with secondary CNS involvement (MARIETTA): an international, single-arm, phase 2 trial.

BACKGROUND Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma. METHODS This international, single-arm, phase 2 trial was done in 24 hospitals in Italy, the UK, the Netherlands, and Switzerland. Adults (aged 18-70 years) with histologically diagnosed diffuse large B-cell lymphoma and CNS involvement at the time of primary diagnosis or at relapse and Eastern Cooperative Oncology Group Performance Status of 3 or less were enrolled and received three courses of MATRix (rituximab 375 mg/m2, intravenous infusion, day 0; methotrexate 3·5 g/m2, the first 0·5 g/m2 in 15 min followed by 3 g/m2 in a 3 h intravenous infusion, day 1; cytarabine 2 g/m2 every 12 h, in 1 h intravenous infusions, days 2 and 3; thiotepa 30 mg/m2, 30 min intravenous infusion, day 4) followed by three courses of RICE (rituximab 375 mg/m2, day 1; etoposide 100 mg/m2 per day in 500-1000 mL over a 60 min intravenous infusion, days 1, 2, and 3; ifosfamide 5 g/m2 in 1000 mL in a 24 h intravenous infusion with mesna support, day 2; carboplatin area under the curve of 5 in 500 mL in a 1 h intravenous infusion, day 2) and carmustine-thiotepa and autologous HSCT (carmustine 400 mg/m2 in 500 mL glucose 5% solution in a 1-2 h infusion, day -6; thiotepa 5 mg/kg in saline solution in a 2 h infusion every 12 h, days -5 and -4). The primary endpoint was progression-free survival at 1 year. Overall and complete response rates before autologous HSCT, duration of response, overall survival, and safety were the secondary endpoints. Analyses were in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02329080. The trial ended after accrual completion; the database lock was Dec 31, 2019. FINDINGS Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. 75 patients were assessable. 319 (71%) of the 450 planned courses were delivered. At 1 year from enrolment the primary endpoint was met, 42 patients were progression free (progression-free survival 58%; 95% CI 55-61). 49 patients (65%; 95% CI 54-76) had an objective response after MATRix-RICE, 29 (39%) of whom had a complete response. 37 patients who responded had autologous HSCT. At the end of the programme, 46 patients (61%; 95% CI 51-71) had an objective response, with a median duration of objective response of 26 months (IQR 16-37). At a median follow-up of 29 months (IQR 20-40), 35 patients were progression-free and 33 were alive, with a 2-year overall survival of 46% (95% CI 39-53). Grade 3-4 toxicity was most commonly haematological: neutropenia in 46 (61%) of 75 patients, thrombocytopenia in 45 (60%), and anaemia in 26 (35%). 79 serious adverse events were recorded in 42 (56%) patients; four (5%) of those 79 were lethal due to sepsis caused by Gram-negative bacteria (treatment-related mortality 5%; 95% CI 0·07-9·93). INTERPRETATION MATRix-RICE plus autologous HSCT was active in this population of patients with very poor prognosis, and had an acceptable toxicity profile. FUNDING Stand Up To Cancer Campaign for Cancer Research UK, the Swiss Cancer Research foundation, and the Swiss Cancer League

Targeting GD2-positive glioblastoma by chimeric antigen receptor empowered mesenchymal progenitors

Tumor targeting by genetically modified mesenchymal stromal/stem cells (MSCs) carrying anti-cancer molecules represents a promising cell-based strategy. We previously showed that the pro-apoptotic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can be successfully delivered by MSCs to cancer sites. While the interaction between TRAIL and its receptors is clear, more obscure is the way in which MSCs can selectively target tumors and their antigens. Several neuroectoderm-derived neoplasms, including glioblastoma (GBM), sarcomas, and neuroblastoma, express high levels of the tumor-associated antigen GD2. We have already challenged this cell surface disialoganglioside by a chimeric antigen receptor (CAR)-T cell approach against neuroblastoma. With the intent to maximize the therapeutic profile of MSCs delivering TRAIL, we here originally developed a bi-functional strategy where TRAIL is delivered by MSCs that are also gene modified with the truncated form of the anti-GD2 CAR (GD2 tCAR) to mediate an immunoselective recognition of GD2-positive tumors. These bi-functional MSCs expressed high levels of TRAIL and GD2 tCAR associated with a robust anti-tumor activity against GD2-positive GBM cells. Most importantly, the anti-cancer action was reinforced by the enhanced targeting potential of such bi-functional cells. Collectively, our results suggest that a truncated anti-GD2 CAR might be a powerful new tool to redirect MSCs carrying TRAIL against GD2-expressing tumors. This affinity-based dual targeting holds the promise to combine site-specific and prolonged retention of MSCs in GD2-expressing tumors, thereby providing a more effective delivery of TRAIL for still incurable cancers

Gain-of-function mutant p53 enhances mitochondrial ROS through the inhibition of PGC-1\u3b1/UCP2 axis in cancer cells

Mutations in the TP53 gene occur in over 50% of the human cancers and most of them are missense mutations that result in the expression of mutant forms of p53. In addition, p53 mutated proteins acquire new biological properties referred as gain-of-function (GOF) that contribute to the induction and maintenance of cancer. Reactive oxygen species (ROS) are radicals, ions or molecules highly reactive that are produced as an inevitable byproduct of mitochondrial oxidative phosphorylation. ROS can act as second messengers in cellular signaling in human cancer and are implicated in a plethora of biological events addressed to sustain each aspect of its progression. Uncoupling protein 2 (UCP2) is located in the mitochondrial inner membrane and plays an essential role is critical in energy regulation and in the maintenance of cellular ROS homeostasis by limiting the production of mitochondrial superoxide. We have investigated the molecular mechanisms by which mutant p53 regulates the redox status in cancer cells and its role in sustaining cancer progression and chemoresistance. We found that mutant p53 proteins, contrarily to wild type p53, enhance mitochondrial ROS in cancer cells which are crucial mediators of their oncogenic activity leading: i) cancer cell proliferation, ii) inhibition of apoptosis, and iii) chemoresistance. Importantly, we unveiled that mutant p53 inhibits SESN/AMPK-\u3b1 interaction leading an inhibition of AMPK phosphorylation. Consequently to the deregulation of AMPK signaling by mutant p53, but not by wild type p53, the expression of its effector PGC-1\u3b1 was also affected, driving a reduction of UCP2 expression and an increase of mitochondrial superoxide. These data reveal a novel mechanism by which mutant p53 sustains tumor progression and lightened on the importance that plays the redox cellular status in the tumors carrying oncogenic mutant p53 proteins

Wide transcriptional investigation unravel novel insights of the on-tree maturation and postharvest ripening of \u2018Abate Fetel\u2019 pear fruit

To decipher the transcriptomic regulation of the on-tree fruit maturation in pear cv. \u2018Abate Fetel\u2019, a RNA-seq transcription analysis identified 8939 genes differentially expressed across four harvesting stages. These genes were grouped into 11 SOTA clusters based on their transcriptional pattern, of which three included genes upregulated while the other four were represented by downregulated genes. Fruit ripening was furthermore investigated after 1 month of postharvest cold storage. The most important variation in fruit firmness, production of ethylene and volatile organic compounds were observed after 5 days of shelf-life at room temperature following cold storage. The role of ethylene in controlling the ripening of \u2018Abate Fetel\u2019 pears was furthermore investigated through the application of 1-methylcyclopropene, which efficiently delayed the progression of ripening by reducing fruit softening and repressing both ethylene and volatile production. The physiological response of the interference at the ethylene receptor level was moreover unraveled investigating the expression pattern of 12 candidate genes, initially selected to validate the RNA-seq profile. This analysis confirmed the effective role of the ethylene competitor in downregulating the expression of cell wall (PG) and ethylene-related genes (ACS, ACO, ERS1, and ERS2), as well as inducing one element involved in the auxin signaling pathway (Aux/IAA), highlighting a possible cross-talk between these two hormones. The expression patterns of these six elements suggest their use as molecular toolkit to monitor at molecular level the progression of the fruit on-tree maturation and postharvest ripening