Evaluation of serum calprotectin as novel biomarker in psoriatic patients: a prospective pilot study.

BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory disease characterized by erythematous plaques that can extend along the entire skin surface. In the latest years, it has been shown that serum calprotectin correlated strongly with several inflammatory biomarkers. Since high levels of calprotectin have been found in psoriatic lesions, it is of paramount importance to investigate the role of serum calprotectin as a possible novel diagnostic marker of psoriasis. Aim of our prospective pilot study was to assess the level of serum calprotectin in psoriatic patients. METHODS: Between January 2018 and July 2019, 45 subjects were enrolled at the Dermatology Unit of Magna Graecia University of Catanzaro, Italy. Thirty-two of them were psoriatic patients and 13 healthy controls. Psoriasis severity was assessed by the Psoriasis Area Severity Index. RESULTS: A statistically significant difference between the two groups (P=0.01) was found in terms of body mass index, higher among patients than in controls. By performing the Student's t-test for unpaired data, serum calprotectin resulted significantly higher (P=0.033) among psoriatic patients than in controls. Furthermore, performing the receiver operator characteristic curve analysis, serum calprotectin showed a significant area under the curve, implying its possible role in finding psoriatic patients. Our study aimed to evaluate the serum levels of calprotectin in a group of psoriatic patients and in a control group. The results showed that serum calprotectin levels were significantly higher in the patient group than in the control group. This result confirms the observations present in the literature. CONCLUSIONS: In this pilot study psoriatic patients had a significant high level of serum calprotectin than healthy subjects, and this biomarker had high accuracy in identifying patients. Further studies, with larger sample size will need to confirm our data.

Laboratory Parameters of Hemostasis, Adhesion Molecules, and Inflammation in Type 2 Diabetes Mellitus: Correlation with Glycemic Control.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by a prothrombotic state, predisposing to vascular complications. Some related markers, linking thrombophilia to hemostasis and inflammation, however, have been poorly explored in relation to patients' glycemia. We therefore investigated the association of laboratory hemostatic parameters, circulating adhesion molecules (ADMs), white blood cell (WBC) count, and neutrophil/lymphocyte ratio (NLR) with T2DM and glycemic control. RESEARCH DESIGN: In this study, 82 subjects, grouped into T2DM patients (n = 41) and healthy individuals (n = 41) were enrolled. To evaluate glycemic control, the T2DM cohort was expanded to 133 patients and sub-classified according to glycated hemoglobin (HbA1c) <7% and ≥ 7% (n = 58 and n = 75, respectively). We assessed glycemia, HbA1c, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), platelet and leukocyte parameters, vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and selectins (E-, P-, L-). RESULTS: PT % activity, PAI-1, VCAM-1, WBC, and neutrophil counts were significantly higher in T2DM patients than in healthy subjects. Poor glycemic control (HbA1c ≥ 7%) was correlated with increased PT activity (p = 0.015), and higher levels of E-selectin (p = 0.009), P-selectin (p = 0.012), and NLR (p = 0.019). CONCLUSIONS: Both T2DM and poor glycemic control affect some parameters of hemostasis, inflammation, and adhesion molecules. Further studies are needed to establish their clinical utility as adjuvant markers for cardio-vascular risk in T2DM patients.

Accumulation of Circulating CCR7+ Natural Killer Cells Marks Melanoma Evolution and Reveals a CCL19-Dependent Metastatic Pathway.

Immune checkpoint blockade therapy has changed prognoses for many melanoma patients. However, immune responses that correlate with clinical progression of the disease are still poorly understood. To identify immune responses correlating with melanoma clinical evolution, we analyzed serum cytokines as well as circulating NK and T-cell subpopulations from melanoma patients. The patients' immune profiles suggested that melanoma progression leads to changes in peripheral blood NK and T-cell subsets. Stage IV melanoma was characterized by an increased frequency of CCR7+CD56bright NK cells as well as high serum concentrations of the CCR7 ligand CCL19. CCR7 expression and CCL19 secretion were also observed in melanoma cell lines. The CCR7+ melanoma cell subpopulation coexpressed PD-L1 and Galectin-9 and had stemness properties. Analysis of melanoma-derived cancer stem cells (CSC) showed high CCR7 expression; these CSCs were efficiently recognized and killed by NK cells. An accumulation of CCR7+, PD-L1+, and Galectin-9+ melanoma cells in melanoma metastases was demonstrated ex vivo Altogether, our data identify biomarkers that may mark a CCR7-driven metastatic melanoma pathway.

Iron and Ferritin Modulate MHC Class I Expression and NK Cell Recognition.

The ability of pathogens to sequester iron from their host cells and proteins affects their virulence. Moreover, iron is required for various innate host defense mechanisms as well as for acquired immune responses. Therefore, intracellular iron concentration may influence the interplay between pathogens and immune system. Here, we investigated whether changes in iron concentrations and intracellular ferritin heavy chain (FTH) abundance may modulate the expression of Major Histocompatibility Complex molecules (MHC), and susceptibility to Natural Killer (NK) cell cytotoxicity. FTH downregulation, either by shRNA transfection or iron chelation, led to MHC surface reduction in primary cancer cells and macrophages. On the contrary, mouse embryonic fibroblasts (MEFs) from NCOA4 null mice accumulated FTH for ferritinophagy impairment and displayed MHC class I cell surface overexpression. Low iron concentration, but not FTH, interfered with IFN-γ receptor signaling, preventing the increase of MHC-class I molecules on the membrane by obstructing STAT1 phosphorylation and nuclear translocation. Finally, iron depletion and FTH downregulation increased the target susceptibility of both primary cancer cells and macrophages to NK cell recognition. In conclusion, the reduction of iron and FTH may influence the expression of MHC class I molecules leading to NK cells activation.

IL-1 inhibition improves insulin resistance and adipokines in rheumatoid arthritis patients with comorbid type 2 diabetes: An observational study.

Recently, it has been shown that some well-known pathogenic mediators in rheumatoid arthritis (RA), such as interleukin-1ß (IL-1ß) and tumor necrosis factor (TNF), could play a pathogenic role in insulin resistance and (IR) and type 2 diabetes (T2D).In this 6-month longitudinal study, we aimed at investigating if the inhibition of IL-1 or TNF is associated with an improvement of IR in RA patients with comorbid T2D and the possible effects on selected serum adipokines. RA patients with comorbid T2D were recruited among those undergoing treatment with anakinra (ANA) or with TNF inhibitor (TNFi). The 1998-updated version of the Homeostasis Model Assessment (HOMA2) was used to calculate surrogate indexes of IR (HOMA2-IR) and steady-state beta cell function (%B) from fasting values of glucose and C-peptide. Glucagon, adiponectin, adipsin, leptin, and resistin were also measured. All these parameters were collected at baseline, after 3 and 6 months of treatment.ANA-treated patients showed a significant improvement in HOMA2-%ß, HOMA2-IR, and glucagon. In TNFi-treated patients, no significant difference was observed analyzing these metabolic parameters. Adipsin and resistin decreased after 6 months in ANA-treated patients whereas, no difference was recognized analyzing adiponectin and leptin. In TNFi-treated patients, leptin and resistin significantly increased, whereas no difference was found analyzing adiponectin and adipsin, during the follow-up.Our data may suggest a beneficial effect of IL-1 inhibition on measures of metabolic derangement in RA-associated T2D. If further confirmed by larger studies, IL-1 targeting therapies may represent a tailored approach in these patients.

Evolution of glomerular filtration rates and neutrophil gelatinase-associated lipocalin during treatment with direct acting antivirals.

Background/Aims: Correct renal function evaluation is based on estimated glomerular filtration rates (eGFR) and complementary renal damage biomarkers, such as neutrophil gelatinase associated lipocalin (NGAL). The aim of this study was to evaluate eGFR and NGAL modifications and renal impairment during treatment with a direct acting antiviral (DAA) for chronic hepatitis C virus (HCV) infection. METHODS: A retrospective cohort study evaluated eGFR modification during treatment with DAA. Subgroup analysis on serum NGAL was conducted in those receiving sofosbuvir/ledipasvir, with complete follow-up until week 12 after the end of treatment (FU-12). RESULTS: In the 102 enrolled patients, eGFR reduction was observed (from 86.22 mL/min at baseline to 84.43 mL/min at FU-12, P=0.049). Mean NGAL increased in 18 patients (from 121.89 ng/mL at baseline to 204.13 ng/mL at FU-12, P=0.014). At FU-12, 38.8% (7/18) of patients had a plasmatic NGAL value higher than the normal range (36-203 ng/mL) compared with 11.1% (2/18) at baseline (χ 2 =3,704; P=0.054). In contrast, eGFR did not change significantly over the follow-up in this subgroup. Conclusions: In conclusion, compared to a negligible eGFR decline observed in the entire cohort analyzed, a significant NGAL increase was observed after HCV treatment with DAA in a small subgroup. This could reflect tubular damage during DAA treatment rather than glomerular injury.

Effect of Mediterranean Diet and Antioxidant Formulation in Non-Alcoholic Fatty Liver Disease: A Randomized Study.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, characterized by liver fatty acid accumulation and fibrosis, not due to excessive alcohol consumption. Notably, nutritional habits have been reported to be implicated in the onset and severity of the hepatic damage, while the Mediterranean diet has shown beneficial effects on NAFLD. Free radicals and oxidative stress were suggested to be involved in the pathogenesis and progression of NAFLD, and several data highlighted the efficacy of antioxidant supplementation in its treatment. The aim of this study was to compare the effects of the Mediterranean diet, with or without an antioxidant complex supplement, in overweight patients suffering from NAFLD. In this prospective study, fifty Caucasian overweight patients were randomized into three groups (Groups A-C). A personalized moderately hypocaloric Mediterranean diet was prescribed to all patients included in the A and B groups. In addition to the diet, Group B was administered antioxidant supplementation daily and for the period of six months. Group C did not have any type of treatment. The study proved that the Mediterranean diet alone or in association with the antioxidant complex improved anthropometric parameters, lipid profile and reduced hepatic fat accumulation and liver stiffness. However, Group B patients, in which the diet was associated with antioxidant intake, showed not only a significant improvement in insulin sensitivity, but also a more consistent reduction of anthropometric parameters when compared with Group A patients. Taken together, these results support the benefit of antioxidant supplementation in overweight patients with NAFLD.

Effects of acute physical exercise on oxidative stress and inflammatory status in young, sedentary obese subjects.

Circulating oxidative stress and pro-inflammatory markers change after regular physical exercise; however, how a short session of acute physical activity affects the inflammatory status and redox balance in sedentary individuals is still unclear. Aim of this study is to assess antioxidant and inflammatory parameters, both at rest and after acute exercise, in sedentary young men with or without obesity. Thirty sedentary male volunteers, aged 20-45 (mean age 32 ± 7 years), were recruited, divided into 3 groups (normal weight: BMI < 25 kg/m2; overweight to moderate obesity: 25-35 kg/m2; severe obesity: 35-40 kg/m2), and their blood samples collected before and after a 20-min run at ~ 70% of their VO2max for the measurement of Glutathione Reductase, Glutathione Peroxidase, Superoxide Dismutase, Total Antioxidant Status (TAS) and cytokines (IL-2, IL-4, IL-6, IL-8, IL-10, IL-1α, IL-1ß, TNFα, MCP-1, VEGF, IFNγ, EGF). Inter-group comparisons demonstrated significantly higher Glutathione Reductase activity in severely obese subjects in the post-exercise period (P = 0.036), and higher EGF levels in normal weight individuals, either before (P = 0.003) and after exercise (P = 0.05). Intra-group comparisons showed that the acute exercise stress induced a significant increase in Glutathione Reductase activity in severely obese subjects only (P = 0.007), a significant decrease in MCP-1 in the normal weight group (P = 0.02), and a decrease in EGF levels in all groups (normal weight: P = 0.025, overweight/moderate obesity: P = 0.04, severe obesity: P = 0.018). Altogether, these findings suggest that in sedentary individuals with different ranges of BMI, Glutathione Reductase and distinct cytokines are differentially involved into the adaptive metabolic changes and redox responses induced by physical exercise. Therefore, these biomarkers may have the potential to identify individuals at higher risk for developing diseases pathophysiologically linked to oxidative stress.

Impact of legumes and plant proteins consumption on cognitive performances in the elderly.

BACKGROUND: Numerous studies have investigated the role of the dietary factors in the prevention of cognitive decline but the short-term effects of foods choice on cognitive performances in the elderly are poorly explored. Our aim was to investigate the choice of foods among elderly Italian individuals and the association with cognitive function. METHODS: In this longitudinal study, the participants were 214 individuals aged ≥65 years with a score >20 at the Mini Mental State Examination. The cognitive sub-test of ADAScale was used to detect cognitive decline progression over 12 months. Food choices was measured by a combination of a 24-h recall and a seven-day diet record and Principal Components Analysis. RESULTS: The Principal Components Analysis identified four food and four nutrient patterns. MMSE and ADAS-cog score after 1 year were found to be associated with legumes pattern (B = 0.25, p = 0.007; 95% CI 0.07/0.44; and B = -0.10, p = 0.006; CI -0.79/-0.30, respectively). A dietary pattern including plant proteins was independently associated with an improved ADAS-cog after 1 year (B = 0.584, p = 0.04; OR 1.79, CI 0.04-0.42). CONCLUSIONS: The Principal Components Analysis is useful to investigate the choice of foods and nutrients in the elderly. We demonstrated an association between legumes pattern with cognitive performances.

Oleuropein Decreases Cyclooxygenase-2 and Interleukin-17 Expression and Attenuates Inflammatory Damage in Colonic Samples from Ulcerative Colitis Patients.

Oleuropein (OLE) is the major phenolic secoiridoid of olive tree leaves, and its antioxidant and anti-inflammatory activities have been demonstrated in in vitro and in vivo animal models. The aim of this study was to investigate the activity of OLE in the colonic mucosa from patients with ulcerative colitis (UC). Biopsies obtained during colonoscopy from 14 patients with active UC were immediately placed in an organ culture chamber and challenged with lipopolysaccharide from Escherichia coli (EC-LPS) at 1 µg/mL in the presence or absence of 3 mM OLE. The expression of cyclooxygenase (COX)-2 and interleukin (IL)-17 was assessed in total protein extracts from treated colonic biopsies by Western blotting. Levels of IL-17 were also measured in culture supernatant by ELISA. A microscopic evaluation of the cultured biopsies was performed by conventional histology and immunohistochemistry. The expression of COX-2 and IL-17 were significantly lower in samples treated with OLE + EC-LPS compared with those treated with EC-LPS alone (0.80 ± 0.15 arbitrary units (a.u.) vs. 1.06 ± 0.19 a.u., p = 0.003, and 0.71 ± 0.08 a.u. vs. 1.26 ± 0.42 a.u., p = 0.03, respectively) as were the levels of IL-17 in culture supernatants of OLE + EC-LPS treated colonic samples (21.16 ± 8.64 pg/mL vs. 40.67 ± 9.24 pg/mL, p = 0.01). Histologically, OLE-treated colonic samples showed an amelioration of inflammatory damage with reduced infiltration of CD3, CD4, and CD20 cells, while CD68 numbers increased. The anti-inflammatory activity of OLE was demonstrated in colonic biopsies from UC patients. These new data support a potential role of OLE in the treatment of UC.

IL-15, TIM-3 and NK cells subsets predict responsiveness to anti-CTLA-4 treatment in melanoma patients.

Despite the success of immune checkpoint blockade in melanoma, the majority of patients do not respond. We hypothesized that the T and NK cell subset frequencies and expression levels of their receptors may predict responses and clinical outcome of anti-CTLA-4 treatment. We thus characterized the NK and T cell phenotype, as well as serum levels of several cytokines in 67 melanoma patients recruited in Italy and Sweden, using samples drawn prior to and during treatment. Survival correlated with low expression of the inhibitory receptor TIM-3 on circulating T and NK cells prior to and during treatment and with the increased frequency of mature circulating NK cells (defined as CD3-CD56dim CD16+) during treatment. Survival also correlated with low levels of IL-15 in the serum. Functional experiments in vitro demonstrated that sustained exposure to IL-15 enhanced the expression of PD-1 and TIM-3 on both T and NK cells, indicating a causative link between high IL-15 levels and enhanced expression of TIM-3 on these cells. Receptor blockade of TIM-3 improved NK cell-mediated elimination of melanoma metastasis cell lines in vitro. These observations may lead to the development of novel biomarkers to predict patient response to checkpoint blockade treatment. They also suggest that induction of additional checkpoints is a possibility that needs to be considered when treating melanoma patients with IL-15.

Dietary Patterns and Fractures Risk in the Elderly.

PURPOSE: Although the role of dietary factors in the prevention of bone loss and fractures has been investigated in many studies, few studies have examined the association between dietary patterns and total body bone density. Our aim was to determine the relations between dietary patterns and whole-body bone mineral density (WB-BMD) and the association between dietary patterns, fractures, and multiple fractures in the elderly. METHODS: This cross-sectional study included 177 individuals aged ≥65 years. A dual X-ray absorptiometry scan was performed to measure BMD. Dietary patterns were ascertained by a combination of dietary intake assessment and principal components analysis. RESULTS: Only three dietary patterns correlated with whole-body bone density. The multivariate-adjusted mean bone density across tertiles of these dietary patterns showed that the highest tertile of both the patterns 1 and 2 had a significantly higher bone density than the lowest tertile (pattern 1: 1.021 ± 0.01 and 1.070 ± 0.01 g/cm2 for T1 and T3, respectively; p = 0.043; pattern 2: 1.023 ± 0.01, and 1.081 ± 0.01 g/cm2 for T1 and T3, respectively; p = 0.003). We also find significant gender difference in these results. The highest adherence to the dietary pattern 5 was associated with decreased odds of having fractures (OR = 0.20, p = 0.009), and adherence to the pattern 1 was negatively associated with multiple fractures. CONCLUSION: A high adherence to the dietary pattern 1 (high intake of grains, fish and olive oil) was associated with a high BMD and a low number of fractures. The highest adherence to the dietary pattern 5 (legumes and wine) was associated with decreased odds of having fractures. Our finding would suggest a potential bone-preserving properties of specific dietary patterns in the elderly.

How to improve duration and efficiency of the antiproteinuric response to Ramipril: RamiPROT-a prospective cohort study.

BACKGROUND: The antiproteinuric pharmacokinetics of Ramipril in response to different doses and modalities of administration has been poorly investigated so far. STUDY DESIGN: Prospective, open-label and not placebo controlled study. SETTING AND PARTICIPANTS: 40 Caucasian adult patients having GFR ≥ 50 mL/min, proteinuria 1-3 g/day; SBP/DBP ≤ 150/90 mmHg were recruited between June 2014 and November 2014. FACTOR AND OUTCOME: Impact on 24 h proteinuria and fractioned proteinuria of Ramipril given at different dosages (2.5 mg/day or Ramipril 5 mg/day or Ramipril 10 mg/day) and with different daily administration modalities (single or two divided doses) for cycles of 10 days. MEASUREMENTS: At the end of each cycle, 24 h and fractioned proteinuria on three timed urinary collections (morning, afternoon and night) were measured. RESULTS: Compared to baseline, Ramipril significantly reduced 24 h proteinuria at each dose and modality of administration. In particular, the greatest effects were evident with the higher and divided dose of the drug. The analysis of the fractioned proteinuria showed that the greatest reduction was obtained in the night urinary collection by administering Ramipril 10 mg/day in two divided doses. LIMITATIONS: Small sample size. CONCLUSIONS: Ramipril reduces proteinuria at any of the tested doses. Although the using of high and divided doses seems to maximize the antiproteinuric effect of the drug, possibly due to a better pharmacological coverage of the nocturnal period.

A polymorphism of HMGA1 protects against proliferative diabetic retinopathy by impairing HMGA1-induced VEGFA expression.

Diabetic retinopathy (DR) is a major complication of diabetes mellitus, and is the leading cause of blindness in working-age people. Usually, DR progresses from the asymptomatic non-proliferative DR that does not significantly alter vision, to proliferative DR (PDR), which can result in aberrant retinal neovessel formation and blindness. The High-Mobility-Group A1 (HMGA1) protein is a transcriptional master regulator of numerous genes, including metabolic and inflammatory genes, which, by modulating the expression of angiogenic factors, may induce retinal neovascularization, a hallmark of PDR. Herein, we examined the relationship between HMGA1 rs139876191 variant and DR. Results revealed that patients with type 2 diabetes, who were carriers of the HMGA1 rs139876191 variant had a significantly lower risk of developing PDR, compared to non-carrier diabetic patients. From a mechanistic point of view, our findings indicated that, by adversely affecting HMGA1 protein expression and function, the HMGA1 rs139876191 variant played a key role in this protective mechanism by downregulating the expression of vascular endothelial growth factor A (VEGFA), a major activator of neovascularization in DR. These data provide new insights into the pathogenesis and progression of DR, and may offer opportunities for discovering novel biomarkers and therapeutic targets for diagnosis, prevention and treatment of PDR.

Is neutrophil gelatinase associated lipocalin useful in hepatitis C virus infection?

AIM: To evaluate neutrophil gelatinase associated lipocalin (NGAL) in patients infected by hepatitis C virus (HCV) before and during treatment with directly acting antivirals (DAAs). METHODS: NGAL was measured in a group of patients with chronic HCV infection ranked, at baseline, by age, gender, anti-hypertensive therapy, HCV viral load, liver fibrosis stage and, either at baseline or after 1 year, estimated glomerular filtration rate (eGFR). Then, NGAL and eGFR evolutions were monitored in a subgroup of patients who started antiviral therapy with DAAs. Differences of median NGAL levels were evaluated through Wilcoxon-Mann-Whitney test for non-parametric data. Differences in dichotomous variables were evaluated through χ (2) test. At baseline, a univariate regression analysis was conducted to verify if NGAL values correlated with other quantitative variables [age, fibrosis four (FIB-4), AST to platelet ratio index (APRI), and eGFR]. RESULTS: Overall, 48 patients were enrolled, 8 of them starting HCV treatment. At baseline, statistically significant differences were found in median NGAL values only between patients with eGFR < 60 mL/min vs patients with eGFR ≥ 90 mL/min. Differences in NGAL were not significant among patients ranked by HCV viral load, FIB-4 score and APRI, when patients with NGAL > 118.11 ng/dL were compared with those of NGAL ≤ 118.11 ng/dL, not statistically significant differences were present for age, gender, chronic kidney disease classification and liver fibrosis (P > 0.05). Linear correlation was found between NGAL and both age (P = 0.0475) and eGFR (P = 0.0282) values. Not statistically significant predictions of NGAL at baseline were demonstrated for eGFR evolution 1 year later. Interestingly, in the 8 patients treated with DAAs, median NGAL significantly increased at week 12 compared to baseline (P = 0.0239). CONCLUSION: Our results suggest that NGAL should be further evaluated as an adjunct marker of kidney function in these patients.

The correct renal function evaluation in patients with thyroid dysfunction.

Thyroid dysfunction induces several renal derangements involving all nephron portions. Furthermore, dysthyroidism is a recognized risk factor associated with the development of chronic kidney disease. Current data, in fact, demonstrate that either subclinical or overt thyroid disease is associated with significant changes in creatinine, estimated glomerular filtration rate, measured glomerular filtration rate and Cystatin C. Herein, we systematically reviewed several relevant studies aiming at the identification of the most sensitive and specific parameter for the correct renal function evaluation in patients with thyroid dysfunction, that are usually treated as outpatients. Our systematic review indicates that estimated glomerular filtration rate, preferably with CKD-EPI equation, appears to be the most reliable and wieldy renal function parameter. Instead, Cystatin C should be better used in the grading of thyroid dysfunction severity.

The Akt1/IL-6/STAT3 pathway regulates growth of lung tumor initiating cells.

Here we report that the PI3K/Akt1/IL-6/STAT3 signalling pathway regulates generation and stem cell-like properties of Non-Small Cell Lung Cancer (NSCLC) tumor initiating cells (TICs). Mutant Akt1, mutant PIK3CA or PTEN loss enhances formation of lung cancer spheroids (LCS), self-renewal, expression of stemness markers and tumorigenic potential of human immortalized bronchial cells (BEAS-2B) whereas Akt inhibition suppresses these activities in established (NCI-H460) and primary NSCLC cells. Matched microarray analysis of Akt1-interfered cells and LCSs identified IL-6 as a critical target of Akt signalling in NSCLC TICs. Accordingly, suppression of Akt in NSCLC cells decreases IL-6 levels, phosphorylation of IkK and IkB, NF-kB transcriptional activity, phosphorylation and transcriptional activity of STAT3 whereas active Akt1 up-regulates them. Exposure of LCSs isolated from NSCLC cells to blocking anti-IL-6 mAbs, shRNA to IL-6 receptor or to STAT3 markedly reduces the capability to generate LCSs, to self-renew and to form tumors, whereas administration of IL-6 to Akt-interfered cells restores the capability to generate LCSs. Finally, immunohistochemical studies in NSCLC patients demonstrated a positive correlative trend between activated Akt, IL-6 expression and STAT3 phosphorylation (n = 94; p < 0.05). In conclusion, our data indicate that aberrant Akt signalling contributes to maintaining stemness in lung cancer TICs through a NF-kB/IL-6/STAT3 pathway and provide novel potential therapeutic targets for eliminating these malignant cells in NSCLC.

High Vegetable Fats Intake Is Associated with High Resting Energy Expenditure in Vegetarians.

It has been demonstrated that a vegetarian diet may be effective in reducing body weight, however, the underlying mechanisms are not entirely clear. We investigated whether there is a difference in resting energy expenditure between 26 vegetarians and 26 non-vegetarians and the correlation between some nutritional factors and inflammatory markers with resting energy expenditure. In this cross-sectional study, vegetarians and non-vegetarians were matched by age, body mass index and gender. All underwent instrumental examinations to assess the difference in body composition, nutrient intake and resting energy expenditure. Biochemical analyses and 12 different cytokines and growth factors were measured as an index of inflammatory state. A higher resting energy expenditure was found in vegetarians than in non-vegetarians (p = 0.008). Furthermore, a higher energy from diet, fibre, vegetable fats intake and interleukin-ß (IL-1ß) was found between the groups. In the univariate and multivariable analysis, resting energy expenditure was associated with vegetarian diet, free-fat mass and vegetable fats (p < 0.001; Slope in statistic (B) = 4.8; ß = 0.42). After adjustment for cytokines, log10 interleukin-10 (IL-10) still correlated with resting energy expenditure (p = 0.02). Resting energy expenditure was positively correlated with a specific component of the vegetarian's diet, i.e., vegetable fats. Furthermore, we showed that IL-10 was positively associated with resting energy expenditure in this population.

OvAge: a new methodology to quantify ovarian reserve combining clinical, biochemical and 3D-ultrasonographic parameters.

BACKGROUND: In the last decade, both endocrine and ultrasound data have been tested to verify their usefulness for assessing ovarian reserve, but the ideal marker does not yet exist. The purpose of this study was to find, if any, a statistical advanced model able to identify a simple, easy to understand and intuitive modality for defining ovarian age by combining clinical, biochemical and 3D-ultrasonographic data. METHODS: This is a population-based observational study. From January 2012 to March 2014, we enrolled 652 healthy fertile women, 29 patients with clinical suspect of premature ovarian insufficiency (POI) and 29 patients with Polycystic Ovary syndrome (PCOS) at the Unit of Obstetrics & Gynecology of Magna Graecia University of Catanzaro (Italy). In all women we measured Anti Müllerian Hormone (AMH), Follicle Stimulating Hormone (FSH), Estradiol (E2), 3D Antral Follicle Count (AFC), ovarian volume, Vascular Index (VI) and Flow Index (FI) between days 1 and 4 of menstrual cycle. We applied the Generalized Linear Models (GzLM) for producing an equation combining these data to provide a ready to use information about women ovarian reserve, here called OvAge. To introduce this new variable, expression of ovarian reserve, we assumed that in healthy fertile women ovarian age is identical to chronological age. RESULTS: GzLM applied on the healthy fertile controls dataset produced the following equation OvAge = 48.05 - 3.14*AHM + 0.07*FSH - 0.77*AFC - 0.11*FI + 0.25*VI + 0.1*AMH*AFC + 0.02*FSH*AFC. This model showed a high statistical significance for each marker included in the equation. We applied the final equation on POI and PCOS datasets to test its ability of discovering significant deviation from normality and we obtained a mean of predicted ovarian age significantly different from the mean of chronological age in both groups. CONCLUSIONS: OvAge is one of the first reliable attempt to create a new method able to identify a simple, easy to understand and intuitive modality for defining ovarian reserve by combining clinical, biochemical and 3D-ultrasonographic data. Although design data prove a statistical high accuracy of the model, we are going to plan a clinical validation of model reliability in predicting reproductive prognosis and distance to menopause.

[Is it feasible to improve the duration and the efficiency of Ramipril anti-proteinuric response?]. / È possibile migliorare la durata e l'efficacia della risposta anti-proteinurica di Ramipril?

BACKGROUND: Ramipril administered once daily is characterized by an attenuation of its pharmacological activity in the following 24 hours, whose effects on antiproteinuric activity have not yet been investigated. METHODS: The antiproteinuric efficacy of Ramipril has been evaluated in a cross-over study in 20 patients with renal disease, proteinuria and hypertension (GFR50 mL / min, proteinuria <3 g / day; SBP/DBP 150/90 mmHg). Proteinuria was measured over 24 hours on three consecutive urine collections (morning, afternoon and night) in the absence of antiproteinuric drugs and after ten days of treatment with single morning administration of Ramipril 2.5 mg or Ramipril 10 mg. RESULTS: At baseline: mean proteinuria was not significantlychanged over the course of the three urinary collections (88 7.2 mg/h in the morning of 80 10.5 mg/h in the afternoon and 81 10.1 mg/hr during the night). After Ramipril 2.5 mg/day: slight reduction in mean proteinuria, with no significant differences between collections (80 11 mg/h in the morning, 69 7.4 mg/h in the afternoon and 75 9.1 mg/h during the night). After Ramipril 10 mg/day: afternoon and night values of proteinuria were significantly reduced compared to baseline; noctural proteinuria was significantly lower than morning value (51 7.5 mg/h vs. 81 10 mg/h, p <0.05). CONCLUSION: The antiproteinuric effectiveness of Ramipril tends to decrease significantly over the 24hours after a single daily administration. An increase and/or division of Ramipril dose might help to stabilize and to maximizeits antiproteinuric effectiveness.