Blocking the inhibitory receptor PD-1 on antitumour T lymphocytes is the main rationale underlying the clinical successes of cancer immunotherapies with checkpoint inhibitor (CI) antibodies (Abs). ...Besides this main paradigm, there is recent evidence of unconventional and "ectopic" signalling pathways of PD-1, found to be expressed not only by lymphocytes but also by peculiar subsets of cancer cells. Several groups reported on the tumour-intrinsic role of PD-1 in multiple settings, including melanoma, hepatocellular, thyroid, lung, pancreatic and colorectal cancer. Its functional activity appears intriguing but is not yet conclusively clarified. The initial studies are, in fact, supporting either a pro-tumourigenic role involved in chemoresistance and disease relapse or, oppositely, tumour-suppressive functions. The implications connected to the therapeutic administration of PD-1 blocking Abs are, of course, potentially relevant, respectively inferring an anti-tumour activity contrasting PD-1+ tumourigenic cells or a pro-tumoural effect by tackling PD-1 tumour suppressive signalling. The progressive exploration and consideration of this new paradigm of tumour-intrinsic PD-1 signalling may improve the interpretation of the observed clinical effects by anti-PD-1 Abs, likely resulting from multiple cumulative activities, and might provide important bases for dedicated clinical studies that take into account such composite roles of PD-1.
Purpose of our study was to explore a new immunotherapy for high grade soft tissue sarcomas (STS) based on cytokine-induced killer cells (CIK) redirected with a chimeric antigen receptor (CAR) ...against the tumor-promoting antigen CD44v6. We aimed at generating bipotential killers, combining the CAR specificity with the intrinsic tumor-killing ability of CIK cells (CAR
+
.CIK). We set a patient-derived experimental platform. CAR
+
.CIK were generated by transduction of CIK precursors with a lentiviral vector encoding for anti-CD44v6-CAR. CAR
+
.CIK were characterized and assessed in vitro against multiple histotypes of patient-derived STS. The anti-sarcoma activity of CAR
+
.CIK was confirmed in a STS xenograft model. CD44v6 was expressed by 40% (11/27) of patient-derived STS. CAR
+
.CIK were efficiently expanded from patients (n = 12) and killed multiple histotypes of STS (including autologous targets, n = 4). The killing activity was significantly higher compared with unmodified CIK, especially at low effector/target (E/T) ratios: 98% vs 82% (E/T = 10:1) and 68% vs 26% (1:4), (p<0.0001). Specificity of tumor killing was confirmed by blocking with anti-CD44v6 antibody. CAR
+
.CIK produced higher amounts of IL6 and IFN-γ compared to control CIK. CAR
+
.CIK were highly active in mice bearing subcutaneous STS xenografts, with significant delay of tumor growth (p<0.0001) without toxicities.
We report first evidence of CAR
+
.CIK's activity against high grade STS and propose CD44v6 as an innovative target in this setting. CIK are a valuable platform for the translation of CAR-based strategies to challenging field of solid tumors. Our findings support the exploration of CAR
+
.CIK in clinical trials against high grade STS.
Recent studies have shown that hyperinsulinemia may increase the cancer risk. Moreover, many tumors demonstrate an increased activation of IR signaling pathways. Phosphatidylinositol 3-kinase (PI3K) ...is necessary for insulin action. In epithelial cells, which do not express GLUT4 and gluconeogenic enzymes, insulin-mediated PI3K activation regulates cell survival, growth, and motility. Although the involvement of the regulatory subunit of PI3K ( p 85 α PI 3 K ) in insulin signal transduction has been extensively studied, the function of its N-terminus remains elusive. It has been identified as a serine (S83) in the p 85 α PI 3 K that is phosphorylated by protein kinase A (PKA). To determine the molecular mechanism linking PKA to insulin-mediated PI3K activation, we used p 85 α PI 3 K mutated forms to prevent phosphorylation (p85A) or to mimic the phosphorylated residue (p85D). We demonstrated that phosphorylation of p 85 α PI 3 K S83 modulates the formation of the p 85 α PI 3 K / IRS - 1 complex and its subcellular localization influencing the kinetics of the insulin signaling both on MAPK-ERK and AKT pathways. Furthermore, the p 85 α PI 3 K S83 phosphorylation plays a central role in the control of insulin-mediated cell proliferation, cell migration, and adhesion. This study highlights the p 85 α PI 3 K S83 role as a key regulator of cell proliferation and motility induced by insulin in MCF-7 cells breast cancer model.
Nanospheres of poly(methacrylic acid-grafted-poly(ethylene glycol)) were prepared by solution/precipitation polymerization. As colloidal drug delivery carriers, they present unique properties that ...render them promising candidates for oral protein delivery. The polymerization was carried out in water and the resulting suspension was freeze-dried. As with many colloidal systems, the freeze-dried suspension showed strong agglomeration after drying. The effects of preparation conditions on the particle size and redispersion were investigated using photon correlation spectroscopy. Furthermore, the ability of different types and concentrations of stabilizers (cryoprotectants and steric stabilizers) in preventing this phenomenon was addressed. Pluronics®, block copolymers widely used as nonionic surfactants, were the most effective in stabilizing the particles during the freeze-drying process. Pluronic® P123, however, increased significantly the particle size of the nanospheres. On the other hand, lyophilizates obtained in the presence of Pluronic® F68 had good redispersion properties and no change in particle size was observed.
OBJECTIVE:The recent results of the SPRINT study suggest that “intensive” reduction of systolic blood pressure (BP) (to less than 120 mmHg) might provide greater cardiovascular protection as compared ...to less intensive (<140 mmHg) reduction of BP, at least in some subsets of patients. Only few studies, have investigated the possible effect of tight blood pressure control on indices of left ventricular hypertrophy, and have been mainly based on electrocardiography.Aim of our studywas to evaluate cardiac organ damage according to “on treatment” blood pressure values in a large cohort of hypertensive patients undergoing echocardiography (2D, M-mode with conventional and tissue Doppler analysis) at the echo-lab of an ESH Excellence Centre in Italy.
DESIGN AND METHOD:The analysis included 976 treated hypertensive patients (43% female, age 59 ± 12 yrs, age range 15–90). Patients were subdivided in three groups according to BP values at the time of the echocardiogram, defined as followsuncontrolled (UC; SBP >or equal to 140 mmHg), controlled <140 (C140; SBP between 139 and 120 mmHg) and controlled <120 (C120; SBP <120 mmHg).
RESULTS:In 407 patients (42%) SBP values were >140 mmHg, 449 patients (46%) had SBP was between 139 and 120 mmHg (C140) and in 120 (12%) SBP was <120 mmHg (C120).Left ventricular mass (LVM) and LVM index (LVMI) were progressively lower in UC, C140 and C120 (LVM162 ± 51, 159 ± 47 and 149 ± 44 gr respectively, p for trend <0,001; LVMI40 ± 11,38 ± 10 and 35 ± 9 gr/m2.7 respectively, p for trend <0,001). No significant difference was observed for relative wall thickness. Left atrial volume (LAV) and LAV/BSA were progressively lower in UC, C140 and C120 (LAV/BSA25.6 ± 7.6, 23.7 ± 7.9, 22.7 ± 8.5, respectively, p for trend <0,001). These differences remained significant even after adjusting for possible confounders.
CONCLUSIONS:Lower achieved BP targets are associated with a progressive lower left ventricular mass, left ventricular mass index and left atrial volumes. These findings are in line with previous results indicating a favorable effect of tight BP control on electrocardiographic indices of LV hypertrophy. Prospective studies are needed to confirm the possible favorable effect of tight BP control on echocardiographic indices of LVH, and their relation to CV events.
OBJECTIVE:Few data are available on the relationship between left ventricular (LV) circumferential and longitudinal systolic function in hypertensive patients with preserved LV ejection fraction ...(EF). The aim of this study is to analyze LV circumferential and longitudinal systolic function and their main determinants in a group of hypertensive patients.
DESIGN AND METHOD:In 1285 hypertensive patients (547 female, mean age 57 ± 13 yrs, 77% treated) a standard echocardiographic examination was performed, to assess LV anatomy and systolic function parameters, including EF, Midwall fractional shortening (MidFS) and MidFS adjusted for endsystolic stress (ESS_MidFS). In addition longitudinal systolic function was evaluated by the measurement of tissue Doppler peak systolic velocity of the mitral annulus (Sm). A reduced systolic function was defined in the presence of ESS_MidFS lower than 89% or Sm lower than 8 cm/sec.
RESULTS:A modest but statistically significant relationship between MidFS or ESS_MidFS and Sm (r = 0,08, p < 0,001) was observed. MidFS was independently related to age, body mass index (BMI), LV mass index, relative wall thickness (RWT) and hear rate, while the main determinants of Sm were age, heart rate, systolic blood pressure and LV mass index. According to previously defined criteria a reduction of Sm and ESS_MidFS was observed in 47% and 26% of patients, respectively.
CONCLUSIONS:Longitudinal systolic function is impaired in a high percentage of hypertensive patients with preserved EF and identifies a higher number of patients with impaired systolic function. The determinants of longitudinal and circumferential systolic function are, at least in part, different.
OBJECTIVE:In patients with systemic lupus erythematosus (SLE) a greater prevalence of structural and functional cardiovascular (CV) alterations has been described, possibly explaining the higher ...incidence of CV events, as compared to subjects matched for age and sex.Aim of this study was to analyze the presence of target organ damage in premenopausal women with SLE and in controls matched not only for demographic characteristics but also for other cardiovascular risk factors.
DESIGN AND METHOD:34 patients with SLE clinically stable (SLEDAI Score 2.5 +/- 1.5) (mean age 32 ± 7 years, range 19–44) and 34 controls matched for sex, age, body mass index (BMI), clinic blood pressure (BP) and antihypertensive treatment (if present), underwent24 hours BP monitoring, echocardiography with tissue Doppler analysis (TDI) for the evaluation of left ventricular (LV) structure and of systolic and diastolic function, carotid ultrasound for intima-media thickness (IMT) and carotid distensibility measurement, and pulse wave velocity measurement for aortic stiffness (PWV).
RESULTS:By definition no difference was observed for age, sex, BMI and clinic BP values and a similar Framingham risk score was observed between SLE and controls (1.3 ± 2.7 vs 1.5 ± 2.3%, p = ns). No significant differences were observed for all echocardiographic parameters except LV longitudinal systolic function (Sm), an early index of LV systolic dysfunction (see Table). Carotid IMT and distensibility, as well as PWV and the prevalence of an abnormal aortic stiffness were both similar in the two groups. At the logistic analysis, PWV was independently associated with LV mass in controls and with the steroid weekly dose in SLE patients.(Figure is included in full-text article.)
CONCLUSIONS:In patients with SLE and low activity index of the disease we did not observe significant vascular alterations as compared to controls with similar cardiovascular risk. The early LV systolic impairment observed in this group of patients needs confirmation in larger cohorts.
OBJECTIVE:Primary aldosteronism is a relatively common condition in hypertensive patients. Only few studies, in small groups of patients, have evaluated large arteries alterations. In some, but not ...in all studies, positive relationship with vascular damage was observed.Aim of the studyTo compare the prevalence of cardiac and large arteries vascular organ damage in patients with essential hypertension (EH) or primary aldosteronism (PA).
DESIGN AND METHOD:In 243 consecutive patients with no interfering therapy (147 M, mean age 48 ± 11 years) a routine blood sample, including measurement of aldosterone/renin ratio (ARR) and saline load if ARR>30, was obtained. Echocardiography, carotid ultrasound and measurement of pulse wave velocity (PWV) were performed. We considered 3 groups48 patients with EH (ARR < 30); 122 patients with positive ARR screening but negative saline load (indeterminate aldosteronism, IA); 73 patients with PA (positive ARR and post saline aldosterone >100ng/ml)(51 % with adrenal adenoma).
RESULTS:No differences between groups were observed in age, gender, BMI, BP values (clinic and 24 hours), glucose, lipids and renal function. LVMI was greater in PA vs both IA and EH (PA 45 ± 18, IA 39 ± 12, EH 39 ± 10 gr/m2.7, p < 0,05). Left atrial volume/BSA was significantly greater in PA vs EH (PA 27 ± 10, IA 24 ± 8, EH 23 ± 6 ml/m2, p < 0,05 for PA vs EH). A positive correlation was observed between ARR and LVMI (r = 0,20 p = 0,002), left atrium volume (r = 0,201,p < 0,001) and relative wall thickness (r = 0,394, p < 0,005). Indices of vascular damage did not differ between groups (see table). Aldosterone levels and ARR were not significantly correlated with indices of vascular damage.(Figure is included in full-text article.)
CONCLUSIONS:A greater prevalence of cardiac, but not of large arteries damage is observed in PA as compared to EH when a simultaneous assessment of cardiac and vascular OD is performed.
Background
In patients with Systemic lupus erythematosus (SLE) a greater prevalence of structural and functional cardiovascular (CV) alterations has been described, possibly explaining the higher ...incidence of CV events, as compared to subjects matched for age and sex.
Aim of this study was to analyze the presence of target organ damage in premenopausal women with SLE and in controls matched not only for demographic characteristics but also for other cardiovascular risk factors.
Subjects and methods
4 patients with SLE clinically stable(SLEDAI Score 2.5±1.5)(age 32±7years, range 19–44) and 34 controls matched for sex, age, BMI, clinic blood pressure(BP) and antihypertensive treatment(if present), underwent:24 hours BP monitoring, echocardiography with tissue Doppler analysis(TDI) for the evaluation of left ventricular(LV)structure and of systolic and diastolic function, carotid ultrasound for intima-media thickness(IMT), carotid distensibility measurement, and pulse wave velocity measurement(PWV).
Results
By definition no difference was observed for age, sex, BMI and clinic BP values and a similar Framingham risk score was observed between SLE and controls(1.3±2.7 vs 1.5±2.3%, p = ns). No significant differences were observed for all echocardiographic parameters except LV longitudinal systolic function(Sm), an early index of LV systolic dysfunction(see Table). Carotid IMT and distensibility, as well as PWV and the prevalence of an abnormal aortic stiffness were both similar in the two groups. At the logistic analysis, PWV was independently associated with LV mass in controls and with the steroid weekly dose in SLE patients.
Conclusions
In patients with SLE and low activity index of the disease we did not observe significant vascular alterations as compare to controls with similar cardiovascular risk. The early LV systolic impairment observed in this group of patients needs confirmation in larger cohorts.
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