87 research outputs found
Prospective evaluation of pro/anti-inflammatory cytokines during TKI treatment in chronic myeloid leukemia patients
No full textChronic myeloid leukemia (CML) treatment with tyrosine kinase inhibitors (TKIs) has been associated to an increased risk of Arterial Occlusive Events (AOEs), mainly with nilotinib, but the mechanisms underlying these events have been not clarified yet.
Previously, we confirmed in our retrospective cross-sectional study a higher cardiovascular (CV) risk in nilotinib treated patients, particularly if harboring the unfavorable OLR1 polymorphism and we found a nilotinib-associated pro-inflammatory effect.
We started a multicenter prospective study of tyrosine Kinase Inhibitors induced pro-AtherothROmbotic (KIARO) status in CML patients to furtherly investigate a possible pro-atherothrombotic nilotinib-induced status in a cohort of chronic phase (CP)-CML patients treated with first-line imatinib, nilotinib and dasatinib. In particular, our intents were: to assess any changes in the inflammation status during TKI treatment by measuring pro/anti-inflammatory cytokines (IL-6, IL-10, TNFα and ox-LDL) plasma levels; 2) to record AOEs after applying CV SCORE and evaluate its predictive role; 3) to correlate AOEs with altered inflammation status.
A total of 186 CP-CML patients were enrolled in this study of which 89/186 (48%) were treated with imatinib, 59/186 (32%) with nilotinib and 38/186 (20%) with dasatinib. Results from biochemical analyses performed by enzyme-linked immunosorbent assay (ELISA) test showed higher IL-10 levels at 6 and 12 months in imatinib (p=0.012 and p=0.009, respectively) and dasatinib (p=0.032 and p=0.014, respectively) cohorts compared to nilotinib, while ox-LDL levels increased at 12 months in the nilotinib cohort (p=0.041) in contrast to imatinib and dasatinib. Consequently, IL-6/IL-10 and TNFα/IL-10 ratios were higher in nilotinib cohort compared to imatinib (p=0.042, p=0.044 at 6 months; p=0.040, p=0.041 at 12 months) and dasatinib (p=0.049, p=0.040 at 6 months; p=0.041, p=0.044 at 12 months), suggesting a TKI-driven pro-inflammatory status in nilotinib treated patients. We recorded an AOE only in 5% of patients and, due to the small number of events detected, it was not possible to establish a correlation between AOEs and pro/anti-inflammatory cytokine levels.
Although we applied the SCORE chart in all CML patients enrolled to better identify patients with high risk to experience AOEs, this parameter was not predictive for our cohort. This result may be explained by the strategic choice of TKI at diagnosis, as documented also by the lower median age of the nilotinib treated patients compared to the other two TKI subgroups and by the higher number of traditional CV risk factors in imatinib cohort respect to nilotinib and dasatinib.
Considering that our results showed a pro-inflammatory status in nilotinib subgroup during the first year of treatment and that AOEs occurred after a median treatment duration of 19,1 months, we believe that a further evaluation of pro/anti-inflammatory cytokines at longer treatment follow-up should be performed to better investigate the correlation between pro-atherothrombotic status and AOEs.
In conclusion, we suggest a careful selection of the TKI treatment, according to the presence of baseline CV risk factors and/or previous CV history, in order to offer the best and safe long-term TKI treatment for CML patients, considering as ultimate goal the possibility of reaching a safe TFR and reducing AOEs associated comorbidities
Interazione tra infiammazione, autoimmunità e tumori solidi: approfondimenti sui checkpoint immunitari
No full textInfiammazione, autoimmunità e tumori sono collegati. La deregolazione del sistema immunitario e l'infiammazione sono alla base dell'insorgenza di malattie autoimmuni. Inoltre, l'infiammazione cronica può favorire la progressione dei tumori. Questo progetto di ricerca si proponeva di indagare la relazione tra infiammazione, autoimmunità e tumori solidi in due diverse direzioni: i) esplorare le caratteristiche che contraddistinguono le malattie autoimmuni associate a tumore; ii) indagare gli effetti dell'infiammazione sui checkpoint immunitari nei tumori solidi.
La prima parte del progetto ha riguardato lo studio di biomarcatori sierici in pazienti affetti da dermatomiosite (DM) con e senza tumore, per identificare i pazienti maggiormente a rischio di sviluppare neoplasie. La DM è la malattia autoimmune con la più alta associazione con i tumori. Per caratterizzare i pazienti con DM maggiormente a rischio, abbiamo studiato la presenza di anticorpi diretti contro le proteine di membrana di mioblasti del muscolo scheletrico umani commerciali (HSMM), nel siero di pazienti con DM con e senza tumore. Abbiamo anche analizzato i livelli sierici di checkpoint immunitari solubili, MICA, MICB e PTX3 tra i pazienti con DM con e senza tumore e confrontato i pazienti con DM con i soggetti sani (HC) e i pazienti con artrite reumatoide (RA). Non sono state riscontrate differenze nei biomarcatori analizzati tra i pazienti con e senza tumore. Tuttavia, sono state riscontrate differenze tra pazienti con DM, pazienti con RA e HC. La percentuale di cellule HSMM legate da anticorpi IgG sierici era più alta nei pazienti con DM rispetto agli HC. Inoltre, diverse molecole solubili sono risultate aumentate nei pazienti con DM, suggerendo un potenziale ruolo patogenetico. Le molecole solubili VISTA, CD27 e PTX3 sono risultate i migliori classificatori dei pazienti con DM e i target più promettenti.
La seconda parte del progetto ha riguardato lo studio dell'espressione dei checkpoint immunitari in relazione alle citochine infiammatorie e alla chemioterapia, per fornire indicazioni sui meccanismi patogenetici delle malattie autoimmuni e dei tumori. L'infiammazione promuove lo sviluppo dei tumori, come ad esempio il tumore del colon. Le citochine infiammatorie nel microambiente tumorale e i farmaci utilizzati in terapia possono alterare l'espressione dei checkpoint immunitari. Tuttavia, manca ancora una conoscenza approfondita dei loro effetti. Abbiamo valutato gli effetti di diverse citochine infiammatorie o di farmaci chemioterapici (5-Fluorouracile, Oxaliplatino e Irinotecano) sui livelli dei checkpoint immunitari (PD-L1, PD-L2, GAL9 – inibitori; 4-1BBL, ICOSL – stimolatori; CD155 con duplice funzione) espressi da tre linee cellulari di tumore del colon: HT-29, HCT116 e DLD-1. L'IFNγ aumentava l'espressione di PD-L1 in tutte le linee. Il TNFα aumentava PD-L1 e GAL9 nelle HT-29, aumentava PD-L1 e CD155 e diminuiva 4-1BBL nelle HCT116. PD-L1 aumentava anche con trattamento con IL-1β nelle HT-29 e HCT116 e con IL-6+IL-6Rα solubile nelle DLD-1. PD-L1 è risultato aumentato anche da tutti i farmaci nelle cellule HT-29 e DLD-1, e da 5-Fluorouracile e Irinotecano nelle HCT116. Tutti i farmaci aumentavano leggermente PD-L2 nelle HT-29 e DLD-1 e aumentavano 4-1BBL, CD155 e GAL9 in tutte le linee. L'ICOSL non è risultato espresso né indotto. I dati suggeriscono un aumento dei checkpoint immunitari inibitori e una diminuzione di quelli stimolatori da parte di IFNγ, TNFα, IL-1β e IL-6, che potrebbero influenzare i meccanismi di evasione tumorale o le manifestazioni autoimmuni. I risultati suggeriscono anche un ruolo modulante dei farmaci chemioterapici sul sistema immunitario, che dovrebbe essere preso in considerazione, ad esempio, per pianificare trattamenti combinati.Inflammation, autoimmunity, and cancer are linked. The deregulation of the immune system and inflammation are at the basis of the onset of autoimmune diseases. In addition, chronic inflammation can favor cancer progression. The present research aimed to investigate the relationship between inflammation, autoimmunity, and solid tumors in two different directions: i) exploring the features that characterize cancer-associated autoimmune diseases; ii) investigating the effects of inflammation on immune checkpoint axes in solid tumors.
Part 1 of the project concerned the study of serum biomarkers in patients with dermatomyositis (DM) with and without cancer to identify patients at higher risk of developing cancer. DM is the autoimmune disease with the highest association with cancers. To characterize patients with DM most at risk, we investigated the presence of antibodies directed against plasma membrane proteins of commercial human skeletal muscle myoblasts (HSMM), in the serum of patients with DM with and without cancer. We also analyzed serum levels of soluble immune checkpoints, MICA, MICB, and PTX3 between patients with DM with and without cancer and compared patients with DM to healthy subjects (HC) and patients with rheumatoid arthritis (RA). No differences were found in the investigated biomarkers comparing patients with and without cancer. However, differences were found between patients with DM, patients with RA, and HC. The percentages of HSMMs stained with serum IgG antibodies were higher in DM patients than in HC. In addition, several soluble molecules were increased in patients with DM, suggesting a potential pathogenic role. Soluble VISTA, CD27, and PTX3 resulted in the best classifiers of patients with DM and the most promising targets.
Part 2 of the project concerned the study of immune checkpoint expression in relation to inflammatory cytokines and chemotherapy to provide clues in pathogenic mechanisms in both autoimmune diseases and cancer. Inflammation plays a promoting role in cancer development, e.g. in tumors of the gastrointestinal tract such as colon cancers. Inflammatory cytokines in the tumor microenvironment and drugs used in cancer therapy can alter the expression of immune checkpoints, crucial regulators of the immune system. However, extensive knowledge of their effects is still lacking. We evaluated the effects of different inflammatory cytokines or chemotherapeutic drugs (5-Fluorouracil, Oxaliplatin, and Irinotecan) on immune checkpoint levels expressed by three colon cancer cell lines: HT-29, HCT116, and DLD-1. The following immune checkpoints were investigated: PD-L1, PD-L2, and GAL9 with inhibitory activities; 4-1BBL and ICOSL with stimulatory activities; CD155 with a dual function. Heterogeneity in the responses by the three cell lines tested emerged. IFNγ increased PD-L1 expression in all the cell lines. TNFα increased PD-L1 and GAL9 in HT-29 cells. In addition, TNFα increased PD-L1 and CD155 while it decreased 4-1BBL in HCT116 cells. PD-L1 was also increased by IL-1β in HT-29 and HCT116 and by IL-6+soluble IL-6Rα in DLD-1 cells. Regarding drug treatment, PD-L1 was increased by all the drugs in HT-29 and DLD-1 cells and by 5-Fluorouracil and Irinotecan in HCT116 cells. All the drugs slightly increased PD-L2 on HT-29 and DLD-1 cells and increased 4-1BBL, CD155, and GAL9 expression in the three cell lines. ICOSL was not expressed nor induced. Data suggest an increase in inhibitory immune checkpoints and a decrease of the stimulatory ones by IFNγ, TNFα, IL-1β, and IL-6, which might affect cancer immune escape mechanisms or autoimmune manifestations. Data also suggest a modulating role of chemotherapeutic drugs on the immune system, which should be considered e.g. to plan combined treatments
Optimization-Based Variable Impedance Control of Robotic Manipulator for Medical Contact Tasks
No full textThis work presents an optimization-based variable impedance control strategy for controlling a robotic manipulator in medical contact tasks. Specifically, the optimal robot stiffness for performing the medical contact task is obtained using online Quadratic programming (QP). In the meantime, an energy tank approach is incorporated into the control loop to regulate the system's passivity. To verify the performance of the proposed strategy, experiments are conducted on both 'static' and 'scanning' medical contact tasks, utilizing materials with different properties, different magnitudes of contact forces, as well as uneven conditions with a human torso phantom model and slope surface. The maximum Root Mean Square Error (RMSE) of force tracking with the proposed method in the 'static' and 'scanning' tasks, across all setups, is 0.88 and 0.5 N, respectively. The experiment results demonstrate the superiority of the proposed control strategy compared with traditional manual contact and constant stiffness (CS) impedance control-based ones. The proposed control framework is promising to be integrated into robot-assisted medical contact tasks, for example, the palpation and Ultrasound (US) imaging scenarios
Optimization-Based Variable Impedance Control of Robotic Manipulator for Medical Scanning Task
No full textStudy of gene polymorphisms as predictors of treatment efficacy and toxicity in patients with indolent non-hodgkin lymphomas and mantle cell lymphoma receiving bendamustine and rituximab
No full textBendamustine is used in combination with rituximab (BR) to treat indolent non-Hodgkin lymphomas (iNHL) and mantle cell lymphoma (MCL). The variability in treatment efficacy and toxicity could be related to single nucleotide polymorphisms (SNPs) in immune response genes. We would like to show a correlation between SNPs and treatment outcome in iNHL and MCL patients receiving BR. We investigated some SNPs that had already been associated with NHL outcome. Samples were genotyped for the IL2 (rs2069762), IL10 (rs1800890, rs10494879), VEGFA (rs3025039), IL8 (rs4073), CFH (rs1065489) and MTHFR (rs1801131) SNPs by allelic discrimination assays. We enrolled 70 patients that received rituximab 375 mg/m2 and bendamustine 90 mg/m2 every 28 days, both as first-line treatment and ≥ second-line regimens. Overall response rate was 97·1% (complete response [CR] rate 73·9%). Treatment toxicity included grade 3–4 neutropenia (24/70 patients), infections (21/70 patients; 1/70 grade 3), skin rash (26/70 patients; 2/70 grade 3). After a median follow-up of 24 months we did find any correlation between the analysed SNPs, CR rate and PFS. However, we demonstrated an association between the SNP in IL2 (rs2069762) and the onset of skin rash (P = 0·0001). Our study suggests a role for cytokine SNPs in bendamustine-related toxicity, which could represent a promising research field
Heterocyclic compounds used in the treatment of kinetoplastid infection and their preparation
No full textThe invention relates to compds. of formula I, pharmaceutical compns. comprising these compds., their use in the treatment of kinetoplastid infections and their prepn. Compds. of formula I, wherein A is absent, O, S, etc.; B is absent, (CH2)n and CO; Z is absent, CO, SO2, etc.; X and Y are independently H, halo, C1-6 alkyl, etc.; m and n are 1 or 2 wherein at least one must be 1; p is 0 , 1 and 2; Het is 1H-imidazole, 4H-1,2,4-triazole, oxazole, etc.; R1 is naphthalen-2-yl, 2-methoxyquinolin-3-yl, pryimdin-5-yl, etc.; R2 is H, C6-10 aryl, C3-15 heterocyclyl, etc.; and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, are claimed. Compd. II.bul.TFA was prepd. using a multistep procedure (procedure given). Compds. of the invention were tested for their inhibitory activity against T. brucei (data given)
Aumento dei livelli sierici di checkpoint immunitari in pazienti con dermatomiosite con e senza tumore
No full textValidation of a double-color ELISpot assay of IFN-γ and IL-4 production in human peripheral blood mononuclear cells
No full text: The Enzyme-Linked ImmunoSpot (ELISpot) assay detects cytokines secreted during T cell-specific immune responses against pathogens. As this assay has acquired importance in the clinical setting, standard bioanalytical evaluation of this method is required. Here, we describe a formal bioanalytical validation of a double-color ELISpot assay for the evaluation of IFN-γ and IL-4 released by T helper 1 and T helper 2 cells, respectively. As recommended by international guidelines, the parameters assessed were: range and detection limits (limit of detection, LOD; upper and lower limit of quantification, ULOQ and LLOQ), Linearity, Relative Accuracy, Repeatability, Intermediate Precision, Specificity and Robustness. The results obtained in this validation study demonstrate that this assay meets the established acceptability criteria. ELISpot is therefore a reliable technique for measuring T cell-specific immune responses against various antigens of interest
Leadership-focused coaching: An uplifting approach for supporting aspiring leaders
No full textEducational leadership professors prepare aspiring leaders by providing uplifting opportunities to connect theory and practice. This paper proposes a research-based model called leadership-focused coaching, an approach to support graduate students in developing and honing instructional leadership skills and responsibilities (Gray, 2016). This paper addresses the shift in principal preparation programs from theory-to-practice to a knowledge-to-practice approach over the last 20 years (Browne-Ferrigno, 2007; Browne-Ferrigno & Muth, 2004; Cunningham, 2007; Cunningham & Sherman, 2008; Daresh, 2004). While there are numerous models for coaching teachers, we offer this model for aspiring and new instructional leaders of schools.
Keywords: leadership preparation, university-school partnerships, leadership field experience, leadership-focused coaching, and leadership mentoringConference Pape
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