Evans syndrome and antibody deficiency: an atypical presentation of chromosome 22q11.2 deletion syndrome

We report a case of an 8-year-old male patient with Evans syndrome and severe hypogammaglobulinemia, subsequently in whom the 22q11.2 deletion syndrome (22q11.2 DS) was diagnosed. No other clinical sign of 22q11.2 DS was present with the exception of slight facial dysmorphism. The case is of particular interest because it suggests the need to research chromosome 22q11.2 deletion in patients who present with autoimmune cytopenia and peculiar facial abnormalities, which could be an atypical presentation of an incomplete form of 22q11.2 DS

AIM2 Inflammasome Activation Leads to IL-1α and TGF-β Release From Exacerbated Chronic Obstructive Pulmonary Disease-Derived Peripheral Blood Mononuclear Cells

Chronic obstructive pulmonary disease (COPD) is now the fourth-leading cause of death worldwide and its prevalence is increasing. The progressive decline of lung function and airway remodelling are a consequence of chronic inflammatory responses. It was recently postulated the involvement of the inflammasome in COPD, although the underlying mechanism/s still need to be elucidated. Therefore, we isolated peripheral blood mononuclear cells (PBMCs) from exacerbated/unstable COPD patients. The stimulation of PBMCs with an AIM2 inflammasome activator, Poly dA:dT, led to IL-1α, but not IL-1β, release. The release of this cytokine was caspase-1- and caspase-4-dependent and correlated to higher levels of 8-OH-dG in COPD compared to non-smoker and smoker-derived PBMCs. Interestingly, AIM2-depedent IL-1α release was responsible for higher TGF-β levels, crucial mediator during pro-fibrotic processes associated to COPD progression. In conclusion, our data highlight the involvement of AIM2/caspase-1/caspase-4 in IL-1α-induced TGF-β release in unstable COPD-derived PBMCs, opening new therapeutic perspectives for unstable COPD patients

Intracellular Sphingosine-1-Phosphate Receptor 3 Contributes to Lung Tumor Cell Proliferation.

Background/Aims: The pleiotropic lipid mediator sphingosine-1-phosphate (S1P) exerts a multitude of effects on respiratory cell physiology and pathology through five S1P receptors (S1PR1-5). Epidemiological studies proved high levels of circulating S1P in non-small cell lung cancer (NSCLC) patients. Studies in literature suggest that high levels of S1P support carcinogenesis but the exact mechanism is still elusive. The aim of this study was to understand the mechanism/s underlying S1P-mediated lung tumor cell proliferation. Methods: We used human samples of NSCLC, a mouse model of first-hand smoking and of Benzo(a)pyrene (BaP)-induced tumor-bearing mice and A549 lung adenocarcinoma cells. Results: We found that the expression of S1PR3 was also into the nucleus of lung cells in vitro, data that were confirmed in lung tissues of NSCLC patients, smoking and tumor bearing BaP-exposed mice. The intranuclear, but not the membrane, localization of S1PR3 was associated to S1P-mediated proliferation of lung adenocarcinoma cells. Indeed, the inhibition of the membrane S1PR3 did not alter tumor cell proliferation after Toll Like Receptor (TLR) 9 activation. Instead, according to the nuclear localization of sphingosine kinase (SPHK) II, the inhibition of the kinase completely blocked the endogenous S1P-induced tumor cell proliferation. Conclusion: These results prove that the nuclear S1PR3/SPHK II axis is involved in lung tumor cell proliferation, highlighting a novel molecular mechanism which could provide differential therapeutic approaches especially in non-responsive lung cancer patients

Clinical Features, Cardiovascular Risk Profile, and Therapeutic Trajectories of Patients with Type 2 Diabetes Candidate for Oral Semaglutide Therapy in the Italian Specialist Care

Introduction: This study aimed to address therapeutic inertia in the management of type 2 diabetes (T2D) by investigating the potential of early treatment with oral semaglutide. Methods: A cross-sectional survey was conducted between October 2021 and April 2022 among specialists treating individuals with T2D. A scientific committee designed a data collection form covering demographics, cardiovascular risk, glucose control metrics, ongoing therapies, and physician judgments on treatment appropriateness. Participants completed anonymous patient questionnaires reflecting routine clinical encounters. The preferred therapeutic regimen for each patient was also identified. Results: The analysis was conducted on 4449 patients initiating oral semaglutide. The population had a relatively short disease duration (42%  60% of patients, and more often than sitagliptin or empagliflozin. Conclusion: The study supports the potential of early implementation of oral semaglutide as a strategy to overcome therapeutic inertia and enhance T2D management

Drug resistance in non-small cell lung Cancer (NSCLC): Impact of genetic and non-genetic alterations on therapeutic regimen and responsiveness

The discovery of genetic alterations, that can be targeted therapeutically, has launched a new era for lung cancer research and personalized therapy. However, not all the identified new genetic driver mutations are therapeutically targetable due to high toxicity profile. On the other hand, those genetic alterations that could be pharmacologically targeted, are often subject of alternative mutations that lead to drug resistance, which represents one of the major clinical limitation. Mechanisms of acquired resistance in oncogene-driven malignancies occur after additional genetic alterations of the primary oncogene. In this scenario, the secondary genetic alteration can lead to up-regulation of bypass-signaling pathways, changes in tumor histology or alterations in drug metabolism, that are able to promote drug resistance with an ensuing lower survival rate of the patient. Another aspect to be considered is that non-genetically mutated patients still have poor pharmacological options and therefore still represent an unmet medical need. Therefore, identifying mechanisms underlying both drug resistance in genetically mutated patients and novel therapeutic alternatives for non-mutated NSCLC patients is still an area of intense investigation

Activation of the Absent in Melanoma 2 Inflammasome in Peripheral Blood Mononuclear Cells From Idiopathic Pulmonary Fibrosis Patients Leads to the Release of Pro-Fibrotic Mediators

Idiopathic pulmonary fibrosis (IPF) is a chronic fibro-proliferative disease characterized by poor prognosis, with a mean survival of ~2–3 years after definite diagnosis. The cause of IPF is still unknown but it is a heterogeneous condition in which the aberrant deposition of extracellular matrix leads to extensive lung remodeling. This remodeling is a consequence of inflammatory responses, but the mechanisms involved are poorly understood. In this study, we first analyzed a bleomycin-induced mouse model, which showed that higher expression of IL-1β, but not IL-18, was correlated to pulmonary cell infiltration and fibrosis. Then, we found that peripheral blood mononuclear cells (PBMCs) from IPF patients released IL-1α and IL-18 in a NLRP3- and calpain-independent manner after LPS ± ATP stimulation. Instead, the activation of the absent in melanoma 2 (AIM2) inflammasome induced the release of IL-1α in a caspase-1-/caspase-8-independent manner; whereas IL-18 release was caspase-1 dependent. These effects correlated with the release of the pro-fibrotic TGF-β, which was induced by AIM2 activation in a caspase-1- and TLR4-independent manner, but dependent on IL-1α. In this context, the activation of AIM2 induced the release of caspase-4 from IPF-derived PBMCs, which correlated with the mRNA levels of this caspase that was higher in IPF than in healthy PBMCs. In conclusion, our findings identify a novel molecular mechanism whereby the activation of AIM2 could lead to the activation of the non-canonical inflammasome (caspase-4 dependent) that induces the release of IL-1α responsible for the release of TGF-β from PBMCs of IPF patients

Role of the inflammasome in chronic obstructive pulmonary disease (COPD)

Inflammation is central to the development of chronic obstructive pulmonary disease (COPD), a pulmonary disorder characterized by chronic bronchitis, chronic airway obstruction, emphysema, associated to progressive and irreversible decline of lung function. Emerging genetic and pharmacological evidence suggests that IL-1-like cytokines are highly detected in the sputum and broncho-alveolar lavage (BAL) of COPD patients, implying the involvement of the multiprotein complex inflammasome. So far, scientific evidence has focused on nucleotide-binding oligomerization domain-like receptors protein 3 (NLRP3) inflammasome, a specialized inflammatory signaling platform that governs the maturation and secretion of IL-1-like cytokines through the regulation of caspase-1-dependent proteolytic processing. Some studies revealed that it is involved during airway inflammation typical of COPD. Based on the influence of cigarette smoke in various respiratory diseases, including COPD, in this view we report its effects in inflammatory and immune responses in COPD mouse models and in human subjects affected by COPD. In sharp contrast to what reported on experimental and clinical studies, randomized clinical trials show that indirect inflammasome inhibitors did not have any beneficial effect in moderate to severe COPD patients

IL-1α and IL-1β-producing macrophages populate lung tumor lesions in mice.

Macrophages highly populate tumour microenvironment and are referred to as tumor-associated macrophages (TAMs). The inflammasome is a multiprotein complex responsible of IL-1 like cytokines release, which biology has been widely studied by using bone-marrow-derived macrophages to mimic a physiological and/or host defense condition. To understand the role of this complex in lung tumor-associated macrophages (TAMs), we isolated and cultured broncho-alveolar lavage (BAL)-derived cells of lung tumor-bearing mice. The stimulation of lung TAMs with LPS+ATP increased the release of IL-1β. The inhibition of NLRP3 by means of glybenclamide significantly reduced IL-1β release. Similarly, C3H-derived, caspase-1 ko and caspase-11 ko TAMs released significantly reduced levels of IL-1β. Moreover, the stimulation of lung TAMs with the sole LPS induced a significant release of IL-1α, which was significantly reduced after caspase-1 pharmacological inhibition, and in TAMs genetically lacking caspase-1 and caspase-11. The inhibition of calpain I/II by means of MDL28170 did not alter IL-1α release after LPS treatment of lung TAMs. To note, the inoculation of LPS-treated bone marrow-derived macrophages into carcinogen-exposed mice increased lung tumor formation. In contrast, the depletion of TAMs by means of clodronate liposomes reduced lung tumorigenesis, associated to lower in vivo release of IL-1α and IL-1β.In conclusion, our data imply lung tumor lesions are populated by macrophages which pro-tumor activity is regulated by the activation of the NLRP3 inflammasome that leads to the release of IL-1α and IL-1β in a caspase-11/caspase-1-dependent manner

The combination of N-Acetyl-L-Cysteine, Pelargonium sidoides and Justicia adhatoda (NAXX) exerts bacteriostatic activity against S. aureus and E. coli

Many herbal agents and medicinal plants have provided clinical interest due to their therapeutic properties, availability and lower side effects. The aim of this study was to understand the anti-bacterial activity of the combination of Pelargonium sidoides (PEL), Justicia adhatoda (ADH) and N-Acetyl-L-Cysteine (NAC) (NAXX). We found that NAXX had strong and long-term bacteriostatic activity, which was related to its anti-oxidant activity. Our data demonstrate that NAXX is an innovative medicinal plant-derived strategy to manage of oxidative stress- and microbial-based diseases