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Previous research has shown that young adults are more hesitant/resistant to COVID-19 vaccine uptake than older age groups, although the factors underlying this tendency are still under debate. The current study aimed to identify the sociodemographic and psychological correlates of vaccine hesitancy and resistance among young adults (18–40 years) during the nationwide COVID-19 vaccination campaign in Italy, the first country after China being hit by the pandemic and which suffered a large number of fatalities. This is a cross-sectional, web-based study conducted in Italy using an ISO-certified international survey company (respondi.com). Data were collected on 1200 participants in June 2021. Vaccine hesitancy/resistance was found for 25% of the sample. In multinomial logistic regression (N = 1159), being aged 30–40 years, residing in northern Italy, having lower educational and income level, being unemployed, and not knowing any friends/relatives diagnosed with COVID-19 were associated with higher odds of hesitancy or resistance. In multivariate analysis of variance (N = 1177), both vaccine hesitant and resistant young adults perceived significantly less social support from friends and family than vaccine accepting ones. Resistant individuals reported significantly higher levels of conspiracy theories and negative attitudes toward vaccines than their accepting and hesitant counterparts. Moreover, resistant individuals reported significantly lower levels of attachment to country and perceptions of a just government compared to accepting ones, with hesitant young adults scoring in between. Our findings support the idea that young adults with a hesitant (vs. resistant) attitude show a more nuanced and less extreme psychological profile. Public health messaging should capitalize on social media to provide accessible, transparent, and age-appropriate information concerning COVID-19 vaccine safety. Moreover, policy efforts improving the availability of social support systems are warranted to strengthen connectedness and foster trust in institutions amongst this particular segment of the population.

While both the classroom cultural diversity climate and curriculum-based interventions can promote cultural identity development, they have not been studied together. Drawing on theories of ethnic-racial identity development, the current study aimed to understand the dynamic interplay of a curriculum-based intervention (the Identity Project) with the classroom cultural diversity climate (heritage culture and intercultural learning, critical consciousness socialization and equal treatment) on cultural identity exploration and resolution. Our sample included 906 mid-adolescents in Italy (32.36% immigrant descent, Mage (SD) = 15.12 (0.68) years, 51.73% female), and 504 early adolescents in Germany (53.86% immigrant descent, Mage (SD) = 12.82 (0.89) years, 42.37% female). Bayesian multivariate linear models show that the Identity Project and a stronger critical consciousness climate in the classroom before the intervention promoted cultural identity exploration at post-test in both countries. However, effects of the intervention and facets of the diversity climate on subsequent resolution were only observed in Italy. There was some evidence that the intervention could alter the classroom cultural diversity climate in Germany, while the intervention could compensate for a less positive diversity climate in the slightly older sample in Italy. Thus, it seems promising to systematically build in opportunities to engage with students’ diverse heritage cultures and identities when developing new curricula, as well as to train teachers to implement such curricula.

Cultural identity formation is a complex developmental task that influences adolescents’ adjustment. However, less is known about individual variations in trajectories of cultural identity processes and how they relate to youth psychosocial outcomes. Using a person-centered approach, this study investigated patterns of change over a year in cultural identity exploration and resolution, respectively, among ethnically diverse adolescents in Italy. The sample included 173 high school students (Mage = 15 yrs, SD = 0.62, range = 14–17; 58.4% female; 26% immigrant background) who had participated in the Identity Project, a school-based intervention targeting ethnic-racial identity development. Longitudinal latent profile analysis revealed only one profile of change for exploration, whereas four unique profiles for resolution emerged (“stable low,” “stable average,” “increase low-to-average,” “increase high-to-higher”). Overall, youth in the resolution-increase profiles reported the best outcomes. The findings highlight the heterogeneity of adolescents’ resolution trajectories and the benefits of an increased sense of clarity concerning one’s cultural identity for positive psychosocial functioning.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the RNA virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although SARS-CoV-2 was reported to alter several cellular pathways, its impact on DNA integrity and the mechanisms involved remain unknown. Here we show that SARS-CoV-2 causes DNA damage and elicits an altered DNA damage response. Mechanistically, SARS-CoV-2 proteins ORF6 and NSP13 cause degradation of the DNA damage response kinase CHK1 through proteasome and autophagy, respectively. CHK1 loss leads to deoxynucleoside triphosphate (dNTP) shortage, causing impaired S-phase progression, DNA damage, pro-inflammatory pathways activation and cellular senescence. Supplementation of deoxynucleosides reduces that. Furthermore, SARS-CoV-2 N-protein impairs 53BP1 focal recruitment by interfering with damage-induced long non-coding RNAs, thus reducing DNA repair. Key observations are recapitulated in SARS-CoV-2-infected mice and patients with COVID-19. We propose that SARS-CoV-2, by boosting ribonucleoside triphosphate levels to promote its replication at the expense of dNTPs and by hijacking damage-induced long non-coding RNAs’ biology, threatens genome integrity and causes altered DNA damage response activation, induction of inflammation and cellular senescence. Gioia, Tavella et al. show that severe acute respiratory syndrome coronavirus 2 causes DNA damage through CHK1 degradation and impairs 53BP1 recruitment to DNA lesions. The induced DNA damage is associated with expression of pro-inflammatory cytokines and senescence markers.

Background Polypharmacy is regarded as an important risk factor for fallingand several studies and meta-analyses have shown an increased fall risk in users of diuretics, type 1a antiarrhythmics, digoxin and psychotropic agents. In particular, recent evidence has shown that fall risk is associated with the use of polypharmacy regimens that include at least one established fall risk-increasing drug, rather than with polypharmacy per se . We studied the role of polypharmacy and the role of well-known fall risk-increasing drugs on the incidence of injurious falls. Methods A retrospective observational study was carried out in a population of elderly nursing home residents. An unmatched, post-stratification design for age class, gender and length of stay was adopted. In all, 695 falls were recorded in 293 residents. Results 221 residents (75.4%) were female and 72 (24.6%) male, and 133 (45.4%) were recurrent fallers. 152 residents sustained no injuries when they fell, whereas injuries were sustained by 141: minor in 95 (67.4%) and major in 46 (32.6%). Only fall dynamics (p = 0.013) and drugs interaction between antiarrhythmic or antiparkinson class and polypharmacy regimen (≥7 medications) seem to represent a risk association for injuries (p = 0.024; OR = 4.4; CI 95% 1.21 - 15.36). Conclusion This work reinforces the importance of routine medication reviews, especially in residents exposed to polypharmacy regimens that include antiarrhythmics or antiparkinson drugs, in order to reduce the risk of fall-related injuries during nursing home stays.

Most of the anaplastic large-cell lymphoma (ALCL) cases carry the t(2;5; p23;q35) that produces the fusion protein NPM-ALK (nucleophosmin-anaplastic lymphoma kinase). NPM-ALK-deregulated kinase activity drives several pathways that support malignant transformation of lymphoma cells. We found that in ALK-rearranged ALCL cell lines, NPM-ALK was distributed in equal amounts between the cytoplasm and the nucleus. Only the cytoplasmic portion was catalytically active in both cell lines and primary ALCL, whereas the nuclear portion was inactive because of heterodimerization with NPM1. Thus, about 50% of the NPM-ALK is not active and sequestered as NPM-ALK/NPM1 heterodimers in the nucleus. Overexpression or relocalization of NPM-ALK to the cytoplasm by NPM genetic knockout or knockdown caused ERK1/2 (extracellular signal-regulated protein kinases 1 and 2) increased phosphorylation and cell death through the engagement of an ATM/Chk2- and γH2AX (phosphorylated H2A histone family member X)-mediated DNA-damage response. Remarkably, human NPM-ALK-amplified cell lines resistant to ALK tyrosine kinase inhibitors (TKIs) underwent apoptosis upon drug withdrawal as a consequence of ERK1/2 hyperactivation. Altogether, these findings indicate that an excess of NPM-ALK activation and signaling induces apoptosis via oncogenic stress responses. A ‘drug holiday’ where the ALK TKI treatment is suspended could represent a therapeutic option in cells that become resistant by NPM-ALK amplification.

Background Little is known about prognostic factors of brain metastases (BM) from colorectal cancer (CRC). HER2 amplification/overexpression (HER2+) was previously described; its impact on prognosis remains uncertain. Methods In the translational study HEROES, extensive molecular analysis was performed on primary CRC (prCRC) and their matched resected BM by means of NGS comprehensive genomic profiling and HER2 status as assessed by immunohistochemical/ in situ hybridization. Count of tumour-infiltrating lymphocytes (TILs) was also performed. Primary objective: to describe the molecular landscape of paired BM/prCRC. Secondary objectives: to search for new prognostic biomarkers of outcome after BM resection: intracranial-only Progression-Free Survival (BM-iPFS), Progression-Free Survival (BM-PFS), and Overall Survival (BM-OS). Results Out of 22 patients having paired samples of prCRC and BM, HER2+ was found on 4 (18%) BM, 3 (75%) of which also HER2+ in matched prCRC. Lower tumour mutation burden (HR 3.08; 95%CI 1.06–8.93; p  = 0.0386) and HER2-negative BM (HER2neg) (HR 7.75;95%CI 1.97–30.40; p  = 0.0033) were associated with longer BM-iPFS; HER2neg BM (HR 3.44; 95%CI 1.03–11.53; p  = 0.0449) and KRAS mut BM (HR 0.31; 95%CI 0.12–0.80; p  = 0.0153) conferred longer BM-PFS. Longer BM-OS was found in pts with TILs-enriched (≥1.6/HPF) BM (HR 0.11; 95%CI0.01–0.91; p  = 0.0403). Conclusions This study shows HER2+ enrichment in both BM and their prCRC. TILs-enriched BM conferred better BM-OS.

Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma characterized by expression of the oncogenic NPM/ALK fusion protein. When resistant or relapsed to front-line chemotherapy, ALK+ ALCL prognosis is very poor. In these patients, the ALK inhibitor crizotinib achieves high response rates, however 30–40% of them develop further resistance to crizotinib monotherapy, indicating that new therapeutic approaches are needed in this population. We here investigated the efficacy of upfront rational drug combinations to prevent the rise of resistant ALCL, in vitro and in vivo. Different combinations of crizotinib with CHOP chemotherapy, decitabine and trametinib, or with second-generation ALK inhibitors, were investigated. We found that in most cases combined treatments completely suppressed the emergence of resistant cells and were more effective than single drugs in the long-term control of lymphoma cells expansion, by inducing deeper inhibition of oncogenic signaling and higher rates of apoptosis. Combinations showed strong synergism in different ALK-dependent cell lines and better tumor growth inhibition in mice. We propose that drug combinations that include an ALK inhibitor should be considered for first-line treatments in ALK+ ALCL.

Old-growth forests have an important role in maintaining animal and plant diversity, are important carbon (C) reservoirs and are privileged sites to study long-term plant physiological responses, long-term forest dynamics and climate change impact on forest ecosystems. Several studies have highlighted how old-living trees undergo age-related declines with hydraulic limitations and reduction in photosynthesis, though some recent works have suggested that such a decline is not always observed. Our study aims at understanding the role of atmospheric CO2 increase on tree C uptake and stomatal conductance (gs) in old-living trees by analysing the long-term patterns of tree growth and intrinsic water use efficiency (iWUE) in three old-growth forests in the Balkans (Bosnia-Herzegovina and Montenegro), using dendrochronology and isotopic analysis. We hypothesised a long-term increase in iWUE in the studied old-growth forests, mostly related to enhanced photosynthesis rather than reduced stomatal conductance. Tree cores were sampled from dominant silver fir (Abies alba Mill.) trees in each forest. Tree-ring widths were measured and basal area increments (BAI) were assessed for each sampled tree and, from the six longest chronologies, five decades were chosen for cellulose extraction, its isotopic analysis (δ13C, δ18O), iWUE and leaf water 18O evaporative enrichment above the source water (Δ18OL) determination. We observed a continuous and significant increase in iWUE from 1800 to 2010 in the sampled dominant trees at all the three old-growth forests. Our BAI data and our estimates of Δ18OL across the study period support the idea that enhanced photosynthesis rather than reduced stomatal conductance is the major driver of the measured iWUE increase. Thus, our results support some recent findings challenging the hypothesis that iWUE in forests is primarily the result of a CO2-induced reduction in stomatal conductance as well as the so called hydraulic limitation hypothesis.

Paclitaxel plus ramucirumab is recommended as a second-line treatment regimen in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer. We aimed to assess whether switch maintenance or early second-line therapy with paclitaxel plus ramucirumab improved outcomes compared with continuation of oxaliplatin and fluoropyrimidine doublet chemotherapy as a first-line strategy. ARMANI was a multicentre, open-label, randomised, phase 3 trial done in 31 hospitals in Italy. We enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and locally advanced unresectable or metastatic HER2-negative gastric or gastro-oesophageal junction cancer, who had disease control after 3 months of FOLFOX (leucovorin, fluorouracil, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin). Patients were randomly assigned (1:1) to either paclitaxel 80 mg/m2 on days 1, 8, and 15 plus ramucirumab at 8 mg/kg on days 1 and 15 every 28 days intravenously (switch maintenance group) or continuation of oxaliplatin-based doublet chemotherapy (FOLFOX or CAPOX) for an additional 12 weeks, followed by fluoropyrimidine monotherapy maintenance (control group). Randomisation was stratified by previous gastrectomy (no vs yes), peritoneal carcinomatosis (yes vs no), and primary tumour location (gastro-oesophageal junction vs gastric). Treatment group allocation was done using a web-based system with a minimisation algorithm implementing a random component. The primary endpoint was progression-free survival, analysed on an intention-to-treat basis. The safety population included patients who received at least one dose of the study treatment. This study is registered with ClinicalTrials.gov, NCT02934464, and is complete. Between Jan 1, 2017, and Oct 2, 2023, 280 patients were randomly assigned to receive paclitaxel plus ramucirumab (switch maintenance group; n=144) or to continue FOLFOX or CAPOX (control group; n=136). All patients were White. 180 (64%) of 280 patients were male and 100 (36%) were female. At a median follow-up of 43·7 months (IQR 24·0–57·9), 253 (90%) of 280 patients had a progression-free survival event: 131 (91%) of 144 patients in the switch maintenance group and 122 (90%) of 136 patients in the control group. Median progression-free survival was 6·6 months (95% CI 5·9–7·8) in the switch maintenance group and 3·5 months (2·8–4·2) in the control group (HR 0·61, 95% CI 0·48–0·79; p=0·0002). The assumption of proportional hazards was violated; in an analysis of 24-month restricted mean survival time, restricted mean progression-free survival was 8·8 months (95% CI 7·7–9·9) in the switch maintenance group and 6·1 months (5·0–7·2) in the control group (p=0·0010). The most frequent grade 3–4 treatment-related adverse events were neutropenia (37 [26%] patients in the switch maintenance group vs 13 [10%] patients in the control group), peripheral neuropathy (eight [6%] vs nine [7%]) and arterial hypertension (nine [6%] vs none). Serious adverse events occurred in 28 (20%) of 141 patients in the experimental group and 15 (11%) of 135 patients in the control group; these events were treatment-related in two (1%) patients in the switch maintenance group (pulmonary embolism) and two (1%) patients in the control group (mucositis and anaemia). No treatment-related deaths occurred. Paclitaxel and ramucirumab switch maintenance could be a potential treatment strategy in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer who are not eligible for immunotherapy or targeted agents. Partly funded by Eli Lilly.