The inflammatory/immune side of Myelofibrosis: a biological update

Myelofibrosis (MF) is a clonal disorders of hematopoietic stem cell. Mutations in 3 genes (JAK2, CALR, MPL) and chronic inflammation are the hallmark of MF. Infectious complications are the leading cause of morbidity and mortality. Ruxolitinib (RUX) therapy, a JAK1/2 inhibitor, suppresses both clonal myeloproliferation and release of proinflammatory cytokines, exerting also immunosuppressive activity. The main aim of my PhD project was the functional characterization of the immune/inflammatory microenvironment of MF. Specifically, we aimed: 1) to analyse the role of circulating microvesicles as disease biomarker in MF; 2) to investigate the phenotype/function of circulating monocytes in the inflammatory microenvironment of MF patients and to evaluate whether RUX may influence their behaviour. Focusing on circulating microvesicles, we demonstrated that: 1) the circulating megakaryocyte/platelet-derived microvesicles profile is altered; 2) according to IPSS score, Intermediate 2/high risk patients show respectively reduced/increased megakaryocyte/platelet-microvesicles proportion as compared with the intermediate1/low risk patients; 3) at baseline spleen-responders patients show a significantly increased megakaryocyte-microvesicles proportion as compared with the non-responder counterparts. Importantly, a cut-off value below 19.95% of megakaryocyte-microvesicles predicted RUX response. Interestingly, RUX therapy restores the normal megakaryocyte/platelet-microvesicles profile in spleen-responders patients only. On this basis, circulating megakaryocyte/platelet-microvesicles could have a diagnostic and prognostic role in MF. Finally, focusing on the immune microenvironment of JAK2V617F mutated MF patients, circulating monocytes show an altered activation/differentiation program and a reduced in vitro capacity to produce/secrete inflammatory cytokines in response to an infectious stimulus. Importantly, RUX therapy improves intracellular pro-inflammatory cytokines production of MF-monocytes and promotes the in vitro release of inflammatory cytokines associated with monocytes-derived microvesicles in response to an infectious stimulus. These findings contribute to better understand the immune biology in the setting of the MF and refines the biological effects of RUX

Glucose variability: a new risk factor for cardiovascular disease

Aims and data synthesis: glucose variability (GV) is increasingly considered an additional index of glycemic control. Growing evidence indicates that GV is associated with diabetic vascular complications, thus being a relevant point to address in diabetes management. GV can be measured using various parameters, but to date, a gold standard has not been identified. This underscores the need for further studies in this field also to identify the optimal treatment. Conclusions: We reviewed the definition of GV, the pathogenetic mechanisms of atherosclerosis, and its relationship with diabetic complications

Knowledge Gaps and Research Priorities on the Health Effects of Heatwaves: A Systematic Review of Reviews

Although extreme weather events have played a constant role in human history, heatwaves (HWs) have become more frequent and intense in the past decades, causing concern especially in light of the increasing evidence on climate change. Despite the increasing number of reviews suggesting a relationship between heat and health, these reviews focus primarily on mortality, neglecting other important aspects. This systematic review of reviews gathered the available evidence from research syntheses conducted on HWs and health. Following the PRISMA guidelines, 2232 records were retrieved, and 283 reviews were ultimately included. Information was extracted from the papers and categorized by topics. Quantitative data were extracted from meta-analyses and, when not available, evidence was collected from systematic reviews. Overall, 187 reviews were non-systematic, while 96 were systematic, of which 27 performed a meta-analysis. The majority evaluated mortality, morbidity, or vulnerability, while the other topics were scarcely addressed. The following main knowledge gaps were identified: lack of a universally accepted definition of HW; scarce evidence on the HW-mental health relationship; no meta-analyses assessing the risk perception of HWs; scarcity of studies evaluating the efficacy of adaptation strategies and interventions. Future efforts should meet these priorities to provide high-quality evidence to stakeholders

A reinvestigation of the deceptively simple reaction of toluene with OH, and the fate of the benzyl radical : a combined thermodynamic and kinetic study on the competition between OH-addition and H-abstraction reactions

This work reports density functional and composite model chemistry calculations performed on the reactions of toluene with the hydroxyl radical. Both the experimentally observed H-abstraction from the methyl group and possible OH additions to the phenyl ring were investigated. Reaction enthalpies and barrier heights suggest that H-abstraction is more favorable than OH-addition to the ring. The calculated reaction rates at room temperature and the radical intermediate product fractions support this view. At first sight, this might seem to disagree with the fact that, under most experimental conditions, cresols are observed in a larger concentration than benzaldehyde. Since the accepted mechanism for benzaldehyde formation involves H-abstraction, a contradiction arises that calls for a more elaborate explanation. In this first exploratory study, we provide evidence that support the preference of H-abstraction over OH addition and present an alternative mechanism which shows that cresols can be actually produced also through H-abstraction and not only from OH-addition, thus justifying the larger proportion of cresols than benzaldehyde among the products

The protective role of Lactobacillus rhamnosus GG postbiotic on the alteration of autophagy and inflammation pathways induced by gliadin in intestinal models

Celiac disease (CD) is an autoimmune enteropathy caused by an abnormal immune response to gliadin peptides in genetically predisposed individuals. For people with CD, the only available therapy thus far is the lifelong necessity for a gluten-free diet (GFD). Innovative therapies include probiotics and postbiotics as dietary supplements, both of which may benefit the host. Therefore, the present study aimed to investigate the possible beneficial effects of the postbiotic Lactobacillus rhamnosus GG (LGG) in preventing the effects induced by indigested gliadin peptides on the intestinal epithelium. In this study, these effects on the mTOR pathway, autophagic function, and inflammation have been evaluated. Furthermore, in this study, we stimulated the Caco-2 cells with the undigested gliadin peptide (P31-43) and with the crude gliadin peptic-tryptic peptides (PTG) and pretreated the samples with LGG postbiotics (ATCC 53103) (1 × 108). In this study, the effects induced by gliadin before and after pretreatment have also been investigated. The phosphorylation levels of mTOR, p70S6K, and p4EBP-1 were increased after treatment with PTG and P31-43, indicating that the intestinal epithelial cells responded to the gliadin peptides by activating the mTOR pathway. Moreover, in this study, an increase in the phosphorylation of NF-κβ was observed. Pretreatment with LGG postbiotic prevented both the activation of the mTOR pathway and the NF-κβ phosphorylation. In addition, P31-43 reduced LC3II staining, and the postbiotic treatment was able to prevent this reduction. Subsequently, to evaluate the inflammation in a more complex intestinal model, the intestinal organoids derived from celiac disease patient biopsies (GCD-CD) and controls (CTR) were cultured. Stimulation with peptide 31-43 in the CD intestinal organoids induced NF-κβ activation, and pretreatment with LGG postbiotic could prevent it. These data showed that the LGG postbiotic can prevent the P31-43-mediated increase in inflammation in both Caco-2 cells and in intestinal organoids derived from CD patients

Taller-than-wide shape: a new definition improves the specificity of TIRADS systems

Introduction: A taller-than-wide (TTW) shape is a suspicious feature of thyroid nodules commonly defined as an anteroposterior/transverse diameter (AP/T) ratio >1. An intraobserver variability of up to 18% in AP diameter evaluations has been described, which may lead to overreporting of this feature. To potentially improve the reliability of the TTW definition, we propose an arbitrary ratio of ≥1.2. Objective: The aim of this study was to estimate the impact of this definition on diagnostic performance. Methods: We prospectively analyzed 553 thyroid nodules referred for cytology evaluation at an academic center. Before fine-needle aspiration, two examiners jointly defined all sonographic features considered in risk stratification systems developed by the American Thyroid Association (ATA), the American Association of Clinical Endocrinologists (AACE), the American College of Radiology (ACR TIRADS), the European Thyroid Association (EU-TIRADS), and the Korean Society of Thyroid Radiology (K-TIRADS). TTW was defined according to the current definition (AP/T diameter ratio >1) and an arbitrary alternative definition (AP/T ratio >1.2). Results: The alternative definition classified fewer nodules as TTW (28, 5.1% vs. 94, 17%). The current and proposed definitions have a sensitivity of 26.2 and 11.9% (p = 0.03) and a specificity of 83.8 and 95.5% (p < 0.001). Thus, as a single feature, the arbitrary definition has a lower sensitivity and a higher specificity. When applied to sonographic risk stratification systems, however, the proposed definition would increase the number of avoided biopsies (up to 58.2% for ACR TIRADS) and the specificity of all systems, without negative impact on sensitivity or diagnostic odds ratio. Conclusions: Re-defining TTW nodules as those with an AP/T ratio ≥1.2 improves this marker's specificity for malignancy. Using this definition in risk stratification systems will increase their specificity, reducing the number of suggested biopsies without significantly diminishing their overall diagnostic performance