Chemotherapy accelerates immune-senescence and functional impairments of Vδ2pos T cells in elderly patients affected by liver metastatic colorectal cancer.

Human (gamma delta) γδ T cells are unconventional innate-like lymphocytes displaying a broad array of anti-tumor activities with promising perspectives in cancer immunotherapy. In this context, Vδ2pos T cells represent the preferential target of several immunotherapy protocols against solid tumors. However, the impact of both aging and chemotherapy (CHT) on Vδ2pos T cells is still unknown. The present study evaluates with multi-parametric flow cytometry the frequencies, terminal differentiation, senescence and effector-functions of peripheral blood and tumor infiltrating Vδ2pos T cells purified from liver metastases (CLM) of patients affected by colorectal cancer (CRC) compared to those of sex- and age-matched healthy donors. The peripheral blood of CLM patients underwent CHT is characterized by decreased amounts of Vδ2pos T cells showing a relative increase of terminally-differentiated CD27neg/CD45RApos (TEMRA) cells. The enrichment of this latter subset is associated with an increased expression of the senescent marker CD57. The acquisition of CD57 on TEMRA Vδ2pos T cells is also coupled with impairments in cytotoxicity and production of TNF-α and IFN-γ. These features resemble the acquisition of an immune-senescent profile by Vδ2pos T cells from CLM patients that received CHT, a phenomenon that is also associated with the loss of the co-stimulatory marker CD28 and with the induced expression of CD16. The group of CLM patients underwent CHT and older than 60 years old showed higher frequencies of CD57pos and TEMRA Vδ2pos T cells. Similar results were found for tumor infiltrating Vδ2pos T cell subset purified from CLM specimens of patients treated with CHT. The toxicity of CHT regimens also affects the homeostasis of Vδ2pos T cells by inducing higher frequencies of circulating CD57pos TEMRA subset in CLM underwent CHT and younger than 60 years old. Taken together, our data demonstrate that the enrichment of senescent Vδ2pos T cells in CLM patients is not only induced by patients' aging but also by the toxicity of CHT that further accelerates the accumulation of CD57pos TEMRA cells highly dysfunctional in their anti-tumor activities. These results are important to both predict the clinical outcome of CLM and to optimize those protocols of cell cancer immunotherapy employing unconventional Vδ2pos T cells

Risk perception and media in shaping protective behaviors: insights from the early phase of COVID-19 Italian outbreak

In the absence of target treatments or vaccination, the SARS-CoV-2 pandemic can be impeded by effectively implementing containment measures and behaviors. This relies on individuals’ adoption of protective behaviors, their perceived risk, and the use and trust of information sources. During a health emergency, receiving timely and accurate information enables individuals to take appropriate actions to protect themselves, shaping their risk perception. Italy was the first western country plagued by COVID-19 and one of the most affected in the early phase. During this period, we surveyed 2,223 Italians before the national lockdown. A quarter of the sample perceived COVID-19 less threatening than flu and would not vaccinate, if a vaccine was available. Besides, most people perceived containment measures, based on social distancing or wearing masks, not useful. This perceived utility was related to COVID-19 threat perception and efficacy beliefs. All these measures were associated with the use of media and their truthfulness: participants declared to mainly use the Internet, while health organizations’ websites were the most trusted. Although social networks were frequently used, they were rated lower for trustfulness. Our data differ from those obtained in other community samples, suggesting the relevance to explore changes across different countries and during the different phases of the pandemic. Understanding these phenomena, and how people access the media, may contribute to improve the efficacy of containment measures, tailoring specific policies and health communications

La Data Science nella Giustizia Predittiva

I mezzi di comunicazione sono una straordinaria fonte di conoscenza e di informazione, ma gli aspetti positivi del loro utilizzo possono essere tanti quanti gli aspetti negativi. Oggi il progresso tecnologico attraversa la maggior parte delle attività quotidiane: basti pensare alle transazioni bancarie, alle vendite online e alle altre attività che virtualmente trovano la loro sede nella rete. Un settore in cui il progresso tecnologico potrebbe essere di grande aiuto è quello giuridico: attraverso la giustizia predittiva si eviterebbero incomprensioni di natura soggettiva e si potrebbe prevedere l’esito delle sentenze. L’art. 101 della Costituzione e l’art. 65 dell’Ordinamento Giudiziario esprimono l’impersonale oggettività del diritto e la funzionalità tecnica della sua applicazione, eliminando eventuali giudizi precoci. Il diritto è oggettivo, basato su leggi predeterminate e vincolanti, e proprio per questo è possibile affidarsi alla giustizia predittiva: la sua applicazione può favorire sistemi di risoluzione alternativi alle controversie come mediazione, negoziazione e proposta conciliativa. Nel 1666, Leibniz enunciava già la possibilità di utilizzare modelli di giustizia predittiva attraverso gli algoritmi matematici: secondo lui, davanti a una disputa, un giorno, si sarebbe potuto evitare il processo, promuovendo un calcolo delle controversie attraverso i modelli matematici. Oggi l’uomo, attraverso l’interazione con l’Intelligenza Artificiale, può progettare software che svolgano compiti complessi nel minor tempo possibile anche all’interno di contesti aziendali, per contrastare i rischi, proteggere le informazioni e i dati e combattere il cybercrime. L’obiettivo della presente monografia è quello di applicare la Statistica alla Giustizia, in particolare al cybercrime economico-finanziario, al fine di effettuare previsioni e trovare soluzioni per impedire la riproduzione dei reati

Validation of the Pediatric Evaluation of Disability Inventory in an Italian Population with Autism Spectrum Disorder: a Cross-Sectional Study

Objective To measure psychometric properties of the Italian version of the Pediatric Evaluation of Disability Inventory (PEDI-I) in a population with Autism Spectrum Disorder (ASD). Methods The PEDI-I was administered to different children with ASD. The internal consistency was examined by using Cronbach’s Alpha, while the intraclass correlation coefficient (ICC) was used to investigate both inter-observer and intra-observer reproducibility. Its concurrent validity was evaluated with the Italian version of the Barthel Index. Results The PEDI-I was administered to 60 children with a diagnosis of ASD. Cronbach’s Alpha showed statistically significant values (.885-.965). Inter-observer and intra-observer investigations confirm the reproducibility of the scale with a range of high and very high parameters. The Pearson Correlation Coefficient with the Barthel Index showed significant data for all PEDI-I subscales with a p<0.01. Conclusions The PEDI-I showed good psychometric properties and it is possible to confirm its validity and reliability in ASD population. However, for better understanding of how PEDI-I works in clinical practice, further researches are recommende

Tumor microenvironment in primary liver tumors : A challenging role of natural killer cells

In the last years, several studies have been focused on elucidate the role of tumor microenvironment (TME) in cancer development and progression. Within TME, cells from adaptive and innate immune system are one of the main abundant components. The dynamic interactions between immune and cancer cells lead to the activation of complex molecular mechanisms that sustain tumor growth. This important cross-talk has been elucidate for several kind of tumors and occurs also in patients with liver cancer, such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Liver is well-known to be an important immunological organ with unique microenvironment. Here, in normal conditions, the rich immune-infiltrating cells cooperate with non-parenchymal cells, such as liver sinusoidal endothelial cells and Kupffer cells, favoring self-tolerance against gut antigens. The presence of underling liver immunosuppressive microenvironment highlights the importance to dissect the interaction between HCC and iCCA cells with immune infiltrating cells, in order to understand how this cross-talk promotes tumor growth. Deeper attention is, in fact, focused on immune-based therapy for these tumors, as promising approach to counteract the intrinsic anti-tumor activity of this microenvironment. In this review, we will examine the key pathways underlying TME cell-cell communications, with deeper focus on the role of natural killer cells in primary liver tumors, such as HCC and iCCA, as new opportunities for immune-based therapeutic strategies

Understanding the role of the primary care physician in the management of patients with Crohn’s perianal fistulas

To understand the role of primary care physicians (PCPs) in the recognition, diagnosis, and management of Crohn’s perianal fistulas (CPF) and their referral patterns and treatment expectations. This survey-based study was conducted between September 2020 and October 2020. US-based PCPs managing at least one patient with Crohn’s disease per week were included. Participants were presented with two case vignettes relevant to primary care practice; Case Vignette 1 comprised three parts and focused on initial CPF presentation and progression to partial response; Case Vignette 2 focused on recurrent CPF. Survey questions elicited the physician’s clinical approach to each case. Data were presented as descriptive statistics. Overall, 151 PCPs (median 23 years in practice) who saw about three patients per month with new/existing CPF responded. For Case Vignette 1, upon identification of a fistulous tract, 89% of respondents would refer the patient, mostly to a colorectal surgeon or gastroenterologist. Most PCPs (69%) would begin the patient on medication; 46% would conduct a diagnostic/imaging study. Treatment expectations after referral varied: 55% of respondents believed surgeons would place a seton or use one prior to surgery; 23% expected medical management only; 23% were unsure. Case Vignette 2 revealed that 98% of PCPs preferred to be involved in patient care after referral; however, only 49% were. Of these, 76% considered reinforcing patient treatment adherence as their primary role. While 80% of PCPs were at least moderately satisfied with communication and care coordination with multidisciplinary teams, 52% considered lack of access to specialists as at least a moderate barrier to multidisciplinary team management. PCPs want more involvement in multidisciplinary management of patients with CPF. Continuing education providing PCPs with up-to-date information on diagnostic modalities, treatment options, early diagnosis, the role of PCPs within a multidisciplinary team, and effective initial CPF care is required. What were the study’s aims? To understand how primary care physicians recognize, treat, and monitor patients with Crohn’s disease-related perianal fistulas (small tunnels between the bowel and skin near the anus). How was the study done? US-based primary care physicians, including internists, were included if they had experience in treating patients with Crohn’s disease. Descriptions of the history and symptoms of two hypothetical patients were provided: one patient who may have Crohn’s perianal fistulas and another patient whose Crohn’s perianal fistulas had returned after being treated. After reading these descriptions, the physicians completed a questionnaire designed to show how they would help each patient. What did the study find out? Not all physicians treat patients with Crohn’s perianal fistulas in the same way in terms of diagnostic tests and medical treatments, although most said they would refer them to a specialist if a fistula was identified. Many wanted to be involved in patient care after referral to a specialist but only half were. Of those, most thought their main role was to ensure patients followed the treatments given by specialists. More than half of primary care physicians thought a lack of access to specialists could be a barrier to care. How does this impact care? The physicians surveyed want more involvement in multidisciplinary teams who look after patients with Crohn’s perianal fistulas. To do this, they need more education about the diagnosis and treatment of Crohn’s perianal fistulas, and clarity around their role within multidisciplinary teams who manage these patients.</p

APOL1 polymorphism modulates sphingolipid profile of human podocytes

Apolipoprotein L1 (APOL1) wild type (G0) plays a role in the metabolism of sphingolipids, glycosphingolipids, sphingomyelin and ceramide, which constitute bioactive components of the lipid rafts (DRM). We asked whether APOL1 variants (APOL1-Vs) G1 and G2 carry the potential to alter the metabolism of sphingolipids in human podocytes. The sphingolipid pattern in HPs overexpressing either APOL1G0 or APOL1-Vs was analysed by using a thin mono- and bi-dimensional layer chromatography, mass-spectrometry and metabolic labelling with [1-3H]sphingosine. HP G0 and G1/G2-Vs exhibit a comparable decrease in lactosylceramide and an increase in the globotriaosylceramide content. An analysis of the main glycohydrolases activity involved in glycosphingolipid catabolism showed an overall decrease in the activeness of the tested enzymes, irrespective of the type of APOL1-Vs expression. Similarly, the high throughput cell live-based assay showed a comparable increased action of the plasma membrane glycosphingolipid-glycohydrolases in living cells independent of the genetic APOL1 expression profile. Importantly, the most significative modification of the sphingolipid pattern induced by APOL1-Vs occurred in DRM resulted with a drastic reduction of radioactivity associated with sphingolipids. G1/G2-Vs present a decrease amount of globotriaosylceramide and globopentaosylceramide compared to G0. Additionally, ceramide at the DRM site and lactosylceramide in general, showed a greatest fall in G1/G2 in comparison with G0. Additionally, the levels of glucosylceramide decreased only in the DRM of human podocytes overexpressing G1/G2-Vs. These findings suggest that altered sphingolipidsprofiles may contribute to the deranged functionality of the plasma membrane in APOL1 risk milieu

Identification of Tissue-Resident Natural Killer and T Lymphocytes with Anti-Tumor Properties in Ascites of Ovarian Cancer Patients

Women with ovarian cancer have limited therapy options, with immunotherapy being unsatisfactory for a large group of patients. Tumor cells spread from the ovary or the fallopian tube into the abdominal cavity, which is commonly accompanied with massive ascites production. The ascites represents a unique peritoneal liquid tumor microenvironment with the presence of both tumor and immune cells, including cytotoxic lymphocytes. We characterized lymphocytes in ascites from patients with high-grade serous ovarian cancer. Our data reveal the presence of NK and CD8+ T lymphocytes expressing CD103 and CD49a, which are markers of tissue residency. Moreover, these cells express high levels of the inhibitory NKG2A receptor, with the highest expression level detected on tissue-resident NK cells. Lymphocytes with these features were also present at the primary tumor site. Functional assays showed that tissue-resident NK cells in ascites are highly responsive towards ovarian tumor cells. Similar results were observed in an in vivo mouse model, in which tissue-resident NK and CD8+ T cells were detected in the peritoneal fluid upon tumor growth. Together, our data reveal the presence of highly functional lymphocyte populations that may be targeted to improve immunotherapy for patients with ovarian cancer.This research was funded by a Research Award from the Wellbeing of Women (RG2331; F.C., E.B., J.B.), a Wellcome Investigator Award (094073/Z/10/Z; F.C.), the Cambridge NIHR BRC Cell Phenotyping Hub (F.C.), the Swedish cancer foundation society (20 0226 P 01 H; E.B. and CAN 2018/384; K.S.), the Swedish research council (2019-06328; E.B.), the Swedish Society for Medical Research (E.B.), the Swedish Society for Medicine (SLS-881711; E.B.), the Assar Gabrielsson founda- tion (BRG20-06; E.B.), Swedish state under the agreement between the Swedish government and the county council, the ALF agreement (ALFGBG-965552; K.S.), Italian Ministry of Health (Bando Ri- cerca Finalizzata PE-2016-02363915, D.M.), Associazione Italiana per la Ricerca sul Cancro (IG 14687; D.M.), Intramural research and clinical funding programs of Humanitas Research Hospital (5 X 1000; D.M.) and University of Milan (D.M.). O.H. was supported by a AstraZeneca-MedImmune- Cambridge PhD fellowship. V.C. is a recipient of a competitive fellowship awarded from the Ph.D. program of Experimental Medicine at the University of Milan

Identification of Tissue-Resident Natural Killer and T Lymphocytes with Anti-Tumor Properties in Ascites of Ovarian Cancer Patients.

Peer reviewed: TrueFunder: Cambridge NIHR BRC Cell Phenotyping HubFunder: Swedish Society for Medical ResearchFunder: University of MilanFunder: AstraZeneca-MedImmune-Cambridge PhD fellowshipFunder: Experimental Medicine at the University of MilanFunder: Cancer Research UKFunder: Cancer Research UK Cambridge CentreFunder: Mark Foundation Institute for Integrated Cancer MedicineWomen with ovarian cancer have limited therapy options, with immunotherapy being unsatisfactory for a large group of patients. Tumor cells spread from the ovary or the fallopian tube into the abdominal cavity, which is commonly accompanied with massive ascites production. The ascites represents a unique peritoneal liquid tumor microenvironment with the presence of both tumor and immune cells, including cytotoxic lymphocytes. We characterized lymphocytes in ascites from patients with high-grade serous ovarian cancer. Our data reveal the presence of NK and CD8+ T lymphocytes expressing CD103 and CD49a, which are markers of tissue residency. Moreover, these cells express high levels of the inhibitory NKG2A receptor, with the highest expression level detected on tissue-resident NK cells. Lymphocytes with these features were also present at the primary tumor site. Functional assays showed that tissue-resident NK cells in ascites are highly responsive towards ovarian tumor cells. Similar results were observed in an in vivo mouse model, in which tissue-resident NK and CD8+ T cells were detected in the peritoneal fluid upon tumor growth. Together, our data reveal the presence of highly functional lymphocyte populations that may be targeted to improve immunotherapy for patients with ovarian cancer.This research was funded by a Research Award from the Wellbeing of Women (RG2331; F.C., E.B., J.B.), a Wellcome Investigator Award (094073/Z/10/Z; F.C.), the Cambridge NIHR BRC Cell Phenotyping Hub (F.C.), the Swedish cancer foundation society (20 0226 P 01 H; E.B. and CAN 2018/384; K.S.), the Swedish research council (2019-06328; E.B.), the Swedish Society for Medical Research (E.B.), the Swedish Society for Medicine (SLS-881711; E.B.), the Assar Gabrielsson founda- tion (BRG20-06; E.B.), Swedish state under the agreement between the Swedish government and the county council, the ALF agreement (ALFGBG-965552; K.S.), Italian Ministry of Health (Bando Ri- cerca Finalizzata PE-2016-02363915, D.M.), Associazione Italiana per la Ricerca sul Cancro (IG 14687; D.M.), Intramural research and clinical funding programs of Humanitas Research Hospital (5 X 1000; D.M.) and University of Milan (D.M.). O.H. was supported by a AstraZeneca-MedImmune- Cambridge PhD fellowship. V.C. is a recipient of a competitive fellowship awarded from the Ph.D. program of Experimental Medicine at the University of Milan

Predictors of early discontinuation of dapagliflozin versus other glucose-lowering medications: a retrospective multicenter real-world study

Background and aims: In routine clinical practice, early discontinuation of newly initiated glucose-lowering medications (GLM) is relatively common. We herein evaluated if the clinical characteristics associated with early discontinuation of dapagliflozin were different from those associated with early discontinuation of other GLM. Methods: The DARWIN-T2D was a multicenter retrospective study conducted at diabetes specialist outpatient clinics in Italy. We included 2484 patients who were initiated on dapagliflozin in 2015–2016 and 14,801 patients who were initiated on other GLM (DPP-4 inhibitors, GLP-1 receptor agonists, or gliclazide) in the same period. After excluding patients who had not (yet) returned to follow-up, we compared the characteristics of patients who persisted on drug versus those who were no longer on drug at the first available follow-up after at least 3&nbsp;months. Results: As compared to those who persisted on drug, patients who discontinued dapagliflozin (51.7%) were more often female, had higher baseline fasting plasma glucose (FPG), HbA1c, and eGFR, and less common use of metformin. Upon multiple regression, higher HbA1c, higher eGFR, and lower metformin use remained independently associated with early discontinuation. Among patients who had been initiated on other GLM, 41.7% discontinued. Variables independently associated with discontinuation were older age, longer diabetes duration, higher HbA1c, eGFR, and albumin excretion, more common use of insulin and less metformin. Conclusion: In routine clinical practice, all variables associated with dapagliflozin discontinuation were also associated with discontinuation of other GLM. Thus, despite a distinctive mechanism of action and a peculiar tolerability profile, no specific predictor of dapagliflozin discontinuation was detected