Insight into immune profile associated with vitiligo onset and anti-tumoral response in melanoma patients receiving anti-PD-1 immunotherapy

IntroductionImmunotherapy with checkpoint inhibitors is an efficient treatment for metastatic melanoma. Development of vitiligo upon immunotherapy represents a specific immune-related adverse event (irAE) diagnosed in 15% of patients and associated with a positive clinical response. Therefore, a detailed characterization of immune cells during vitiligo onset in melanoma patients would give insight into the immune mechanisms mediating both the irAE and the anti-tumor response. MethodsTo better understand these aspects, we analyzed T cell subsets from peripheral blood of metastatic melanoma patients undergoing treatment with anti-programmed cell death protein (PD)-1 antibodies. To deeply characterize the antitumoral T cell response concomitant to vitiligo onset, we analyzed T cell content in skin biopsies collected from melanoma patients who developed vitiligo. Moreover, to further characterize T cells in vitiligo skin lesion of melanoma patients, we sequenced T cell receptor (TCR) of cells derived from biopsies of vitiligo and primary melanoma of the same patient.Results and discussionStratification of patients for developing or not developing vitiligo during anti-PD-1 therapy revealed an association between blood reduction of CD8-mucosal associated invariant T (MAIT), T helper (h) 17, natural killer (NK) CD56bright, and T regulatory (T-reg) cells and vitiligo onset. Consistently with the observed blood reduction of Th17 cells in melanoma patients developing vitiligo during immunotherapy, we found high amount of IL-17A expressing cells in the vitiligo skin biopsy, suggesting a possible migration of Th17 cells from the blood into the autoimmune lesion. Interestingly, except for a few cases, we found different TCR sequences between vitiligo and primary melanoma lesions. In contrast, shared TCR sequences were identified between vitiligo and metastatic tissues of the same patient. These data indicate that T cell response against normal melanocytes, which is involved in vitiligo onset, is not typically mediated by reactivation of specific T cell clones infiltrating primary melanoma but may be elicited by T cell clones targeting metastatic tissues. Altogether, our data indicate that anti-PD-1 therapy induces a de novo immune response, stimulated by the presence of metastatic cells, and composed of different T cell subtypes, which may trigger the development of vitiligo and the response against metastatic tumor

Osteogenic differentiation of dental follicle stem cells.

Background: Stem cells are defined as clonogenic cells capable of self-renewal and multi-lineage differentiation. A population of these cells has been identified in human Dental Follicle (DF). Dental Follicle Stem Cells (DFSCs) were found in pediatric unerupted wisdom teeth and have been shown to differentiate, under particular conditions, into various cell types of the mesenchymal tissues. Aim: The aim of this study was to investigate if cells isolated from DF show stem features, differentiate toward osteoblastic phenotype and express osteoblastic markers. Methods: We studied the immunophenotype of DFSCs by flow cytometric analysis, the osteoblastic markers of differentiated DFSCs were assayed by histochemical methods and real-time PCR. Results: We demonstrated that DFSCs expressed a heterogeneous assortment of makers associated with stemness. Moreover DFSCs differentiated into osteoblast-like cells, producing mineralized matrix nodules and expressed the typical osteoblastic markers, Alkaline Phosphatase (ALP) and Collagen I (Coll I). Conclusion: This study suggests that DFSCs may provide a cell source for tissue engineering of bone

The possibilities of Cherenkov telescopes to perform cosmic-ray muon imaging of volcanoes

Volcanic activity is regulated by the interaction of gas-liquid flow with conduit geometry. Hence, the quantitative understanding of the inner shallow structure of a volcano is mandatory to forecast the occurrence of dangerous stages of activity and mitigate volcanic hazards. Among the techniques used to investigate the underground structure of a volcano, muon imaging offers some advantages, as it provides a fine spatial resolution, and does not require neither spatially dense measurements in active zones, nor the implementation of cost demanding energizing systems, as when electric or active seismic sources are utilized. The principle of muon radiography is essentially the same as X-ray radiography: muons are more attenuated by higher density parts inside the target and thus information about its inner structure are obtained from the differential muon absorption. Up-to-date, muon imaging of volcanic structures has been mainly accomplished with detectors that employ planes of scintillator strips. These telescopes are exposed to different types of background noise (accidental coincidence of vertical shower particles, horizontal high-energy electrons, flux of upward going particles), whose amplitude is high relative to the tiny flux of interest. An alternative technique is based on the detection of the Cherenkov light produced by muons. The latter can be imaged as an annular pattern that contains the information needed to reconstruct both direction and energy of the particle. Cherenkov telescopes have never been utilized to perform muon imaging of volcanoes. Nonetheless, thanks to intrinsic features, they offer the possibility to detect the through-target muon flux with negligible levels of background noise. Under some circumstances, they would also provide a better spatial resolution and acceptance than scintillator-based telescopes. Furthermore, contrarily to the latter systems, Cherenkov detectors allow in-situ measurements of the open-sky energy spectrum of atmospheric muons, that is needed to asses a reference model of the through-target integrated flux. Here we describe our plans for the production of a Cherenkov telescope with suitable characteristics for installation in the summit zone of Etna volcano. <P /

Muon imaging of volcanoes with Cherenkov telescopes

The quantitative understanding of the inner structure of a volcano is a key feature to model the processes leading to paroxysmal activity and, hence, to mitigate volcanic hazards. To pursue this aim, different geophysical techniques are utilized, that are sensitive to different properties of the rocks (elastic, electrical, density). In most cases, these techniques do not allow to achieve the spatial resolution needed to characterize the shallowest part of the plumbing system and may require dense measurements in active zones, implying a high level of risk. Volcano imaging through cosmic-ray muons is a promising technique that allows to overcome the above shortcomings. Muons constantly bombard the Earth's surface and can travel through large thicknesses of rock, with an energy loss depending on the amount of crossed matter. By measuring the absorption of muons through a solid body, one can deduce the density distribution inside the target. To date, muon imaging of volcanic structures has been mainly achieved with scintillation detectors. They are sensitive to noise sourced from (i) the accidental coincidence of vertical EM shower particles, (ii) the fake tracks initiated from horizontal high-energy electrons and low-energy muons (not crossing the target) and (iii) the flux of upward going muons. A possible alternative to scintillation detectors is given by Cherenkov telescopes. They exploit the Cherenkov light emitted when charged particles (like muons) travel through a dielectric medium, with velocity higher than the speed of light. Cherenkov detectors are not significantly affected by the above noise sources. Furthermore, contrarily to scintillator-based detectors, Cherenkov telescopes permit a measurement of the energy spectrum of the incident muon flux at the installation site, an issue that is indeed relevant for deducing the density distribution inside the target. In 2014, a prototype Cherenkov telescope was installed at the Astrophysical Observatory of Serra La Nave (southern flank of Mt. Etna, Italy; 1740m a.s.l.), in the framework of ASTRI, a flagship project of the Italian Ministry of Education, University and Research, led by the Italian National Institute of Astrophysics (INAF). This offers the opportunity to test the use of a Cherenkov telescope for imaging volcanic structures. Starting from this know-how, we plan to develop a new prototype of Cherenkov detector with suitable characteristics for installation in the summit zone of Etna volcano (around 3000m a.s.l.)

Iron and Ferritin Modulate MHC Class I Expression and NK Cell Recognition

The ability of pathogens to sequester iron from their host cells and proteins affects their virulence. Moreover, iron is required for various innate host defense mechanisms as well as for acquired immune responses. Therefore, intracellular iron concentration may influence the interplay between pathogens and immune system. Here, we investigated whether changes in iron concentrations and intracellular ferritin heavy chain (FTH) abundance may modulate the expression of Major Histocompatibility Complex molecules (MHC), and susceptibility to Natural Killer (NK) cell cytotoxicity. FTH downregulation, either by shRNA transfection or iron chelation, led to MHC surface reduction in primary cancer cells and macrophages. On the contrary, mouse embryonic fibroblasts (MEFs) from NCOA4 null mice accumulated FTH for ferritinophagy impairment and displayed MHC class I cell surface overexpression. Low iron concentration, but not FTH, interfered with IFN-γ receptor signaling, preventing the increase of MHC-class I molecules on the membrane by obstructing STAT1 phosphorylation and nuclear translocation. Finally, iron depletion and FTH downregulation increased the target susceptibility of both primary cancer cells and macrophages to NK cell recognition. In conclusion, the reduction of iron and FTH may influence the expression of MHC class I molecules leading to NK cells activation

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P &lt; 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P &lt; .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Maria Concetta Carbone (in Piacente)

Video interview with Maria Concetta Carbone (in Piacente) as part of the Italian Cinema Audiences projec

Prevalence and risk factors of actinic keratosis in patients attending Italian dermatology clinics

Background: Actinic keratosis (AK) is a common keratinocyte intraepidermal neoplasia. Objective: To assess AK prevalence and potential risk factors in patients attending Italian general dermatology clinics. Materials & methods: This retrospective study was conducted on clinical data from consecutive white outpatients aged 6530 years, attending 24 general dermatology clinics between December 2014 and February 2015. AK prevalence (entire population) and multivariate risk factor analysis (patients with current/previous AK and complete data) are presented. Results: AK prevalence in 7,284 patients was 27.4% (95% CI: 26.4-28.4%); 34.3% in men and 20.0% in women (p70 years), history of other non-melanoma skin cancers (OR: 2.7 [2.2-3.3]), residence in southern Italy/Sardinia (OR: 2.6 [2.1-3.0]), working outdoors >6 hours/day (OR: 1.9 [1.4-2.4]), male gender (OR: 1.7 [1.4-2.0]), facial solar lentigos (OR: 1.6 [1.4-1.9]), light hair colour (OR: 1.5 [1.2-1.8]), prolonged outdoor recreational activities (OR: 1.4 [1.2-1.7]), light eye colour (OR: 1.3 [1.1-1.6]), skin type I/II (OR: 1.3 [1.1-1.6]), and alcohol consumption (OR: 1.2 [1.0- 3.3]). BMI 6525.0 (OR: 0.6 [0.5-0.7]), regular sunscreen use (OR: 0.7 [0.6-0.8]), and a lower level of education (OR: 0.8 [0.7-1.0]) were independent protective factors. Conclusions: AK prevalence was high in Italian dermatology outpatients. We confirm several well-known AK risk factors and reveal possible novel risk and protective factors. Our results may inform on the design and implementation of AK screening and educational programmes