An Efficient Strategy to Induce and Maintain In Vitro Human T Cells Specific for Autologous Non-Small Cell Lung Carcinoma

BACKGROUND: The efficient expansion in vitro of cytolytic CD8+ T cells (CTLs) specific for autologous tumors is crucial both for basic and translational aspects of tumor immunology. We investigated strategies to generate CTLs specific for autologous Non-Small Cell Lung Carcinoma (NSCLC), the most frequent tumor in mankind, using circulating lymphocytes. PRINCIPAL FINDINGS: Classic Mixed Lymphocyte Tumor Cultures with NSCLC cells consistently failed to induce tumor-specific CTLs. Cross-presentation in vitro of irradiated NSCLC cells by autologous dendritic cells, by contrast, induced specific CTL lines from which we obtained a high number of tumor-specific T cell clones (TCCs). The TCCs displayed a limited TCR diversity, suggesting an origin from few tumor-specific T cell precursors, while their TCR molecular fingerprints were detected in the patient's tumor infiltrating lymphocytes, implying a role in the spontaneous anti-tumor response. Grafting NSCLC-specific TCR into primary allogeneic T cells by lentiviral vectors expressing human V-mouse C chimeric TCRalpha/beta chains overcame the growth limits of these TCCs. The resulting, rapidly expanding CD4+ and CD8+ T cell lines stably expressed the grafted chimeric TCR and specifically recognized the original NSCLC. CONCLUSIONS: This study defines a strategy to efficiently induce and propagate in vitro T cells specific for NSCLC starting from autologous peripheral blood lymphocytes

Insight from an Italian Delphi Consensus on EVAR feasibility outside the instruction for use: the SAFE EVAR Study

BACKGROUND: The SAfety and FEasibility of standard EVAR outside the instruction for use (SAFE-EVAR) Study was designed to define the attitude of Italian vascular surgeons towards the use of standard endovascular repair (EVAR) for infrarenal abdominal aortic aneurysm (AAA) outside the instruction for use (IFU) through a Delphi consensus endorsed by the Italian Society of Vascular and Endovascular Surgery (Societa Italiana di Chirurgia Vascolare ed Endovascolare - SICVE). METHODS: A questionnaire consisting of 26 statements was developed, validated by an 18 -member Advisory Board, and then sent to 600 Italian vascular surgeons. The Delphi process was structured in three subsequent rounds which took place between April and June 2023. In the first two rounds, respondents could indicate one of the following five degrees of agreement: 1) strongly agree; 2) partially agree; 3) neither agree nor disagree; 4) partially disagree; 5) strongly disagree; while in the third round only three different choices were proposed: 1) agree; 2) neither agree nor disagree; 3) disagree. We considered the consensus reached when >70% of respondents agreed on one of the options. After the conclusion of each round, a report describing the percentage distribution of the answers was sent to all the participants. RESULTS: Two -hundred -forty-four (40.6%) Italian Vascular Surgeons agreed to participate the first round of the Delphi Consensus; the second and the third rounds of the Delphi collected 230 responders (94.3% of the first -round responders). Four statements (15.4%) reached a consensus in the first rounds. Among the 22 remaining statements, one more consensus (3.8%) was achieved in the second round. Finally, seven more statements (26.9%) reached a consensus in the simplified last round. Globally, a consensus was reached for almost half of the proposed statements (46.1%). CONCLUSIONS: The relatively low consensus rate obtained in this Delphi seems to confirm the discrepancy between Guideline recommendations and daily clinical practice. The data collected could represent the source for a possible guidelines' revision and the proposal of specific Good Practice Points in all those aspects with only little evidence available

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Benedetto XV : papa Giacomo Della Chiesa nel mondo dell'inutile strage.

"È necessario un grande sforzo di ricerca per capire i molti risvolti della personalità e dell'azione di papa Benedetto XV Spesso la sua figura ha rischiato di venire quasi compressa e quasi trasformata in una semplice premessa a quella frase memorabile, lapidaria al pari di un giudizio profetico, della Prima guerra mondiale come «inutile strage», riducendo la sua azione a un puro contorno a quell'atto. Mi guardo bene dal sottovalutarlo, ma credo che esso trovi il suo senso profondo in una disamina più ampia della sua vicenda." (Dall'Introduzione di Alberto Melloni

Benedict XV: a Pope in the world of the "useless slaughter" (1914-1918)

On August 1, 1917 – three years after the outbreak of World War 1 – pope Benedict XV signed his famous peace note, urging the governments of the belligerent Powers to seek a diplomatic solution to their disputes and stop the "useless slaughter". In order to commemorate the event and to define the place of this "forgotten pope" in twentieth-century history, on November 3-5, 2016, the Fondazione per le Scienze Religiose Giovanni XXIII (Fscire) hosted an international conference, entitled "Benedict XV in the world of the useless slaughter", in which more than a hundred historians from all over the world participated. The aim of the initiative, supported by the Historical and Scientific Committee for Italy’s National Anniversaries, is to shed light on the key issues of this pontificate, from Giacomo Della Chiesa’s education in the theological seminary in Genua to his heritage and memory all along the twentieth century. The volume resulting from this conference provides a comprehensive and systematic reference work about a key figure in Church history that has all too often been neglected

Comparing the Attitude toward the COVID-19 and the 2020/21 and 2019/20 Flu Vaccination Campaigns among Italian Healthcare Workers

Background: While the uptake of the COVID-19 vaccine among healthcare workers (HCWs) is suboptimal, vaccine hesitancy has not been characterized in detail in this population. Objective: The aim of this study was to compare the prevalence of health-related conditions reported by HCWs during the COVID-19, 2020/21 flu, and 2019/20 flu vaccination campaigns, so to test the hypothesis that HCWs were more prone to report health conditions during the COVID-19 campaign. Methods: We analyzed vaccination questionnaires of 176 hospital-based HCWs who underwent the COVID-19 and the 2020/21 flu vaccinations; 2019/20 flu vaccination questionnaires were available for 130 of them. Outcomes included self-reported allergies, chronic diseases, and use of medications. We tested for prevalence equality, analyzed differences using the kappa statistics and concordance correlation, and explored factors associated with differences in reporting. Results: There was no difference in the proportion of HCWs reporting allergies in the three questionnaires, while chronic diseases were more frequently reported in the COVID-19 than in both 2020/21 (p = 0.04) and 2019/20 flu questionnaires (p = 0.02). Furthermore, a higher proportion of HCWs reported medications use in the COVID-19 vaccination questionnaire, compared to both the 2020/21 and the 2019/20 flu vaccination questionnaires (p < 0.001 for both). In each vaccine campaign, women reported more conditions than men, and the difference between chronic disease reports was greater for women than for men. Conclusions: Our results show more frequent reporting of health conditions during the COVID-19 than the flu vaccination campaigns, providing quantitative evidence of hesitancy of HCWs towards the COVID-19 vaccine

Simultaneous Detection of NF1, SPRED1, LZTR1, and NF2 Gene Mutations by Targeted NGS in an Italian Cohort of Suspected NF1 Patients

Neurofibromatosis type 1 (NF1) displays overlapping phenotypes with other neurocutaneous diseases such as Legius Syndrome. Here, we present results obtained using a next generation sequencing (NGS) panel including NF1, NF2, SPRED1, SMARCB1, and LZTR1 genes on Ion Torrent. Together with NGS, the Multiplex Ligation-Dependent Probe Amplification Analysis (MLPA) method was performed to rule out large deletions/duplications in NF1 gene; we validated the MLPA/NGS approach using Sanger sequencing on DNA or RNA of both positive and negative samples. In our cohort, a pathogenic variant was found in 175 patients; the pathogenic variant was observed in NF1 gene in 168 cases. A SPRED1 pathogenic variant was also found in one child and in a one year old boy, both NF2 and LZTR1 pathogenic variants were observed; in addition, we identified five LZTR1 pathogenic variants in three children and two adults. Six NF1 pathogenic variants, that the NGS analysis failed to identify, were detected on RNA by Sanger. NGS allows the identification of novel mutations in five genes in the same sequencing run, permitting unambiguous recognition of disorders with overlapping phenotypes with NF1 and facilitating genetic counseling and a personalized follow-up

Case Report: Analysis of Plasma Extracellular Vesicles in a Triple Negative Spindle-Cell Metaplastic Breast Cancer Patient

Metaplastic breast cancer (MpBC) is a rare tumor representing 1% of all breast malignancies. The prognosis of this histologic subtype is actually poor and there are no current clear-cut therapeutic guidelines. Hence, despite its uniqueness, its aggressive prognostic profile strongly encourages further studies to identify new markers and therapeutic targets. Herein, we report a case of 32-years-old patient affected with of triple negative spindle-shaped MpBC. The research of molecular targets on the primary tumor did not allow performing an effective therapeutic choice. Extracellular Vesicles (EVs) are under intense study as new potential pathophysiological markers and targets for therapeutic applications, in different tumors for their role in tumor onset, progression and aggressiveness. Here, we examined the involvement of EVs in this case, to look into the MpBC microenvironment willing to identify new potential molecular targets, pathways of aggressiveness, and markers of prognosis and therapeutic efficacy. Firstly, we characterized MpBC patient EV dimensions and surface proteins. Moreover, we analyzed the EV RNA cargo supposed to be delivered to nearby and distant recipient cells. Interestingly, we observed a dysregulation EV-contained miRNAs, which could determine an increased expression of oncogenes in the tumor microenvironment, probably enabling cancer progression. These data suggest that the characterization of miRNA cargo of EVs could be important for the identification of new markers and for the application of future new target therapies