Early Investigations and Recent Advances in Intraperitoneal Immunotherapy for Peritoneal Metastasis.

Peritoneal metastasis (PM) is an advanced stage malignancy largely refractory to modern therapy. Intraperitoneal (IP) immunotherapy offers a novel approach for the control of regional disease of the peritoneal cavity by breaking immune tolerance. These strategies include heightening T-cell response and vaccine induction of anti-cancer memory against tumor-associated antigens. Early investigations with chimeric antigen receptor T cells (CAR-T cells), vaccine-based therapies, dendritic cells (DCs) in combination with pro-inflammatory cytokines and natural killer cells (NKs), adoptive cell transfer, and immune checkpoint inhibitors represent significant advances in the treatment of PM. IP delivery of CAR-T cells has shown demonstrable suppression of tumors expressing carcinoembryonic antigen. This response was enhanced when IP injected CAR-T cells were combined with anti-PD-L1 or anti-Gr1. Similarly, CAR-T cells against folate receptor α expressing tumors improved T-cell tumor localization and survival when combined with CD137 co-stimulatory signaling. Moreover, IP immunotherapy with catumaxomab, a trifunctional antibody approved in Europe, targets epithelial cell adhesion molecule (EpCAM) and has shown considerable promise with control of malignant ascites. Herein, we discuss immunologic approaches under investigation for treatment of PM

Cannabinoids in the treatment of epilepsy: current status and future prospects

Cannabidiol (CBD) is one of the prominent phytocannabinoids found in Cannabis sativa, differentiating from Δ9-tetrahydrocannabinol (THC) for its non-intoxicating profile and its antianxiety/antipsychotic effects. CBD is a multi-target drug whose anti-convulsant properties are supposed to be independent of endocannabinoid receptor CB1 and might be related to several underlying mechanisms, such as antagonism on the orphan GPR55 receptor, regulation of adenosine tone, activation of 5HT1A receptors and modulation of calcium intracellular levels. CBD is a lipophilic compound with low oral bioavailability (6%) due to poor intestinal absorption and high first-pass metabolism. Its exposure parameters are greatly influenced by feeding status (ie, high fatcontaining meals). It is mainly metabolized by cytochrome P 450 (CYP) 3A4 and 2C19, which it strongly inhibits. A proprietary formulation of highly purified, plant-derived CBD has been recently licensed as an adjunctive treatment for Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), while it is being currently investigated in tuberous sclerosis complex. The regulatory agencies’ approval was granted based on four pivotal double-blind, placebocontrolled, randomized clinical trials (RCTs) on overall 154 DS patients and 396 LGS ones, receiving CBD 10 or 20 mg/kg/day BID as active treatment. The primary endpoint (reduction in monthly seizure frequency) was met by both CBD doses. Most patients reported adverse events (AEs), generally from mild to moderate and transient, which mainly consisted of somnolence, sedation, decreased appetite, diarrhea and elevation in aminotransferase levels, the last being documented only in subjects on concomitant valproate therapy. The interaction between CBD and clobazam, likely due to CYP2C19 inhibition, might contribute to some AEs, especially somnolence, but also to CBD clinical effectiveness. Cannabidivarin (CBDV), the propyl analogue of CBD, showed anti-convulsant properties in pre-clinical studies, but a plant-derived, purified proprietary formulation of CBDV recently failed the Phase II RCT in patients with uncontrolled focal seizures

The phosphodiesterase 5 inhibitor sildenafil decreases the proinflammatory chemokine IL-8 in diabetic cardiomyopathy: in vivo and in vitro evidence

Purpose: Interleukin (IL)-8 is a proinflammatory C-X-C chemokine involved in inflammation underling cardiac diseases, primary or in comorbid condition, such diabetic cardiomyopathy (DCM). The phosphodiesterase type 5 inhibitor sildenafil can ameliorate cardiac conditions by counteracting inflammation. The study aim is to evaluate the effect of sildenafil on serum IL-8 in DCM subjects vs. placebo, and on IL-8 release in human endothelial cells (Hfaec) and peripheral blood mononuclear cells (PBMC) under inflammatory stimuli. Methods: IL-8 was quantified: in sera of (30) DCM subjects before (baseline) and after sildenafil (100 mg/day, 3-months) vs. (16) placebo and (15) healthy subjects, by multiplatform array; in supernatants from inflammation-challenged cells after sildenafil (1 µM), by ELISA. Results: Baseline IL-8 was higher in DCM vs. healthy subjects (149.14 ± 46.89 vs. 16.17 ± 5.38 pg/ml, p < 0.01). Sildenafil, not placebo, significantly reduced serum IL-8 (23.7 ± 5.9 pg/ml, p < 0.05 vs. baseline). Receiver operating characteristic (ROC) curve for IL-8 was 0.945 (95% confidence interval of 0.772 to 1.0, p < 0.01), showing good capacity of discriminating the response in terms of drug-induced IL-8 decrease (sensitivity of 0.93, specificity of 0.90). Sildenafil significantly decreased IL-8 protein release by inflammation-induced Hfaec and PBMC and downregulated IL-8 mRNA in PBMC, without affecting cell number or PDE5 expression. Conclusion: Sildenafil might be suggested as potential novel pharmacological tool to control DCM progression through IL-8 targeting at systemic and cellular level

High serum osteopontin levels are associated with prevalent fractures and worse lipid profile in post-menopausal women with type 2 diabetes

Purpose: Patients with type 2 diabetes (T2DM) have increased fracture risk. Osteopontin (OPN) is a protein involved in bone remodeling and inflammation. The aim of this study was to evaluate the association of OPN with fracture prevalence and with metabolic parameters in post-menopausal women with T2DM. Methods: Sixty-four post-menopausal women with T2DM (age 67.0 ± 7.8 years, diabetes duration 8.9 ± 6.7 years), enrolled in a previous study, were followed up (3.6 ± 0.9 years). Previous fragility fractures were recorded. The FRAX score (without BMD) was calculated and biochemical parameters (plasma glucose, HbA1c, lipid profile and renal function) were assessed. Serum 25OH-vitamin D, calcium, PTH and OPN were evaluated at baseline. The association between OPN and fracture prevalence at baseline was evaluated by a logistic model. Results: OPN levels were higher in patients with previous fractures (n.25) than in patients without previous fractures at baseline (n.39) (p = 0.006). The odds of having fractures at baseline increased by 6.7 (1.9–31.4, 95% CI, p = 0.007) for each increase of 1 ng/ml in OPN levels, after adjustment for vitamin D and HbA1c levels. Fracture incidence was 4.7%. Higher OPN associated with a decrease in HDL-cholesterol (p = 0.048), after adjustment for age, basal HDL-cholesterol, basal and follow-up HbA1c and follow-up duration. 25OH-vitamin D associated with an increase in FRAX-estimated probability of hip fracture at follow-up (p = 0.029), after adjustment for age, 25OH-vitamin D and time. Conclusions: In post-menopausal women with T2DM, OPN might be a useful marker of fracture and worse lipid profile

Modulation of contractility in human cardiac hypertrophy by myosin essential light chain isoforms

Cardiac hypertrophy is an adaptive response that normalizes wall stress and compensates for increased workload. It is accompanied by distinct qualitative and quantitative changes in the expression of protein isoforms concerning contractility, intracellular Ca2+-homeostasis and metabolism. Changes in the myosin subunit isoform expression improves contractility by an increase in force generation at a given Ca2+-concentration (increased Ca2+-sensitivity) and by improving the economy of the chemo-mechanical transduction process per amount of utilised ATP (increased duty ratio). In the human atrium this is achieved by partial replacement of the endogenous fast myosin by the ventricular slow-type heavy and light chains. In the hypertrophic human ventricle the slow-type β-myosin heavy chains remain unchanged, but the ectopic expression of the atrial myosin essential light chain (ALC1) partially replaces the endogenous ventricular isoform (VLC1). The ventricular contractile apparatus with myosin containing ALC1 is characterised by faster cross-bridge kinetics, a higher Ca2+-sensitivity of force generation and an increased duty ratio. The mechanism for cross-bridge modulation relies on the extended Ala-Pro-rich N-terminus of the essential light chains of which the first eleven residues interact with the C-terminus of actin. A change in charge in this region between ALC1 and VLC1 explains their functional difference. The intracellular Ca2+-handling may be impaired in heart failure, resulting in either higher or lower cytosolic Ca2+-levels. Thus the state of the cardiomyocyte determines whether this hypertrophic adaptation remains beneficial or becomes detrimental during failure. Also discussed are the effects on contractility of long-term changes in isoform expression of other sarcomeric proteins. Positive and negative modulation of contractility by short-term phosphorylation reactions at multiple sites in the myosin regulatory light chain, troponin-I, troponin-T, α-tropomyosin and myosin binding protein-C are considered in detai

Athletes’ basic psychological needs and emotions: the role of cognitive reappraisal

In sport, where high achievements are at stake, athletes often feel pressure and emotions that hinder their performance. Emotion regulation becomes essential for athletes to handle stress, achieve optimal performance, and enhance their overall well-being. To advance both research and practical applications, it is crucial to examine the antecedents of emotion regulation and the impact on emotions and other feelings associated with performance. Specifically, the purpose of this cross-sectional study was to examine the role of athletes’ emotion regulation strategies (i.e., cognitive reappraisal and expressive suppression) in the relationship between basic psychological needs satisfaction, emotions, and psychobiosocial experiences. The sample consisted of 424 competitive athletes (246 men and 178 women) involved in individual sports (n = 164; e.g., fencing, gymnastics, martial arts, swimming, and tennis) or team sports (n = 260; e.g., basketball, rugby, soccer, and volleyball), aged 16–36  years (M = 23.08, SD = 7.65). Their competitive experience ranged from 1 to 21  years (M = 9.71, SD = 6.34) at regional (71%), national (18%), or international (11%) level, and they practiced their sport on average 3.74 times a week (SD = 1.73). Participants completed measures of basic needs satisfaction (i.e., competence, autonomy, and relatedness), emotion regulation style, emotions, and psychobiosocial experiences. Structural equation modeling results showed that competence need satisfaction was positively associated with pleasant emotions and psychobiosocial experiences that are perceived as functional for performance, and negatively associated with a maladaptive emotion regulation style (i.e., expressive suppression) and unpleasant emotions. Relatedness need satisfaction was positively related to an adaptive emotion regulation style (i.e., cognitive reappraisal), pleasant emotions, and psychobiosocial experiences, and negatively related to expressive suppression and unpleasant emotions. Finally, mediation analysis showed positive indirect effects from autonomy and relatedness satisfaction to pleasant emotions and psychobiosocial experiences via cognitive reappraisal. Findings suggest that the satisfaction of athletes’ basic psychological needs of autonomy and relatedness is related to the experience of pleasant emotions and functional psychobiosocial states when they adopt an adaptive emotion regulation style

The Melanocortin-4 Receptor Integrates Circadian Light Cues and Metabolism

The melanocortin system directs diverse physiological functions from coat color to body weight homoeostasis. A commonality among melanocortin-mediated processes is that many animals modulate similar processes on a circannual basis in response to longer, summer days, suggesting an underlying link between circadian biology and the melanocortin system. Despite key neuroanatomical substrates shared by both circadian and melanocortin-signaling pathways, little is known about the relationship between the two. Here we identify a link between circadian disruption and the control of glucose homeostasis mediated through the melanocortin-4 receptor (Mc4r). Mc4r-deficient mice exhibit exaggerated circadian fluctuations in baseline blood glucose and glucose tolerance. Interestingly, exposure to lighting conditions that disrupt circadian rhythms improve their glucose tolerance. This improvement occurs through an increase in glucose clearance by skeletal muscle and is food intake and body weight independent. Restoring Mc4r expression to the paraventricular nucleus prevents the improvement in glucose tolerance, supporting a role for the paraventricular nucleus in the integration of circadian light cues and metabolism. Altogether these data suggest that Mc4r signaling plays a protective role in minimizing glucose fluctuations due to circadian rhythms and environmental light cues and demonstrate a previously undiscovered connection between circadian biology and glucose metabolism mediated through the melanocortin system

MicroRNA modulation by dietary supplements in obesity

The prevalence of obesity has dramatically increased over the last decades. Weight loss obtained through diet and exercise leads to a significant decrease in morbidity and mortality. Recently, there has been growing interest in the possible beneficial effects of dietary supplements (DSs), including polyphenols, fatty acids, and other plant-derived substances, as adjuvants in the management of obesity and metabolic diseases. Specifically, polyphenols, widely spread in vegetables and fruits, significantly modulate adipose tissue activities, contrasting inflammation and improving insulin sensitivity in preclinical and clinical studies. Remarkably, polyphenols are involved in complex microRNA networks, which play crucial roles in metabolic processes. The administration of different polyphenols and other plant-derived compounds led to significant changes in the microRNA expression profile in peripheral tissues in a growing number of preclinical studies. In particular, these compounds were able to revert obesity-induced microRNA dysregulation, leading to the inhibition of adipogenesis and the induction of weight loss. Furthermore, through microRNA modulation, they attenuated key metabolic alterations, including insulin resistance and lipid anomalies, in animal models of obesity. Some of them were also able to reduce proinflammatory cytokines in adipose tissue. The aim of this review is to summarize current evidence about the effect of plant-derived DSs on microRNA expression in obesity

Tissue and circulating microRNAs as biomarkers of response to obesity treatment strategies

Background: Obesity, characterized by an increased amount of adipose tissue, is a metabolic chronic alteration which has reached pandemic proportion. Lifestyle changes are the first line therapy for obesity and a large variety of dietary approaches have demonstrated efficacy in promoting weight loss and improving obesity-related metabolic alterations. Besides diet and physical activity, bariatric surgery might be an effective therapeutic strategy for morbid obese patients. Response to weight-loss interventions is characterised by high inter-individual variability, which might involve epigenetic factors. microRNAs have critical roles in metabolic processes and their dysregulated expression has been reported in obesity. Aim: The aim of this review is to provide a comprehensive overview of current studies evaluating changes in microRNA expression in obese patients undergoing lifestyle interventions or bariatric surgery. Results: A considerable number of studies have reported a differential expression of circulating microRNAs before and after various dietary and bariatric surgery approaches, identifying several candidate biomarkers of response to weight loss. Significant changes in microRNA expression have been observed at a tissue level as well, with entirely different patterns between visceral and subcutaneous adipose tissue. Interestingly, relevant differences in microRNA expression have emerged between responders and non-responders to dietary or surgical interventions. A wide variety of dysregulated microRNA target pathways have also been identified, helping to understand the pathophysiological mechanisms underlying obesity and obesity-related metabolic diseases. Conclusions: Although further research is needed to draw firm conclusions, there is increasing evidence about microRNAs as potential biomarkers for weight loss and response to intervention strategies in obesity

Cardiomyopathy associated with diabetes. the central role of the cardiomyocyte

The term diabetic cardiomyopathy (DCM) labels an abnormal cardiac structure and performance due to intrinsic heart muscle malfunction, independently of other vascular co-morbidity. DCM, accounting for 50%-80% of deaths in diabetic patients, represents a worldwide problem for human health and related economics. Optimal glycemic control is not sufficient to prevent DCM, which derives from heart remodeling and geometrical changes, with both consequences of critical events initially occurring at the cardiomyocyte level. Cardiac cells, under hyperglycemia, very early undergo metabolic abnormalities and contribute to T helper (Th)-driven inflammatory perturbation, behaving as immunoactive units capable of releasing critical biomediators, such as cytokines and chemokines. This paper aims to focus onto the role of cardiomyocytes, no longer considered as "passive" targets but as "active" units participating in the inflammatory dialogue between local and systemic counterparts underlying DCM development and maintenance. Some of the main biomolecular/metabolic/inflammatory processes triggered within cardiac cells by high glucose are overviewed; particular attention is addressed to early inflammatory cytokines and chemokines, representing potential therapeutic targets for a prompt early intervention when no signs or symptoms of DCM are manifesting yet. DCM clinical management still represents a challenge and further translational investigations, including studies at female/male cell level, are warranted