The Effect of a Ketogenic Diet versus Mediterranean Diet on Clinical and Biochemical Markers of Inflammation in Patients with Obesity and Psoriatic Arthritis: A Randomized Crossover Trial.

The effect of different diet patterns on psoriasis (PSO) and psoriatic arthritis (PSA) is unknown. Τhe aim of our study was to evaluate the effectiveness of a Mediterranean diet (MD) and Ketogenic diet (KD), in patients with PSO and PSA. Twenty-six patients were randomly assigned to start either with MD or KD for a period of 8 weeks. After a 6-week washout interval, the two groups were crossed over to the other type of diet for 8 weeks. At the end of this study, MD and KD resulted in significant reduction in weight (p = 0.002, p < 0.001, respectively), in BMI (p = 0.006, p < 0.001, respectively), in waist circumference (WC) (p = 0.001, p < 0.001, respectively), in total fat mass (p = 0.007, p < 0.001, respectively), and in visceral fat (p = 0.01, p < 0.001, respectively), in comparison with baseline. After KD, patients displayed a significant reduction in the Psoriasis Area and Severity Index (PASI) (p = 0.04), Disease Activity Index of Psoriatic Arthritis (DAPSA) (p = 0.004), interleukin (IL)-6 (p = 0.047), IL-17 (p = 0.042), and IL-23 (p = 0.037), whereas no significant differences were observed in these markers after MD (p > 0.05), compared to baseline. The 22-week MD-KD diet program in patients with PSO and PSA led to beneficial results in markers of inflammation and disease activity, which were mainly attributed to KD.

Next-generation sequencing (NGS) profiling of matched tumor and circulating tumor DNA (ctDNA) in head and neck squamous cell carcinoma (HNSCC).

OBJECTIVES: The aim of this pilot study was to evaluate the presence of somatic mutations in matched tumor and circulating DNA (ctDNA) samples from patients with primary head and neck squamous cell carcinoma (HNSCC) and assess the association of changes in ctDNA levels with survival. MATERIALS AND METHODS: Our study included 62 patients with stage I-IVB HNSCC treated with surgery or radical chemoradiotherapy with curative intent. Plasma samples were obtained at baseline, at the end of treatment (EOT), and at disease progression. Tumor DNA was extracted from plasma (ctDNA) and tumor tissue (tDNA). The Safe Sequencing System was used assess the presence of pathogenic variants in four genes (TP53, CDKN2A, HRAS and PI3KCA) in both ctDNA and tDNA. RESULTS: Forty-five patients had available tissue and plasma samples. Concordance of genotyping results between tDNA and ctDNA at baseline was 53.3%. TP53 mutations were most commonly identified at baseline in both ctDNA (32.6%) and tDNA (40%). The presence of mutations in this restricted set of 4 genes in tissue samples at baseline was associated with decreased overall survival (OS) [median 58.3 months for patients with mutations vs. 89 months for patients without mutations, p < 0.013]. Similarly, patients presenting with mutations in ctDNA had shorter OS [median 53.8 vs. 78.6 months, p < 0.037]. CtDNA clearance at EOT did not show any association with PFS or OS. CONCLUSIONS: Liquid biopsy enables real-time molecular characterization of HNSCC and might predict survival. Larger studies are needed to validate the utility of ctDNA as a biomarker in HNSCC.

Distinct type I interferon responses between younger women and older men contribute to the variability of COVID-19 outcomes: Hypothesis generating insights from COVID-19 convalescent individuals.

BACKGROUND/OBJECTIVE: Older age and male sex have been consistently found to be associated with dismal outcomes among COVID-19 infected patients. In contrast, premenopausal females present the lowest mortality among adults infected by SARS-CoV-2. The goal of the present study was to investigate whether peripheral blood type I interferon (IFN) signature and interleukin (IL)-6 serum levels -previously shown to contribute to COVID-19-related outcomes in hospitalized patients- is shaped by demographic contributors among COVID-19 convalescent individuals. PATIENTS AND METHODS: Type I IFN-inducible genes in peripheral blood, as well as serum IL-6 levels were quantified in 61 COVID-19 convalescent healthy individuals (34 females, 27 males; age range 18-70 years, mean 35.7 ± 15.9 years) who recovered from COVID-19 without requiring hospitalization within a median of 3 months prior to inclusion in the present study. Among those, 17 were older than 50 years (11 males, 6 females) and 44 equal to or less than 50 years (16 males, 28 females). Expression analysis of type I IFN-inducible genes (MX-1, IFIT-1, IFI44) was performed by real time PCR and a type I IFN score, reflecting type I IFN peripheral activity, was calculated. IL-6 and C-reactive protein levels were determined by a commercially available ELISA. RESULTS: COVID-19 convalescent individuals older than 50 years exhibited significantly decreased peripheral blood type I IFN scores along with significantly increased IL-6 serum levels compared to their younger counterparts less than 50 years old (5.4 ± 4.3 vs 16.8 ± 24.7, p = 0.02 and 10.6 ± 16.9 vs 2.9 ± 8.0 ng/L, p = 0.03, respectively). Following sex stratification, peripheral blood type I IFN score was found to be significantly higher in younger females compared to both younger and older males (22.9 ± 29.2 vs 6.3 ± 4.6 vs 4.5 ± 3.7, p = 0.01 and p = 0.002, respectively). Regarding IL-6, an opposite pattern was observed, with the highest levels being detected among older males and the lowest levels among younger females (11.6 ± 18.9 vs 2.5 ± 7.8 ng/L, p = 0.03). CONCLUSION: Constitutive higher type I IFN responses and dampened IL-6 production observed in younger women of premenopausal age, along with lower type I IFN responses and increased IL-6 levels in older males, could account for the discrete clinical outcomes seen in the two population groups, as consistently revealed in COVID-19 epidemiological studies.

Plasma nesfatin-1 and DDP-4 levels in patients with coronary artery disease: Kozani study.

BACKGROUND: Nesfatin-1, a novel adipokine and dipeptidyl peptidase-4 (DPP4), a mam malian serine protease, are potent factors of atherosclerosis. In the present cross-sectional study, we investigated whether the plasma nesfatin-1 and DPP4 is associated with the prevalence and severity of coronary artery disease (CAD) with and without diabetes mellitus (DM). METHODS: We consecutively enrolled a total of 240 patients with significant CAD (previous revascularization or angiographically-proven coronary artery stenosis > 50%) presented with either unstable angina (UA, N = 76) or stable chronic CAD (SCAD, N = 165). 85 patients with at least 2 classical cardiovascular risk factors but without significant CAD served as controls. The severity of CAD was assessed using coronary angiography by the Gensini score. Clinical parameters, glycemic and lipid profile, high-sensitivity CRP (hsCRP), nesfatin-1 and DPP4 levels were assayed. RESULTS: No differences were found for age, sex, hypertension and diabetes distribution between groups. Low nesfatin-1 levels were found in both CAD groups (UA & SCAD) with respect to controls. The difference between UA and SCAD groups was marginally non-significant. There was a significant increase of DPP4 along UA to SCAD and control groups. Differences between groups remained unchanged in non-diabetic participants. Nesfatin-1 significantly correlated to hsCRP (r = - 0.287, p = 0.036), HOMA-IR (r = - 0.587, p = 0.007) and hyperlipidemia (r = - 0.331, p = 0.034). DPP4 was significantly associated with hs-CRP (r = 0.353 p < 0.001) and FPG (r = 0.202, p = 0.020) in univariate analysis, but those correlations were lost in multiple regression analysis. There was a negative correlation between nesfatin-1 and the severity of CAD, quantified by the Gensini score (r = - 0.511, p < 0.001), but no association was found for DPP4. CONCLUSIONS: Serum DPP4 levels are increased in patients with CAD, while serum nesfatin-1 levels have a negative association with both the incidence and the severity of CAD. These results are independent of the presence of diabetes mellitus. In addition, both peptides have a strong association with hsCRP. Trial registration ClinicalTrials.gov Identifier: NCT00306176.

Association of Glycemic Indices (Hyperglycemia, Glucose Variability, and Hypoglycemia) with Oxidative Stress and Diabetic Complications.

Oxidative stress (OS) is defined as a disturbance in the prooxidant-antioxidant balance of the cell, in favor of the former, which results in the antioxidant capacity of the cell to be overpowered. Excess reactive oxygen species (ROS) production is very harmful to cell constituents, especially proteins, lipids, and DNA, thus causing damage to the cell. Oxidative stress has been associated with a variety of pathologic conditions, including diabetes mellitus (DM), cancer, atherosclerosis, neurodegenerative diseases, rheumatoid arthritis, ischemia/reperfusion injury, obstructive sleep apnea, and accelerated aging. Regarding DM specifically, previous experimental and clinical studies have pointed to the fact that oxidative stress probably plays a major role in the pathogenesis and development of diabetic complications. It is postulated that hyperglycemia induces free radicals and impairs endogenous antioxidant defense systems through several different mechanisms. In particular, hyperglycemia promotes the creation of advanced glycation end-products (AGEs), the activation of protein kinase C (PKC), and the hyperactivity of hexosamine and sorbitol pathways, leading to the development of insulin resistance, impaired insulin secretion, and endothelial dysfunction, by inducing excessive ROS production and OS. Furthermore, glucose variability has been associated with OS as well, and recent evidence suggests that also hypoglycemia may be playing an important role in favoring diabetic vascular complications through OS, inflammation, prothrombotic events, and endothelial dysfunction. The association of these diabetic parameters (i.e., hyperglycemia, glucose variability, and hypoglycemia) with oxidative stress will be reviewed here.

Prognostic impact of indoleamine 2,3-dioxygenase 1 (IDO1) mRNA expression on circulating tumour cells of patients with head and neck squamous cell carcinoma.

BACKGROUND: We sought to determine the prognostic role of indoleamine 2,3-dioxygenase 1 (IDO1) by evaluating IDO1 expression in circulating tumour cells (CTCs) at baseline and after completion of chemoradiotherapy in patients with locally advanced (LA) head and neck squamous cell carcinoma (HNSCC) treated with curative intent. METHODS: In a prospective cohort of 113 patients with LA HNSCC, we evaluated expression of IDO1 in the EpCAM+ CTC fraction at baseline and after cisplatin chemoradiation. The prognostic value of combined programmed cell death ligand-1 (PDL-1) and IDO1 expression was assessed. RESULTS: IDO1 was significantly overexpressed at baseline compared with the post-treatment counterparts (p=0.007). IDO1 messenger RNA (mRNA) expression at baseline was associated with better survival in terms of progression-free survival (PFS) (HR=0.19, p=0.017). Post-treatment IDO1 mRNA levels were correlated with unfavourable prognosis in terms of overall survival (OS) (HR=3.27, p=0.008). Patients with combined decreased expression levels of PDL-1 and IDO1 after treatment exhibited superior PFS (p=0.043) and OS (p=0.021). CONCLUSIONS: Our results strongly suggest that IDO1 mRNA expression is an independent prognostic factor for clinical outcome. Our study provides useful information for future trials combining chemoradiation with immune checkpoint inhibitors and IDO1 inhibitors.

ß-Amyloid and mitochondrial-derived peptide-c are additive predictors of adverse outcome to high-on-treatment platelet reactivity in type 2 diabetics with revascularized coronary artery disease.

BACKGROUND AND AIMS: Increased ß-amyloid and decreased mitochondrial-derived peptide (MOTS-c), are reported in diabetes. We investigated their additive value to high on-clopidogrel platelet reactivity (HPR) for adverse outcome in type 2 diabetics after recent revascularization. PATIENTS AND METHODS: In 121 type II diabetics, treated with clopidogrel and aspirin, (93 males, mean age 67.2 years) we measured: (a) maximum platelet aggregation to adenosine diphosphate (ADP) by light transmission aggregometry (LTAmax), (b) malondialdehyde (MDA), as oxidative stress marker, (c) MOTS-c, (d) ß-amyloid blood levels. Cardiac death and acute coronary syndromes (MACE) were recorded during 2 years of follow-up. RESULTS: Out of 121 patients, 32 showed HPR (LTAmax > 48%,). At baseline, HPR was associated with ß-amyloid > 51 pg/ml (p = 0.006) after adjusting clinical variables, HbA1c, MOTS-c, MDA and medication. During follow-up, 22 patients suffered a MACE. HPR, ß-amyloid > 51 pg/ml and MOTS-c < 167 ng/ml were predictors of MACE (relative risk 3.1, 3.5 and 3.8 respectively, p < 0.05) after adjusting for confounders and medication. There was significant interaction between HPR and ß-amyloid or MOTS-c for the prediction of MACE (p < 0.05). Patients with HPR and ß-amyloid > 51 mg/dl or HPR and MOTS-c concentration < 167 ng/ml had a fourfold higher risk for MACE than patients without these predictors (relative risk 4.694 and 4.447 respectively p < 0.01). The above results were confirmed in an external validation cohort of 90 patients with diabetes and CAD. CONCLUSIONS: Increased ß-amyloid or low MOTS-c are additive predictors to high on-clopidogrel platelet reactivity for adverse outcome in diabetics with CAD during 2-years follow-up. Clinical Trial Registration-URL: https://www.clinicaltrials.gov. Unique identifier: NCT04027712.

Prognostic Significance of IGF-1 Signalling Pathway in Patients With Advanced Non-small Cell Lung Cancer.

BACKGROUND/AIM: Insulin-like growth factor 1 (IGF-1)-mediated molecular pathway has been implicated in non-small cell lung cancer (NSCLC) pathogenesis and progression. We aimed to evaluate serum levels of IGF-1, IGF-2 and IGF-binding protein 3 (IGF-BP3) before and after standard treatment in patients with advanced NSCLC and their prognostic and predictive correlations. PATIENTS AND METHODS: Seventy-three patients were prospectively included. Analysis and quantification of circulating levels of IGF1, IGF2, IGFBP3 were performed by total ELISA in peripheral blood samples at baseline and 3 months post-treatment. RESULTS: The median values of IGF-1 and IGF-1/IGF-BP3 ratios (125.82 vs. 133.4 ng/ml, p=0.087 and 0.01006 vs. 0.01252, p=0.011) were both decreased after treatment. Importantly, the post-treatment value of the ratio was significantly reduced only among responders to treatment (0.01044 from 0.01255, p=0.02). CONCLUSION: Reduction of IGF-1/IGF-BP3 ratio was statistically significant only among patients with NSCLC who responded to first-line treatment. If validated in larger cohorts, IGF-1/IGFBP3 might be a useful predictive tool for response to chemotherapy in NSCLC.

Exhaled Breath Condensate Acidification Occurs During Surgery for Abdominal Cancer.

BACKGROUND/AIM: Acidification of exhaled breath condensate (EBC), reflecting airway inflammation and oxidative stress, has been reported in lung cancer patients undergoing lobectomy. We undertook this study to examine EBC pH changes during surgery for abdominal cancer. PATIENTS AND METHODS: EBC pH was measured from 20 patients undergoing abdominal cancer resection before and during surgery. Repeated-measures of ANOVA and random-effects linear models were applied to compare mean EBC pH values in samples collected at different times. Cox and linear regression models were used to determine the association of EBC pH with occurrence of acute bronchospasm intra-operatively and the duration of hospitalization. RESULTS: Significant acidification of EBC was observed during surgery (p=0.007) associated with 0.77% (95% confidence interval=-0.14-1.68, p-value=0.097) increase in the risk for developing acute bronchospasm, after adjustment for potential confounders. CONCLUSION: EBC acidification occurs in patients undergoing abdominal cancer resection and is associated with the occurrence of acute bronchospasm intraoperatively.

Severe hyperinsulinemia, decreased GLUT3 and GLUT4 expression, and increased retinol binding protein 4 in a patient with chronic graft-versus-host disease post bone marrow transplantation.

Hyperinsulinemia with or without DM2 is a frequent long-term sequela of BMT, especially following cGvHD. In this report, an extensive evaluation of a patient with cGvHD is described: glucose and insulin during OGTT, markers of inflammation, adiponectin and RBP4, body composition analysis, and the kinetics of GLUT3 and GLUT4 in circulating monocytes were evaluated. Hyperinsulinemia, associated with partial lipodystrophy, elevated RBP4, low adiponectin levels, and decreased expression of GLUT3 and GLUT4 were detected. The defects disclosed in this particular patient possibly explain, at least in part, the mechanisms underlying insulin resistance in patients undergoing BMT. It is not clear whether insulin resistance was caused by the drugs, the process itself, or the residual damage to the muscles and/or adipose tissue.

Phosphatidylinositol 3'-kinase catalytic subunit alpha gene amplification contributes to the pathogenesis of mantle cell lymphoma.

PURPOSE: Activation of phosphatidylinositol 3'-kinase pathway is implicated in the pathogenesis of mantle cell lymphoma (MCL). The genetic change in phosphatidylinositol 3'-kinase catalytic subunit alpha (PIK3CA) in MCL has not been identified. EXPERIMENTAL DESIGN: Thirty-five primary MCL cases and 2 MCL cell lines (GRANTA-519 and Rec-1) were used to investigate somatic mutation and gene copy number of PIK3CA. Gene copy number was determined using quantitative real-time PCR and fluorescence in situ hybridization. We used quantitative real-time reverse transcription-PCR to measure PIK3CA transcription levels. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and phoshorylated AKT protein levels were analyzed using Western blotting and immunohistochemistry. Flow cytometry was used to assess apoptosis after treatment of MCL cell lines and one control cell line with LY294002, a specific inhibitor of PI3KCA. RESULTS: Fifteen of 22 (68%) MCL cases and the MCL cell lines harbored a gain (> or =3) of PIK3CA gene copy number. In addition, cases with increased PIK3CA gene copy number had elevated PIK3CA mRNA levels. Furthermore, amplification of PIK3CA correlated with the status of AKT phosphorylation in 7 of 12 (58%) primary MCL cases. Inhibition of PIK3CA induced increased apoptosis in the MCL cell lines. PTEN protein expression was present in all 14 primary MCL cases and cell lines by Western blotting, whereas 5 of 33 (15%) cases tested by immunohistochemistry had loss of PTEN expression. CONCLUSIONS: We conclude that a gain of gene copy number of PIK3CA is frequent genetic alteration that contributes to MCL progression. PIK3CA is a promising therapeutic target in MCL.