1,721,033 research outputs found
Co-inhibitory immune signaling generates the splicing of an immunophilin which marks a Tregs subset associated with immunotherapy response of melanoma patients
No full textCancer immunotherapy has shown surprising efficacy in several types of advanced and incurable tumors, particularly, malignant melanoma. There are several immunotherapeutic strategies aimed at enhancing immunological defenses against tumor. Among these, monoclonal antibodies against the so-called “immune checkpoint inhibitors”, that counteract tumor-induced immune-disarming pathways, have shown the best outcomes. Regulatory T lymphocytes or Tregs are a subset of lymphocytes involved in immune-surveillance and maintenance of self-tolerance. Tumor often exploits Tregs to allow tolerance to its own antigens and avoid immune system attack. Tregs are usually increased in melanoma patients. It is noticeable that Tregs is a heterogeneous population with respect to their immunosuppressive capability. Lymphocytes are particularly rich in FKBP51 (FKBP5 gene), an immunophilin better known as the intracellular receptor for FK506 and rapamycin. Melanoma aberrantly expresses this immunophilin, which supports cancer resistance and invasion. Recently, our group has shown that melanoma interaction with immune cells, through PD-L1/PD1, bidirectionally generated the splicing of FKBP5 gene inducing a lower molecular weight form of FKBP51, termed FKBP51s, in both melanoma and lymphocyte. A study performed on PBMC of 64 patients with advanced melanoma (stage III/IV) showed that FKBP51s marks a Treg subset which was correlated, as an independent variable, to anti-CTLA4 (ipilimumab) response. More precisely, a low frequency of Treg FKBP51spos (<1% of total CD3/CD4 lymphocytes) was associated with unresponsiveness to ipilimumab (Chi-square=9.916, p=0.002). In vitro iTreg generation suggested that FKBP51s was associated with CD25high, Ki67high and p70S6khigh iTregs, corresponding to a highly metabolically active profile associated with strong suppressive capability. FKBP51s silencing by siRNA attenuated the suppressive phenotype of such iTregs. A study performed on a different cohort of patients receiving anti-PD1 reinforced the hypothesis that melanoma patients that benefit from immune checkpoint targeted therapy are recognizable by an expansion of FKBP51s+Treg subset which may be involved in de-activation of stimulatory co-signalling pathways, in support of tumor immune evasion
FKBP5 splicing concurs to Treg differentiation of Tconv cells
No full textFKBP51 (FKBP5 gene) is an immunophilin physiologically expressed by immune cells. Thanks to its scaffold and isomerase activity supporting IKK complex assembly and function, FKBP51 plays a relevant role in NF-κB activation. Recently, we identified a splicing isoform, shorter than the canonical one, termed FKBP51s. FKBP51s acts as a PD-L1 foldase, assisting to protein maturation and expression on plasma membrane. Particularly, FKBP51s was firstly identified in TILs and PBMCs of melanoma patients. In these patients, FKBP51s marked a subset of Tregs with an increased phospho-mTOR and Ki67 expression. Logistic regression analysis suggested that FKBP51sTreg is a valuable element which predicts the probability of response to ipilimumab. Given the foregoing, we attempted to investigate FKBP5 splicing during T lymphocyte activation and assess its role in Treg formation and suppression capability. We found that FKBP5 splicing occurred early in the course of a suboptimal but not maximal PBMCs stimulation. The increase in FKBP51s was transient and associated with a delay in Akt and STAT5 activation. When splicing was prevented, Treg count was decreased and Tconv cell proliferation increased. Moreover, measure of FKBP51s level in Foxp3CD25high Treg subset showed highest levels in PBMCs cultures under suboptimal CD3 co-stimulation. Coculture suppression assays showed that Treg silenced for FKBP51s had a significantly reduced suppressive capability, compared with non-silenced Tregs. In conclusion, our findings suggest that FKBP5 splicing occurs under conditions of suboptimal CD3 co-stimulation of Tconv cells and concurs to their differentiation into Tregs. Manipulating FKBP5 splicing can be a means to control tumor tolerance
The advertisements of Dietary Supplement in a panel of 6 Italian magazines: a quantitative analysis
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Automatic Anonymization of Italian Legal Textual Documents using Deep Learning
No full textThe dissemination of judicial decisions not only provides a valuable source of decision support for judges and legal practitioners but also strengthens public confidence in the judicial system. However, the nature of the data raises privacy concerns as the documents include personal and, often, sensitive data such as health, financial, religious beliefs, sexual orientation, and so on. In recent years, especially since the introduction of GDPR, the international scientific community has paid much attention to the issue of privacy and automatic anonymization tools, but unfortunately, nothing has been done in the Italian legal context.
In this paper, we present a first solution aimed at automatic anonymization of the Italian National Jurisprudential Archive (Archivio Giurisprudenziale Nazionale) domain based on pre-trained Transformers embeddings (Clark et al., 2020, Devlin et al., 2019) and spaCy’s transition-based parsing for entity recognition (Honnibal and Montani, 2017). It achieves more than 94.7% recall (>99% for Person and ID entities) and supports several anonymization methods that can be applied to the text depending on the purpose of anonymizatio
EPIGENETIC REGULATION OF TRAIL-R2 EXPRESSION IN MELANOMA BY THE PEPTIDYL-PROLYL-ISOMERASE FKBP51
No full textMelanoma is one of the most immunogenic tumors and has the highest potential to elicit specific adaptive antitumor immune responses. Immune cells induce apoptosis of cancer cells either by soluble factors or by triggering cell-death pathways, particularly the TRAIL pathway. Melanoma cells exploit multiple mechanisms to escape immune system tumoricidal control. FKBP51 is a relevant pro-oncogenic factor of melanoma cells supporting NF-B-mediated resistance and cancer stemness/invasion epigenetic programs. We investigated whether FKBP51 was involved in TRAIL resistance.Using two different melanoma cell lines and 3 different methods for FKBP51 modulation, namely short interfering RNA (siRNA), short hairpin RNA (sh-RNA), and CRISPR/Cas9 KO, we show that FKBP51-silencing increased DR5 expression and enhanced sensitivity of melanoma cells to TRAIL-induced apoptosis. The mechanism of DR5 regulation involved the repressor activity of YY1 that was attenuated by FKBP51 silencing
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