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  • 1
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    Calreticulin and PDIA3, two markers of endoplasmic reticulum stress, are associated with metabolic alterations and insulin resistance in pediatric obesity: A pilot study
    Frontiers Media SA ; 2022
    In:  Frontiers in Endocrinology Vol. 13 ( 2022-9-23)
    Details
    In: Frontiers in Endocrinology, Frontiers Media SA, Vol. 13 ( 2022-9-23)
    Abstract: Our aim was to evaluate the markers of endoplasmic reticulum (ER) stress among children and adolescents with obesity in relation to metabolic alterations. Calreticulin (CALR) and PDIA3 circulating levels were assessed on 52 pediatric subjects—26 patients with obesity and 26 normal weight controls (4–18 years)—enrolled in a pilot study. Clinical and metabolic evaluations were performed (BMI-SDS, insulin, and glucose at fasting and during an oral glucose tolerance test, lipid profile, blood pressure), and metabolic syndrome was detected. PDIA3 was higher ( p   & lt; 0.02) and CALR slightly higher in children with obesity than in controls. PDIA3 was related positively to the Tanner stages. Both PDIA3 and CALR were positively associated with insulin resistance, cholesterol, and triglycerides and the number of criteria identifying metabolic syndrome and negatively with fasting and post-challenge insulin sensitivity. Our preliminary findings suggest the existence of a link between ER stress and metabolic changes behind obesity complications even at the pediatric age. CALR and PDIA3 could be early markers of insulin resistance and dyslipidemia-related ER stress useful to stratify patients at high risk of further complications.
    Type of Medium: Online Resource
    ISSN: 1664-2392
    URL: Article
    DOI: 10.3389/fendo.2022.1003919
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2592084-4
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  • 2
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    Glucose Alterations, Insulin Resistance, Arterial Hypertension, and Renin are Strictly Associated in Pediatric Obesity
    The Endocrine Society ; 2023
    In:  Journal of the Endocrine Society Vol. 7, No. 8 ( 2023-07-03)
    Details
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 7, No. 8 ( 2023-07-03)
    Abstract: Insulin resistance, glucose alterations, arterial hypertension (HTN), and the renin–angiotensin–aldosterone system (RAAS) are related in adult obesity. This crosstalk is still unexplored in childhood. Objective Characterize the relationships of fasting and postload glucose and insulin levels with new American Academy of Pediatrics classification of HTN and RAAS in pediatric obesity. Methods This was a retrospective observational study; 799 pediatric outpatients (11.4 ± 3.1 years) at a tertiary center who were overweight or obese and not yet on diet were included. The main outcome measures were mean and correlations among parameters of a complete clinical and metabolic screening (body mass index, blood pressure, and glucose and insulin levels during an oral glucose tolerance test, and renin and aldosterone levels and their ratio). Results 774 subjects had all the parameters, of whom 87.6% had HTN (5% elevated blood pressure, 29.2% stage I HTN, and 53.4% stage II HTN). Eighty subjects had 1 or more glucose alterations, and more frequently presented HTN. Blood pressure levels were higher in subjects with glucose alterations than in those with normal glucose levels. Fasting and stimulated glucose and insulin levels were directly related to the HTN stages, and insulin sensitivity was lower in HTN than in normal blood pressure. Aldosterone, renin, and aldosterone–renin ratio (ARR) were similar in sexes, whereas aldosterone was higher in prepubertal individuals. Subjects with impaired glucose tolerance (IGT) had higher renin and lower ARR. Renin was positively correlated with postload glucose, and ARR was negatively correlated with the Homeostatic Model Assessment for Insulin Resistance index. Conclusion A close relationship exists among insulin resistance, glucose alterations, HTN, and renin in childhood obesity. Specific categories of risk could provide indicators for strict clinical surveillance.
    Type of Medium: Online Resource
    ISSN: 2472-1972
    URL: Article
    DOI: 10.1210/jendso/bvad088
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2023
    detail.hit.zdb_id: 2881023-5
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  • 3
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    Stereotactic radiosurgery for the treatment of brainstem metastases: a multicenter retrospective study
    Springer Science and Business Media LLC ; 2022
    In:  Radiation Oncology Vol. 17, No. 1 ( 2022-08-09)
    Details
    In: Radiation Oncology, Springer Science and Business Media LLC, Vol. 17, No. 1 ( 2022-08-09)
    Abstract: Brainstem metastases (BSM) are associated with a poor prognosis and their management represents a therapeutic challenge. BSM are often inoperable and, in absence of randomized trials, the optimal radiation treatment of BSM remains to be defined. We evaluated the efficacy and toxicity of linear accelerator (linac)-based stereotactic radiosurgery (SRS) and hypofractionated steretotactic radiotherapy (HSRT) in the treatment of BSM in a series of patients treated in different clinical centers. Methods We conducted a multicentric retrospective study of patients affected by 1–2 BSM from different histologies who underwent SRS/HSRT. Freedom from local progression (FLP), cancer-specific survival (CSS), overall survival (OS), and treatment-related toxicity were evaluated. In addition, predictors of treatment response and survivals were evaluated. Results Between 2008 and 2021, 105 consecutive patients with 111 BMS who received SRS or HSRT for 1–2 BSM were evaluated. Median follow-up time was 10 months (range 3–130). One-year FLP rate was 90.4%. At the univariate analysis, tumor volume ≤ 0.4 cc, and concurrent targeted therapy were associated with longer FLP, with combined treatment that remained a significant independent predictor [0.058, HR 0.139 (95% CI 0.0182–1.064]. Median OS and CSS were 11 months and 14.6 months, respectively. At multivariate analysis, concurrent targeted therapy administration was significantly associated with longer OS [HR 0.514 (95%CI 0.302–0.875); p = 0.01] . Neurological death occurred in 30.4% of patients, although this was due to local progression in only 3 (2.8%) patients. Conclusion Linac-based SRS/HSRT offers excellent local control to patients with BSM, with low treatment-related toxicity and no apparent detrimental effects on OS. When treated with ablative intent, BSM are an uncommon cause of neurological death. The present results indicates that patients with BSM should not be excluded a priori from clinical trials.
    Type of Medium: Online Resource
    ISSN: 1748-717X
    URL: Article
    DOI: 10.1186/s13014-022-02111-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2224965-5
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  • 4
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    SAT128 Low Concentration Of Butyrate Reverts PA-induced Atrophic Condition On C2C12 Myotubes
    The Endocrine Society ; 2023
    In:  Journal of the Endocrine Society Vol. 7, No. Supplement_1 ( 2023-10-05)
    Details
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 7, No. Supplement_1 ( 2023-10-05)
    Abstract: Disclosure: S. Tini: None. A. Antonioli: None. S. Reano: None. T. Raiteri: None. A. Scircoli: None. V. Antoniotti: None. I. Zaggia: None. N. Filigheddu: None. F. Prodam: None. Sarcobesity is a well-defined medical condition characterized by the coexistence between skeletal muscle atrophy and increased fat mass representing, nowadays, a relevant public health issue among the world population. Sarcobesity is often associated with the development of metabolic syndrome (MetS), insulin-resistance (IR), dyslipidaemia, and other pathologies such as cardiovascular diseases (CVDs) and type 2 diabetes (T2DM). The global increment of this condition has been favoured by changes in lifestyle and dietary habits as largely demonstrated. Particularly, Western Diet (WD), rich in saturated fats and sugars and poor in fibers, vitamins, and minerals seems to be the main cause of sarcobesity in association with low levels of physical activity. In recent years, Ketogenic Diet (KD) has been proposed as a fighting obesity therapy and as a new possible therapeutic strategy to counteract the WD detrimental effects on different tissues, i.e skeletal muscle that plays a key role in whole-body metabolism, glucose homeostasis and lipid use. KD regimen consists in a very low carbohydrates intake, high fat and adequate protein contents that cause the so-called “nutritional ketosis” with the production of Ketone bodies (KBs). KBs, such as beta-hydroxybutyrate (BHB), acetoacetate and acetone are the final products of the partial beta-oxidation of free fatty acid. They are short chain fatty acid produced in liver with different role on metabolism and they are used as a source of energy instead of glucose by different tissues including skeletal muscle. Preliminary experiments in our laboratory demonstrated that palmitate (PA), which is a saturated fat highly present in WD regimen, induces myotubes atrophy in dose dependent manner (100, 250, 500uM). The aim of the present study is to investigate not only if KBs have a direct effect on C2C12 skeletal muscle cells, but also if they are able to contrast the PA-induced atrophy in myotubes. We demonstrated with a co-treatment that sodium butyrate (s-BU), which is the main KB produced during ketogenesis, is able to prevent PA negative effects in skeletal muscle cells when it is used at low concentration. In contrast, high doses of BU reduced C2C12 diameters suggesting that KBs could have opposite effects depending on their concentration. Currently, other short chain fatty acids and KBs, i.e pyruvate and acetoacetate are under investigation in our laboratory. Collectively, these data suggest that KD could represent a promising intervention to contrast WD damages on skeletal muscle in overweight/obese individuals. Presentation: Saturday, June 17, 2023
    Type of Medium: Online Resource
    ISSN: 2472-1972
    URL: Article
    DOI: 10.1210/jendso/bvad114.993
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2023
    detail.hit.zdb_id: 2881023-5
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  • 5
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    Online Resource
    IL-3-zetakine combined with a CD33 costimulatory receptor as a dual CAR approach for safer and selective targeting of AML
    American Society of Hematology ; 2023
    In:  Blood Advances Vol. 7, No. 12 ( 2023-06-27), p. 2855-2871
    Details
    In: Blood Advances, American Society of Hematology, Vol. 7, No. 12 ( 2023-06-27), p. 2855-2871
    Abstract: Acute myeloid leukemia (AML) still represents an unmet clinical need for adult and pediatric patients. Adoptive cell therapy by chimeric antigen receptor (CAR)-engineered T cells demonstrated a high therapeutic potential, but further development is required to ensure a safe and durable disease remission in AML, especially in elderly patients. To date, translation of CAR T-cell therapy in AML is limited by the absence of an ideal tumor-specific antigen. CD123 and CD33 are the 2 most widely overexpressed leukemic stem cell biomarkers but their shared expression with endothelial and hematopoietic stem and progenitor cells increases the risk of undesired vascular and hematologic toxicities. To counteract this issue, we established a balanced dual-CAR strategy aimed at reducing off-target toxicities while retaining full functionality against AML. Cytokine-induced killer (CIK) cells, coexpressing a first-generation low affinity anti-CD123 interleukin-3–zetakine (IL-3z) and an anti-CD33 as costimulatory receptor without activation signaling domains (CD33.CCR), demonstrated a powerful antitumor efficacy against AML targets without any relevant toxicity on hematopoietic stem and progenitor cells and endothelial cells. The proposed optimized dual-CAR cytokine-induced killer cell strategy could offer the opportunity to unleash the potential of specifically targeting CD123+/CD33+ leukemic cells while minimizing toxicity against healthy cells.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    URL: Article
    DOI: 10.1182/bloodadvances.2022008762
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2023
    detail.hit.zdb_id: 2876449-3
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  • 6
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    Immunotherapy in association with stereotactic radiotherapy for non-small cell lung cancer brain metastases: results from a multicentric retrospective study on behalf of AIRO
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. 10 ( 2021-10-01), p. 1750-1764
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. 10 ( 2021-10-01), p. 1750-1764
    Abstract: To define efficacy and toxicity of Immunotherapy (IT) with stereotactic radiotherapy (SRT) including radiosurgery (RS) or hypofractionated SRT (HFSRT) for brain metastases (BM) from non-small cell lung cancer (NSCLC) in a multicentric retrospective study from AIRO (Italian Association of Radiotherapy and Clinical Oncology). Methods NSCLC patients with BM receiving SRT + IT and treated in 19 Italian centers were analyzed and compared with a control group of patients treated with exclusive SRT. Results One hundred patients treated with SRT + IT and 50 patients treated with SRT-alone were included. Patients receiving SRT + IT had a longer intracranial Local Progression-Free Survival (iLPFS) (propensity score-adjusted P = .007). Among patients who, at the diagnosis of BM, received IT and had also extracranial progression (n = 24), IT administration after SRT was shown to be related to a better overall survival (OS) (P = .037). A multivariate analysis, non-adenocarcinoma histology, KPS = 70 and use of HFSRT were associated with a significantly worse survival (P = .019, P = .017 and P = .007 respectively). Time interval between SRT and IT ≤7 days (n = 90) was shown to be related to a longer OS if compared to SRT-IT interval & gt;7 days (n = 10) (propensity score-adjusted P = .008). The combined treatment was well tolerated. No significant difference in terms of radionecrosis between SRT + IT patients and SRT-alone patients was observed. The time interval between SRT and IT had no impact on the toxicity rate. Conclusions Combined SRT + IT was a safe approach, associated with a better iLPFS if compared to exclusive SRT.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab129
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2094060-9
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  • 7
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    Logical Characterization of Bisimulation Metrics
    Open Publishing Association ; 2016
    In:  Electronic Proceedings in Theoretical Computer Science Vol. 227 ( 2016-10-25), p. 44-62
    Details
    In: Electronic Proceedings in Theoretical Computer Science, Open Publishing Association, Vol. 227 ( 2016-10-25), p. 44-62
    Type of Medium: Online Resource
    ISSN: 2075-2180
    URL: Issue
    URL: Article
    DOI: 10.4204/EPTCS.227
    DOI: 10.4204/EPTCS.227.4
    Language: English
    Publisher: Open Publishing Association
    Publication Date: 2016
    detail.hit.zdb_id: 2577794-4
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  • 8
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    DataSheet_2.xlsx
    Frontiers Media SA ; 2023
    In:  Frontiers in Oncology Vol. 13 ( 2023-9-25)
    Details
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 13 ( 2023-9-25)
    Abstract: Constitutive activation of NOTCH1 -wild-type (NT1-WT) signaling is associated with poor outcomes in chronic lymphocytic leukemia (CLL), and NOTCH1 mutation (c.7541_7542delCT), which potentiates NOTCH1 signaling, worsens the prognosis. However, the specific mechanisms of NOTCH1 deregulation are still poorly understood. Accumulative evidence mentioned endoplasmic reticulum (ER) stress/unfolded protein response (UPR) as a key targetable pathway in CLL. In this study, we investigated the impact of NOTCH1 deregulation on CLL cell response to ER stress induction, with the aim of identifying new therapeutic opportunities for CLL. Methods We performed a bioinformatics analysis of NOTCH1 -mutated (NT1-M) and NT1-WT CLL to identify differentially expressed genes (DEGs) using the rank product test. Quantitative real-time polymerase chain reaction (qPCR), Western blotting, cytosolic Ca 2+ , and annexin V/propidium iodide (PI) assay were used to detect curcumin ER stress induction effects. A median-effect equation was used for drug combination tests. The experimental mouse model Eμ-TCL1 was used to evaluate the impact of ER stress exacerbation by curcumin treatment on the progression of leukemic cells and NOTCH1 signaling. Results and discussion Bioinformatics analysis revealed gene enrichment of the components of the ER stress/UPR pathway in NT1-M compared to those in NT1-WT CLL. Ectopic expression of NOTCH1 mutation upregulated the levels of ER stress response markers in the PGA1 CLL cell line. Primary NT1-M CLL was more sensitive to curcumin as documented by a significant perturbation in Ca 2+ homeostasis and higher expression of ER stress/UPR markers compared to NT1-WT cells. It was also accompanied by a significantly higher apoptotic response mediated by C/EBP homologous protein (CHOP) expression, caspase 4 cleavage, and downregulation of NOTCH1 signaling in NT1-M CLL cells. Curcumin potentiated the apoptotic effect of venetoclax in NT1-M CLL cells. In Eμ-TCL1 leukemic mice, the administration of curcumin activated ER stress in splenic B cells ex vivo and significantly reduced the percentage of CD19 + /CD5 + cells infiltrating the spleen, liver, and bone marrow (BM). These cellular effects were associated with reduced NOTCH1 activity in leukemic cells and resulted in prolonged survival of curcumin-treated mice. Overall, our results indicate that ER stress induction in NT1-M CLL might represent a new therapeutic opportunity for these high-risk CLL patients and improve the therapeutic effect of drugs currently used in CLL.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fonc.2023.1218989
    DOI: 10.3389/fonc.2023.1218989.s001
    DOI: 10.3389/fonc.2023.1218989.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2649216-7
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  • 9
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    SiCoDEA: A Simple, Fast and Complete App for Analyzing the Effect of Individual Drugs and Their Combinations
    MDPI AG ; 2022
    In:  Biomolecules Vol. 12, No. 7 ( 2022-06-28), p. 904-
    Details
    In: Biomolecules, MDPI AG, Vol. 12, No. 7 ( 2022-06-28), p. 904-
    Abstract: The administration of combinations of drugs is a method widely used in the treatment of different pathologies as it can lead to an increase in the therapeutic effect and a reduction in the dose compared to the administration of single drugs. For these reasons, it is of interest to study combinations of drugs and to determine whether a specific combination has a synergistic, antagonistic or additive effect. Various mathematical models have been developed, which use different methods to evaluate the synergy of a combination of drugs. We have developed an open access and easy to use app that allows different models to be explored and the most fitting to be chosen for the specific experimental data: SiCoDEA (Single and Combined Drug Effect Analysis). Despite the existence of other tools for drug combination analysis, SiCoDEA remains the most complete and flexible since it offers options such as outlier removal or the ability to choose between different models for analysis. SiCoDEA is an easy to use tool for analyzing drug combination data and to have a view of the various steps and offer different results based on the model chosen.
    Type of Medium: Online Resource
    ISSN: 2218-273X
    URL: Article
    DOI: 10.3390/biom12070904
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2701262-1
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  • 10
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    Ultrasound screening for asymptomatic deep vein thrombosis in critically ill patients: a pilot trial
    Springer Science and Business Media LLC ; 2022
    In:  Internal and Emergency Medicine Vol. 17, No. 8 ( 2022-11), p. 2269-2277
    Details
    In: Internal and Emergency Medicine, Springer Science and Business Media LLC, Vol. 17, No. 8 ( 2022-11), p. 2269-2277
    Abstract: Deep vein thrombosis (DVT) in critically ill patients still represents a clinical challenge. The aim of the study was to investigate whether a systematic ultrasound (US) screening might improve the management of the antithrombotic therapy in intensive care unit (ICU). In this non-randomized diagnostic clinical trial, 100 patients consecutively admitted to ICU of the University Hospital of Perugia were allocated either in the screening group or in the control group. Subjects in the screening group underwent US examination of lower limbs 48 h after admission, and again after 5 days. Subjects in the control group underwent US examination according to the standard of care (SOC) of the enrolling institution. Retrospectively registered at ClinicalTrials.gov (NCT05019092) on 24.08.2021. Lower limb DVT was significantly more frequent in the screening group ( p   〈  0.001), as well as the subsequent extension of a pre-existing DVT ( p  = 0.027). In the control group, DVT of large veins was more frequent ( p  = 0.038). Major bleedings were reported in 5 patients, 4 in the non-screening group and in 1 in the screening group. Patients in the screening group started the antithrombotic treatment later ( p  = 0.038), although the frequency, dose and duration of the treatment were not different between the two groups. The duration of stay in ICU was longer in the screening group ( p  = 0.007). Active screening for DVT is associated with an increased diagnosis of DVT. The screening could be associated with a reduced incidence of proximal DVT and a reduction in the bleeding risk.
    Type of Medium: Online Resource
    ISSN: 1828-0447 , 1970-9366
    URL: Article
    DOI: 10.1007/s11739-022-03085-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2378342-4
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