Short fractionation radiotherapy for early prostate cancer in the time of COVID-19: long-term excellent outcomes from a multicenter Italian trial suggest a larger adoption in clinical practice

Abstract Introduction: To evaluate stereotactic body radiotherapy (SBRT) in low-risk Prostate Cancer patients as preferred treatment option in emergency health conditions. Materials and methods: From April 2013 to September 2015, 28 patients with low-risk prostate cancer were prospectively enrolled. The SBRT prescribed dose was 36.25 Gy in 5 fractions, twice a week. Primary endpoints were acute and late toxicity. Secondary endpoints were biochemical recurrence free survival (bRFS) and overall survival. Results: Median follow-up was 65.5 months (range 52-81). No acute G3 or G4 toxicity was recorded. Acute G1 or G2 genitourinary (GU) toxicity occurred in 43% and acute G1-G2 gastrointestinal (GI) toxicity in 14%. Late G1 and G3 GU toxicity in 18% and 3.5%, respectively. The G3 toxicity was not directly attributable to radiotherapy. Late G1 GI toxicity occurred in 18%. 5yy bRFS was 96.5% (95% CI 82.3-99.4%). Conclusions: Stereotactic body radiotherapy for early prostate cancer reported safe toxicity profile and a good clinical outcome at the median follow-up of 5 years. It may be an useful option if radiotherapy is required in emergency medical conditions

High-Fat Diet with Acyl-Ghrelin Treatment Leads to Weight Gain with Low Inflammation, High Oxidative Capacity and Normal Triglycerides in Rat Muscle

Obesity is associated with muscle lipid accumulation. Experimental models suggest that inflammatory cytokines, low mitochondrial oxidative capacity and paradoxically high insulin signaling activation favor this alteration. The gastric orexigenic hormone acylated ghrelin (A-Ghr) has antiinflammatory effects in vitro and it lowers muscle triglycerides while modulating mitochondrial oxidative capacity in lean rodents. We tested the hypothesis that A-Ghr treatment in high-fat feeding results in a model of weight gain characterized by low muscle inflammation and triglycerides with high muscle mitochondrial oxidative capacity. A-Ghr at a non-orexigenic dose (HFG: twice-daily 200-µg s.c.) or saline (HF) were administered for 4 days to rats fed a high-fat diet for one month. Compared to lean control (C) HF had higher body weight and plasma free fatty acids (FFA), and HFG partially prevented FFA elevation (P<0.05). HFG also had the lowest muscle inflammation (nuclear NFkB, tissue TNF-alpha) with mitochondrial enzyme activities higher than C (P<0.05 vs C, P = NS vs HF). Under these conditions HFG prevented the HF-associated muscle triglyceride accumulation (P<0.05). The above effects were independent of changes in redox state (total-oxidized glutathione, glutathione peroxidase activity) and were not associated with changes in phosphorylation of AKT and selected AKT targets. Ghrelin administration following high-fat feeding results in a novel model of weight gain with low inflammation, high mitochondrial enzyme activities and normalized triglycerides in skeletal muscle. These effects are independent of changes in tissue redox state and insulin signaling, and they suggest a potential positive metabolic impact of ghrelin in fat-induced obesity

Severe Asthma, Telemedicine, and Self-Administered Therapy: Listening First to the Patient

: Severe asthma patients are at an increased risk of major complications and they need to be monitored regularly. The COVID-19 pandemic has notably impacted on the health care resources. The telemedicine approach applied to the follow-up of asthmatic patients has been proven to be effective in monitoring their disease and their adherence to the therapy. The aim of our study was to investigate the satisfaction of severe asthma patients before the activation of a telemedicine management, as well as their current experience with self-administration of injection therapy. An ad hoc questionnaire was developed and sent by e-mail to 180 severe asthma patients. Most of subjects, 82%, were confident with the idea of doing self-measurements and self-managing their disease. Further, 77% of subjects favoured to carry out virtual visits and telemedicine. Regarding the home treatment, 93% of patients considered the self-injection therapy easy, 94% of subjects felt safe, and 93% were not worried while self-administering. Only mild adverse events were reported in 22% of patients after self-administration. Our results showed an agreement between what is considered necessary and practicable by healthcare personnel and what is perceived by the severe asthma patients in terms of treatment and monitoring of the disease with Telehealth. Biologics have a safety profile and can be easily self-administred at home

Serum biomarkers of remodeling in severe asthma with fixed airway obstruction and the potential role of KL-6

Over 3% of asthmatic patients are affected by a particularly severe form of the disease ("severe asthma", SA) which is often refractory to standard treatment. Airway remodeling (AR), which can be considered a critical characteristic of approximately half of all patients with SA and currently thought to be the main mechanism triggering fixed airway obstruction (FAO), seems to be a key factor affecting a patient's outcome. Despite the collective efforts of internationally renowned experts, to date only a few biomarkers indicative of AR and no recognizable biomarkers of lung parenchymal remodeling have been identified. This work examines the pathogenesis of airway and lung parenchymal remodeling and the serum biomarkers that may be able to identify the severe asthmatic patients who may develop FAO. The study also aims to examine if Krebs von den Lungen-6 (KL-6) could be considered a diagnostic biomarker of lung structural damage in SA

Correlation between α1-Antitrypsin Deficiency and SARS-CoV-2 Infection: Epidemiological Data and Pathogenetic Hypotheses

: The most common hereditary disorder in adults, α1-antitrypsin deficiency (AATD), is characterized by reduced plasma levels or the abnormal functioning of α1-antitrypsin (AAT), a major human blood serine protease inhibitor, which is encoded by the SERine Protein INhibitor-A1 (SERPINA1) gene and produced in the liver. Recently, it has been hypothesized that the geographic differences in COVID-19 infection and fatality rates may be partially explained by ethnic differences in SERPINA1 allele frequencies. In our review, we examined epidemiological data on the correlation between the distribution of AATD, SARS-CoV-2 infection, and COVID-19 mortality rates. Moreover, we described shared pathogenetic pathways that may provide a theoretical basis for our epidemiological findings. We also considered the potential use of AAT augmentation therapy in patients with COVID-19

Grape seed extract triggers apoptosis in Caco-2 human colon cancer cells through reactive oxygen species and calcium increase: Extracellular signal-regulated kinase involvement

Grape seed extract (GSE) from Italia, Palieri and Red Globe cultivars inhibits cell growth and induces apoptosis in Caco-2 human colon cancer cells in a dose-dependent manner. In order to investigate the mechanism(s) supporting the apoptotic process, we analysed reactive oxygen species (ROS) production, intracellular Ca2+ handling and extracellular signal-regulated kinase (ERK) activation. Upon exposure to GSE, ROS and intracellular Ca2+ levels increased in Caco-2 cells, concomitantly with ERK inactivation. As ERK activity is thought to be essential for promoting survival pathways, inhibition of this kinase is likely to play a relevant role in GSE-mediated anticancer effects. Indeed, pretreatment with N-acetyl cysteine, a ROS scavenger, reversed GSE-induced apoptosis, and promoted ERK phosphorylation. This effect was strengthened by ethylene glycol tetraacetic acid-mediated inhibition of extracellular Ca2+ influx. ROS and Ca2+ influx inhibition, in turn, increased ERK phosphorylation, and hence almost entirely suppressed GSE-mediated apoptosis. These data suggested that GSE triggers a previously unrecognised ERK-based mechanism, involving both ROS production and intracellular Ca2+ increase, eventually leading to apoptosis in cancer cells

Insulin downregulates SIRT1 and AMPK activation and is associated with changes in liver fat, but not in inflammation and mitochondrial oxidative capacity, in streptozotocin-diabetic rat.

11Involvement of insulin in diabetes-associated liver triglyceride deposition and its potential pathways remain incompletely defined. SIRT1 may negatively modulate lipogenesis and liver triglyceride accumulation, involving AMP-activated protein kinase (AMPK) activation. In streptozotocin-diabetic rats, we hypothesized that insulin negatively modulates liver SIRT1 and activates AMPK-inhibited lipogenic mediators leading to triglyceride accumulation. The impact of insulin deprivation (INS-) and replacement (INS+) on liver inflammation and mitochondrial oxidative capacity (also potentially regulating triglyceride deposition) was also measured.Streptozotocin-diabetic rats under chronic (8-week) INS- and INS+.Compared to INS- (P < 0.05), INS+ had low liver SIRT1 with low AMPK activating phosphorylation, low inactivating phosphorylation of its lipogenic target acetyl-CoA carboxylase and high tissue triglycerides. INS- (P < 0.05 vs Control) had liver inflammation and high mitochondrial oxidative capacity, but neither was modulated by INS+. Pair-feeding showed no influence of spontaneous overeating on insulin-induced changes.Insulin replacement downregulates SIRT1 and AMPK activation in vivo in streptozotocin-diabetic rat liver, likely contributing to insulin-induced liver triglyceride accumulation. Under the current experimental conditions, insulin-deprived diabetes is associated with liver inflammation and high mitochondrial oxidative capacity, that are not affected by insulin replacement and are therefore unlikely to contribute to tissue triglyceride changes in this model.nonemixedBarazzoni, R.; Zanetti, M.; Sturnega, M.; Stebel, M.; Semolic, A.; Pirulli, A.; Vinci, P.; Zentilin, L.; Giacca, M.; Cattin, L.; Guarnieri, G.Barazzoni, Rocco; Zanetti, Michela; Sturnega, M.; Stebel, M.; Semolic, ANNA MARIA; Pirulli, A.; Vinci, P.; Zentilin, L.; Giacca, Mauro; Cattin, Luigi; Guarnieri, Gianfranc

Relationships between desacylated and acylated ghrelin and insulin sensitivity in the metabolic syndrome.

11CONTEXT: Metabolic syndrome shows clustered metabolic abnormalities with major roles for insulin resistance and obesity. Ghrelin is a gastric hormone whose total plasma concentration (T-Ghr) is associated positively with insulin sensitivity and is reduced in obesity. Ghrelin circulates in acylated (A-Ghr) and desacylated (D-Ghr) forms, but their potential differential associations with insulin resistance and whether they are differentially altered in obesity remain undefined. OBJECTIVE: Our objective was to determine potential differential associations of ghrelin forms with insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)] and the impact of obesity on their plasma concentrations in metabolic syndrome. DESIGN: This is a cross-sectional study. SETTING: The study was performed in a metabolic outpatient unit. PATIENTS: Patients with metabolic syndrome (National Cholesterol Education Program-Adult Treatment Panel III; n = 45, 23 males/22 females) were included in the study. MAIN OUTCOMES: The main study outcomes were metabolic syndrome criteria, HOMA-IR, and ghrelin forms. RESULTS: Plasma insulin and HOMA-IR were associated negatively with T-Ghr and D-Ghr but positively with A-Ghr and acylated to desacylated ghrelin (A/D-Ghr) ratio (n = 45; P 27.5 kg/m(2); n = 33) had lower T-Ghr and D-Ghr but comparable A-Ghr and higher A/D-Ghr ratio (P < 0.05). BMI and waist circumference (WC) were positively related with HOMA-IR (n = 45; P < 0.05). However, opposite associations between A/D-Ghr ratio and HOMA-IR remained significant after adjustment for sex and BMI (or WC). Additional obese individuals without metabolic syndrome (n = 10: age-, sex-, BMI-, and WC-matched to obese metabolic syndrome patients) had lower T-Ghr but higher A-Ghr (P < 0.05) compared with age-, sex-matched healthy nonobese counterparts (n = 15). T-Ghr and A-Ghr were comparable in obese with or without metabolic syndrome. CONCLUSION: Obesity could alter circulating ghrelin profile, and relative A-Ghr excess could contribute to obesity-associated insulin resistance in metabolic syndrome.nonemixedBarazzoni R.; Zanetti M.; Ferreira C.; Vinci P.; Pirulli A.; Mucci M.; Dore F.; Fonda M.; Ciocchi B.; Cattin L.; Guarnieri G.Barazzoni, Rocco; Zanetti, Michela; Ferreira, Clara; Vinci, P.; Pirulli, Alessia; Mucci, M.; Dore, F.; Fonda, M.; Ciocchi, B.; Cattin, Luigi; Guarnieri, Gianfranc