•The risk of recurrence and treatment options are unsolved issues in resected NSCLC.•Multidisciplinary approaches may implement the actual pTNM-based prognostic score.•Radiomics was exploited to ...non-invasively decipher tumor immune microenvironment.•We identified a radio-immune signature with prognostic impact in early stage NSCLC.•Integrating imaging and tissue features may enclose new risk stratification models.
Qualitative and quantitative CT imaging features might intercept the multifaceted tumor immune microenvironment (TIME), providing a non-invasive approach to design new prognostic models in NSCLC patients.
Our study population consisted of 100 surgically resected NSCLC patients among which 31 served as a validation cohort for quantitative image analysis. TIME was classified according to PD-L1 expression and the magnitude of Tumor Infiltrating Lymphocytes (TILs) and further defined as hot or cold by the tissue analysis of effector (CD8-to-CD3high/PD-1-to-CD8low) or inert (CD8-to-CD3low/PD-1-to-CD8high) phenotypes. CT datasets acted as source for qualitative (semantic, CT-SFs) and quantitative (radiomic, CT-RFs) features which were correlated with clinico-pathological and TIME profiles to determine their impact on survival outcome.
Specific CT-SFs (texture TXT, effect EFC and margins MRG) strongly correlated to PD-L1 and TILs status and showed significant impact on survival outcome (TXT, HR:3.39, 95 % CI 1.12−10-27, P < 0.05; EFC, HR:0.41, 95 % CI 0.18−0.93, P < 0.05; MRG, HR:1.93, 95 % CI 0.88–4.25, P = 0.09). Seven CT derived radiomic features were able to sharply discriminate cases with hot (inflamed) vs cold (desert) TIME, which also exhibited opposite OS (long vs short, HR:0.09, 95 % CI 0.04−0.23, P < 0.001) and DFS (long vs short, HR:0.31, 95 % CI 0.16−0.58, P < 0.001). Moreover, we identified 6 prognostic radiomic features among which ClusterProminence displayed the highest statistical significance (HR:0.13, 95 % CI 0.06−0.31, P < 0.001). These findings were independently validated in an additional cohort of NSCLC (HR:0.11, 95 % CI 0.03−0.40, P = 0.001). Finally, in our training cohort we developed a multiparametric prognostic model, interlacing TIME and clinico-pathological characteristics with CT-SFs (ROC curve AUC:0.83, 95 % CI 0.71−0.92, P < 0.001) or CT-RFs (AUC: 0.91, 95 % CI 0.83−0.99, P < 0.001), which appeared to outperform pTNM staging (AUC: 0.66, 95 % CI 0.51−0.80, P < 0.05) in the risk assessment of NSCLC.
Higher order CT extracted features associated with specific TIME profiles may reveal a radio-immune signature with prognostic impact on resected NSCLC.
The aim of the present study was to evaluate CD4/CD8 dynamics in patients on dolutegravir (DTG)-based two-drug regimens (2DRs) and compare them with DTG-containing triple-drug regimens (3DRs). A ...prospective observational study was performed in the context of the SCOLTA cohort. Experienced PWH with HIV-RNA < 50 copies/mL were included if they were on the DTG-2DR, the DTG + tenofovir/emtricitabine (TDF/FTC) regimen, the DTG + tenofovir alafenamide (TAF)/FTC regimen, or the DTG + abacavir/lamivudine (ABC/3TC) regimen; they were followed-up for at least one year. A total of 533 PWH were enrolled, 120 in the DTG + 3TC group, 38 in the DTG + protease inhibitors (PI) group, 67 in the DTG + rilpivirine (RPV) group, 49 in the DTG + TDF/FTC group, 27 in the DTG + TAF/FTC group, and 232 in the DTG + ABC/3TC group. After one year, the CD4/CD8 ratio significantly increased in the PWH treated with DTG + 3TC (+0.08 ± 0.26), DTG + TDF/FTC (+0.1 ± 0.19), and DTG + ABC/3TC (+0.08 ± 0.25). At two years, the CD4/CD8 increase was confirmed for PWH on DTG + TDF/FTC (+0.16 ± 0.28) and DTG + ABC/3TC (+0.1 ± 0.3). In the SCOLTA cohort, PWH on 2DRs experienced a CD4/CD8 increase only in the DTG + 3TC group. Controlled studies with longer follow-up will clarify the long-term immunological and clinical impacts of DTG-2DR.
Objectives
The aim of the present study was to compare the efficacy and durability of treatment switch to two‐drug (2DR) vs. three‐drug (3DR) integrase inhibitor (InSTI)‐based regimens in a real‐life ...setting.
Methods
Within the ODOACRE cohort, we selected adult patients with HIV RNA < 50 copies/mL switching to an InSTI‐based 2DR or 3DR. Survival analyses were performed to estimate the probability of virological failure (VF, defined as one HIV RNA > 1000 copies/mL or two consecutive HIV RNA > 50 copies/mL) and treatment discontinuation (TD, defined as any modification, intensification or interruption of the regimen), and to evaluate their predictors.
Results
Overall, 1666 patients were included, of whom 1334 (80%) were treated with a 3DR (19.9%, 25.0% and 55.1% elvitegravir‐, raltegravir‐ and dolutegravir‐based, respectively) and 332 (20%) with a 2DR (79.2% dolutegravir + lamivudine and 20.8% dolutegravir + rilpivirine).
Over a median (interquartile range) follow‐up of 100 (52–150) weeks, 52 (3.1%) patients experienced VF with an incidence of 1.5/100 person‐year of follow‐up (PYFU). The estimated 96‐week probability of VF was similar for the 2DR and 3DR groups (2.3% vs. 2.8%, P = 0.53), but it was higher for elvitegravir (4.9%) and raltegravir (5.0%) than for dolutegravir (1.5%) (P = 0.04).
Four hundred (24%) patients discontinued their InSTI‐based regimen, with an incidence of 11.3/100 PYFU. At 96 weeks, 3DRs showed a higher probability of TD for any reason (20.6% vs. 11.2%, P < 0.001) and TD for toxicity (9.0% vs. 6.6%, P = 0.02) when compared with 2DRs. A higher risk of TD for central nervous system toxicity was observed for dolutegravir than for elvitegravir and raltegravir (4.0% vs. 2.5% vs. 0.6%, P = 0.005).
Conclusions
In virologically suppressed HIV‐infected patients, 2DRs showed an efficacy similar to 3DRs but with better tolerability.
COVID-19 forced healthcare workers to work in unprecedented and critical circumstances, exacerbating already-problematic and stressful working conditions. The "Healthcare workers' wellbeing ...(Benessere Operatori)" project aimed at identifying psychological and personal factors, influencing individuals' responses to the COVID-19 pandemic.
291 healthcare workers took part in the project by answering an online questionnaire twice (after the first wave of COVID-19 and during the second wave) and completing questions on socio-demographic and work-related information, the Depression Anxiety Stress Scale-21, the Insomnia Severity Index, the Impact of Event Scale-Revised, the State-Trait Anger Expression Inventory-2, the Maslach Burnout Inventory, the Multidimensional Scale of Perceived Social Support, and the Brief Cope.
Higher levels of worry, worse working conditions, a previous history of psychiatric illness, being a nurse, older age, and avoidant and emotion-focused coping strategies seem to be risk factors for healthcare workers' mental health. High levels of perceived social support, the attendance of emergency training, and problem-focused coping strategies play a protective role.
An innovative, and more flexible, data mining statistical approach (i.e., a regression trees approach for repeated measures data) allowed us to identify risk factors and derive classification rules that could be helpful to implement targeted interventions for healthcare workers.
The epidermal growth factor receptor (EGFR) is an established target for anti-cancer treatment in different tumour types. Two different strategies have been explored to inhibit this pivotal molecule ...in epithelial cancer development: small molecules TKIs and monoclonal antibodies. ErbB/HER-targeting by monoclonal antibodies such as cetuximab and trastuzumab or tyrosine-kinase inhibitors as gefitinib or erlotinib has been proven effective in the treatment of advanced NSCLC.
In this study we explored the potential of combining either erlotinib with cetuximab or trastuzumab to improve the efficacy of EGFR targeted therapy in EGFR wild-type NSCLC cell lines. Erlotinib treatment was observed to increase EGFR and/or HER2 expression at the plasma membrane level only in NSCLC cell lines sensitive to the drug inducing protein stabilization. The combined treatment had marginal effect on cell proliferation but markedly increased antibody-dependent, NK mediated, cytotoxicity in vitro. Moreover, in the Calu-3 xenograft model, the combination significantly inhibited tumour growth when compared with erlotinib and cetuximab alone.
Our results indicate that erlotinib increases surface expression of EGFR and/or HER2 only in EGFR-TKI sensitive NSCLC cell lines and, in turns, leads to increased susceptibility to ADCC both in vitro and in a xenograft models. The combination of erlotinib with monoclonal antibodies represents a potential strategy to improve the treatment of wild-type EGFR NSCLC patients sensitive to erlotinib.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PCOS treatment should be based on pathophysiology. High-mobility-group-box-1 (HMGB1) was shown to increase in PCOS patients as a consequence of reduced ...cystic-fibrosis-transmembrane-conductance-regulator (CFTR) expression in the ovary, and was associated with insulin resistance and inflammation, both features of PCOS. Inositols and ALA derivatives could have positive effects on insulin sensitivity, reduce androgens, and improve ovulation rhythm. The aim of this study was to verify changes in HMGB1, in metabolic and endocrine parameters in adolescents with PCOS compared with controls and after treatment with a combination of MYO + ALA. Twenty-three PCOS adolescents and 21 controls matched for age and BMI were enrolled. In all subjects, metabolic and hormonal parameters were assayed. Homeostatic index (HOMA-IR) and the triglyceride/HDL-cholesterol ratio were calculated. Ovarian volumes were evaluated. Patients were treated with MYO + ALA for 6 months. HMGB1 was measured using a specific ELISA assay. HMGB1 was increased in PCOS compared with controls (19.76 ± 5.99 versus 5.65 ± 1.88 ng/ml; p < .05) and normalized after treatment (2.27 ± 0.36 ng/ml, p < .05). Treatment significantly reduced insulin (24.0 ± 4.11 versus 12.13 ± 2.13 uU/ml), HOMA-IR (3.91 ± 0.41 versus 2.42 ± 0.45), and 17-hydroxyprogesterone (1.20 ± 0.15 versus 0.78 ± 0.11 ng/ml). Cholesterol, luteinizing hormone, 17-β-estradiol, delta 4-androstenedione, and testosterone were unchanged. Circulating HMGB1 was increased in PCOS adolescents, and treatment was effective in normalizing HMGB1.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
RATIONALE:Long living individuals show delay of aging, which is characterized by the progressive loss of cardiovascular homeostasis, along with reduced endothelial nitric oxide synthase activity, ...endothelial dysfunction, and impairment of tissue repair after ischemic injury.
OBJECTIVE:Exploit genetic analysis of long living individuals to reveal master molecular regulators of physiological aging and new targets for treatment of cardiovascular disease.
METHODS AND RESULTS:We show that the polymorphic variant rs2070325 (Ile229Val) in bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) associates with exceptional longevity, under a recessive genetic model, in 3 independent populations. Moreover, the expression of BPIFB4 is instrumental to maintenance of cellular and vascular homeostasis through regulation of protein synthesis. BPIFB4 phosphorylation/activation by protein-kinase-R–like endoplasmic reticulum kinase induces its complexing with 14-3-3 and heat shock protein 90, which is facilitated by the longevity-associated variant. In isolated vessels, BPIFB4 is upregulated by mechanical stress, and its knock-down inhibits endothelium-dependent vasorelaxation. In hypertensive rats and old mice, gene transfer of longevity-associated variant-BPIFB4 restores endothelial nitric oxide synthase signaling, rescues endothelial dysfunction, and reduces blood pressure levels. Furthermore, BPIFB4 is implicated in vascular repair. BPIFB4 is abundantly expressed in circulating CD34 cells of long living individuals, and its knock-down in endothelial progenitor cells precludes their capacity to migrate toward the chemoattractant SDF-1. In a murine model of peripheral ischemia, systemic gene therapy with longevity-associated variant-BPIFB4 promotes the recruitment of hematopoietic stem cells, reparative vascularization, and reperfusion of the ischemic muscle.
CONCLUSIONS:Longevity-associated variant-BPIFB4 may represent a novel therapeutic tool to fight endothelial dysfunction and promote vascular reparative processes.
Recent reports of excessive weight gain in people living with HIV (PWH) have raised increasing concerns on the possible increase of diabetes mellitus (DM) risk in course of integrase inhibitor ...(INSTIs) treatment. In this study, we aimed at describing DM incidence in course of antiretroviral therapy (ART) and identifying the factors associated with new DM onset.
Observational prospective SCOLTA (Surveillance Cohort Long-Term Toxicity Antiretrovirals) cohort.
All people enrolled in SCOLTA between January 2003 and November 2021 were included. Multivariable Cox regression yielded adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for incident DM.
4,366 PWH were included, 72.6% male, with mean age 45.6 years, and median CD4 460 (IQR 256-710) cells/mm3cells/mm3. During the follow up, 120 incident cases of DM occurred (1.26 cases/100 person year-follow up, 95% CI 1.05-1.50).Baseline weight, but not the amount of weight gain, resulted significantly correlated to diabetes incidence (aHR by 1 Kg 1.03; 95%CI 1.01-1.04), as well as older age (aHR 1.03 by 1 year; 95%CI 1.01-1.06), being ART-experienced with detectable HIV RNA at study entry (aHR 2.27, 95%CI 1.48-3.49), having untreated high blood pressure (aHR 2.90; 95%CI 1.30-6.45) and baseline blood glucose >100 mg/dL (aHR 5.47; 95%CI 3.82-7.85). Neither the INSTI class nor individual antiretrovirals were associated with an increased risk of DM.
baseline weight, but not weight gain or the ART class, was associated with incident DM in this observational cohort.
Previous studies have demonstrated that caffeine administration to adult mice potentiates glial activation induced by 3,4‐methylenedioxymethamphetamine (MDMA). As neuroinflammatory response seems to ...correlate with neurodegeneration, and the young brain is particularly vulnerable to neurotoxicity, we evaluated dopamine neuron degeneration and glial activation in the caudate‐putamen (CPu) and substantia nigra pars compacta (SNc) of adolescent and adult mice. Mice were treated with MDMA (4 × 20 mg/kg), alone or with caffeine (10 mg/kg). Interleukin (IL)‐1β, tumor necrosis factor (TNF)‐α, neuronal nitric oxide synthase (nNOS) were evaluated in CPu, whereas tyrosine hydroxylase (TH), glial fibrillary acidic protein, and CD11b were evaluated in CPu and SNc by immunohistochemistry. MDMA decreased TH in SNc of both adolescent and adult mice, whereas TH‐positive fibers in CPu were only decreased in adults. In CPu of adolescent mice, caffeine potentiated MDMA‐induced glial fibrillary acidic protein without altering CD11b, whereas in SNc caffeine did not influence MDMA‐induced glial activation. nNOS, IL‐1β, and TNF‐α were increased by MDMA in CPu of adults, whereas in adolescents, levels were only elevated after combined MDMA plus caffeine. Caffeine alone modified only nNOS. Results suggest that the use of MDMA in association with caffeine during adolescence may exacerbate the neurotoxicity and neuroinflammation elicited by MDMA.
Previous studies have demonstrated that caffeine potentiated glial activation induced by 3,4‐methylenedioxymethamphetamine (MDMA) in adult mice. In this study, caffeine was shown to potentiate MDMA‐induced dopamine neuron degeneration in substantia nigra pars compacta, astrogliosis, and TNF‐α levels in caudate‐putamen of adolescent mice. Results suggest that combined use of MDMA plus caffeine during adolescence may worsen the neurotoxicity and neuroinflammation elicited by MDMA.
Previous studies have demonstrated that caffeine potentiated glial activation induced by 3,4‐methylenedioxymethamphetamine (MDMA) in adult mice. In this study, caffeine was shown to potentiate MDMA‐induced dopamine neuron degeneration in substantia nigra pars compacta, astrogliosis, and TNF‐α levels in caudate‐putamen of adolescent mice. Results suggest that combined use of MDMA plus caffeine during adolescence may worsen the neurotoxicity and neuroinflammation elicited by MDMA.
Doravirine (DOR) is a newly approved non-nucleoside reverse transcriptase inhibitor (NNRTI). We aimed to investigate, in a real-life setting, how switching to a DOR-based regimen rather than a ...rilpivirine (RPV)-based regimen impacted metabolic and hepatic safety. The analysis included 551 antiretroviral treatment (ART)-experienced people living with HIV (PLWH), starting RPV-based or DOR-based regimens with viral load < 200 copies/mL, baseline (T0), and at least one control visit (6-month visit, T1). We enrolled 295 PLWH in the RPV and 256 in the DOR cohort. At T1, total cholesterol (TC), low-density lipoprotein-C (LDL-C), and triglycerides significantly decreased in both DOR and RPV cohorts, while high-density lipoprotein-C (HDL-C) only decreased in RPV-treated people. Consistently, the TC/HDL-C ratio declined more markedly in the DOR (-0.36,
< 0.0001) than in the RPV cohort (-0.08,
= 0.25) (comparison
= 0.39). Similar trends were observed when excluding the PLWH on lipid-lowering treatment from the analysis. People with normal alanine aminotransferase (ALT) levels showed a slight ALT increase in both cohorts, and those with baseline ALT > 40 IU/L experienced a significant decline (-14 IU/L,
= 0.008) only in the DOR cohort. Lipid profile improved in both cohorts, and there was a significant reduction in ALT in PLWH with higher-than-normal baseline levels on DOR-based ART.
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