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Background Airway smooth muscle (ASM) dysfunction contributes to the airway hyper-responsiveness and airflow obstruction observed in asthma. The receptor for advanced glycosylation end products (RAGE) is a pattern recognition receptor activated by endogenous danger signals, including high mobility group box 1 (HMGB1). RAGE and HMGB1 are implicated in many pathophysiological states, such as diabetes and Alzheimer's disease. RAGE is abundantly expressed in healthy adult lung, where it might serve a homeostatic function, for example, in alveolar type I epithelial cells; however, RAGE expression/function in other airway cell-types is poorly characterised. We hypothesised that changes in RAGE and HMGB1 expression may contribute to ASM dysfunction in asthma. Therefore, RAGE/HMGB1 expression was investigated in human primary ASM cells. Methods ASM was microdissected from bronchial biopsies and large airway specimens obtained at lung resection surgery. Ex-vivo ASM cells were characterised for a-smooth muscle actin and used between passages 2-5. Cells were serum deprived in ITS medium for 72-h prior to experimentation. RAGE and HMGB1 mRNA expression was measured using RT-PCR and qRT-PCR, and protein expression by western blotting, immunofluorescence and flow cytometry. Results ASM cells were shown to express the full-length and three soluble RAGE transcripts by RT-PCR (n=5), and an HMGB1 transcript by qRT-PCR (n=6). By flow cytometry membrane-localised RAGE expression was shown to be significantly increased in ASM cells isolated from asthmatics (18.0±5.4% of the ASM population expressed RAGE, n=6) vs non-asthmatics (8.6±6.5%, n=7; *p<0.05), and a trend towards decreased HMGB1 expression in asthmatics (18.8±10.5%, n=6) vs non-asthmatics (35.7±19.1%, n=6) was observed; however, these values were not significantly different. RAGE and HMGB1 expression were confirmed by immunofluorescence and western blotting. Conclusion Human ASM cells express RAGE and its ligand HMGB1 at the mRNA and protein levels. Membrane-localised RAGE protein expression is significantly increased and there is a trend towards a decrease in HMGB1 protein expression in ASM isolated from asthmatic vs non-asthmatic subjects. The contribution of these changes to ASM dysfunction in asthma requires further investigation. [ABSTRACT FROM AUTHOR]

Background: Phenotypes and endotypes predicting optimal response to bronchial thermoplasty (BT) in patients with severe asthma remain elusive., Objective: Our aim was to compare the clinical characteristics and hallmarks of airway inflammation and remodeling before and after BT in responder and partial responder patients with severe asthma refractory to oral steroids and to omalizumab., Methods: In all, 23 patients with severe refractory asthma were divided into BT responders (n = 15) and BT partial responders (n = 8), according to the decrease in asthma exacerbations at 12 months after BT. Clinical parameters were compared at baseline and 12 months after BT, and hallmarks of airway inflammation and remodeling were analyzed by immunohistochemistry in bronchial biopsy specimens before and 3 months after BT., Results: At baseline, the BT responders were around 8 years younger than the BT partial responders (P = .02) and they had a greater incidence of atopy, higher numbers of blood eosinophils (both P = .03) and IgE levels, higher epithelial IFN-α expression, and higher numbers of mucosal eosinophils and IL-33-positive cells (P ≤ .05). A reduction in blood eosinophil count, serum IgE level, type 2 airway inflammation, and numbers of mucosal IL-33-positive cells and mast cells associated with augmented epithelial MUC5AC and IFN-α/β immunostaining was noted after BT in responders, whereas the numbers of mucosal IL-33-positive cells were augmented in BT partial responders. Most of these changes were correlated with clinical parameters. Subepithelial membrane thickening and airway smooth muscle area were similar in the 2 patient groups at baseline and after BT., Conclusion: By reducing allergic type 2 inflammation and increasing epithelial MUC5AC and anti-viral IFN-α/β expression, BT may enhance host immune responses and thus attenuate exacerbations and symptoms in BT responders. Instead, targeting IL-33 may provide a clinical benefit in BT partial responders., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Lung adenocarcinoma (LUAD) is the main non-small-cell lung cancer diagnosed in ~40-50% of all lung cancer cases. Despite the improvements in early detection and personalized medicine, even a sizable fraction of patients with early-stage LUAD would experience disease relapses and adverse prognosis. Previous reports indicated the existence of LUAD molecular subtypes characterized by specific gene expression and mutational profiles, and correlating with prognosis. However, the biological and molecular features of such subtypes have not been further explored. Consequently, the mechanisms driving the emergence of aggressive LUAD remained unclear. Here, we adopted a multi-tiered approach ranging from molecular to functional characterization of LUAD and used it on multiple cohorts of patients (for a total of 1227 patients) and LUAD cell lines. We investigated the tumor transcriptome and the mutational and immune gene expression profiles, and we used LUAD cell lines for cancer cell phenotypic screening. We found that loss of lung cell lineage and gain of stem cell-like characteristics, along with mutator and immune evasion phenotypes, explain the aggressive behavior of a specific subset of lung adenocarcinoma that we called C1-LUAD, including early-stage disease. This subset can be identified using a 10-gene prognostic signature. Poor prognosis patients appear to have this specific molecular lung adenocarcinoma subtype which is characterized by peculiar molecular and biological features. Our data support the hypothesis that transformed lung stem/progenitor cells and/or reprogrammed epithelial cells with CSC characteristics are hallmarks of this aggressive disease. Such discoveries suggest alternative, more aggressive, therapeutic strategies for early-stage C1-LUAD., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Severe asthma is a chronic lung disease characterised by inflammation, airway hyperresponsiveness (AHR) and airway remodelling. The molecular mechanisms underlying uncontrolled airway smooth muscle cell (aSMC) proliferation involved in pulmonary remodelling are still largely unknown. Small G proteins of the Rho family (RhoA, Rac1 and Cdc42) are key regulators of smooth muscle functions and we recently demonstrated that Rac1 is activated in aSMC from allergic mice. The objective of this study was to assess the role of Rac1 in severe asthma-associated airway remodelling., Methods and Results: Immunofluorescence analysis in human bronchial biopsies revealed an increased Rac1 activity in aSMC from patients with severe asthma compared with control subjects. Inhibition of Rac1 by EHT1864 showed that Rac1 signalling controlled human aSMC proliferation induced by mitogenic stimuli through the signal transducer and activator of transcription 3 (STAT3) signalling pathway. In vivo, specific deletion of Rac1 in SMC or pharmacological inhibition of Rac1 by nebulisation of NSC23766 prevented AHR and aSMC hyperplasia in a mouse model of severe asthma. Moreover, the Rac1 inhibitor prevented goblet cell hyperplasia and epithelial cell hypertrophy whereas treatment with corticosteroids had less effect. Nebulisation of NSC23766 also decreased eosinophil accumulation in the bronchoalveolar lavage of asthmatic mice., Conclusion: This study demonstrates that Rac1 is overactive in the airways of patients with severe asthma and is essential for aSMC proliferation. It also provides evidence that Rac1 is causally involved in AHR and airway remodelling. Rac1 may represent as an interesting target for treating both AHR and airway remodelling of patients with severe asthma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Lung cancer burden can be reduced by adopting primary and secondary prevention strategies such as anti-smoking campaigns and low-dose CT screening for high risk subjects (aged >50 and smokers >30 packs/year). Recent CT screening trials demonstrated a stage-shift towards earlier stage lung cancer and reduction of mortality (~20%). However, a sizable fraction of patients (30-50%) with early stage disease still experience relapse and an adverse prognosis. Thus, the identification of effective prognostic biomarkers in stage I lung cancer is nowadays paramount. Here, we applied a multi-tiered approach relying on coupled RNA-seq and miRNA-seq data analysis of a large cohort of lung cancer patients (TCGA-LUAD, n = 510), which enabled us to identify prognostic miRNA signatures in stage I lung adenocarcinoma. Such signatures showed high accuracy (AUC ranging between 0.79 and 0.85) in scoring aggressive disease. Importantly, using a network-based approach we rewired miRNA-mRNA regulatory networks, identifying a minimal signature of 7 miRNAs, which was validated in a cohort of FFPE lung adenocarcinoma samples (CSS, n = 44) and controls a variety of genes overlapping with cancer relevant pathways. Our results further demonstrate the reliability of miRNA-based biomarkers for lung cancer prognostication and make a step forward to the application of miRNA biomarkers in the clinical routine.

Inflammatory myofibroblastic tumors (IMT) in the head and neck region are rare neoplasms that generally mimic benign/low-grade neoplasms. Overexpression of anaplastic lymphoma kinase ( ALK ) has been reported in 50% of IMT cases, secondary to ALK activation by structural rearrangements in the ALK gene, which results in a fusion protein with echinoderm microtubule associated protein like 4 ( EML4 ) in ~20% of cases. The present study describes a case of a 74-year-old woman with a malignant IMT in the right posterior hypopharynx harboring a previously unreported chromosomal rearrangement resulting in EML4 and ALK gene fusion. Strong ALK immunoreactivity was observed in neoplastic cells, while fluorescent in situ hybridization combined with fluorescent fragment analysis and direct sequencing identified the first case of the 3a/b variants of the EML4-ALK fusion gene in IMT. The results of the current study highlight the uncommon occurrence of ALK-positive IMT in the head/neck region and demonstrate the importance of integrating different molecular methodologies to identify unequivocal gene fusion characterization.

Aims: The aim was to assess the impact of a campaign for general practitioners (GPs) to reduce clinically-important drug-drug interactions (DDIs) in poly-treated elderly patients., Methods: We compiled a list of 53 DDIs and analyzed reimbursed prescriptions dispensed to poly-treated (≥four drugs) elderly (>65 years) patients in the Emilia Romagna region during January 2011-June 2011 (first pre-intervention period), January 2012-June 2012 (second pre-intervention period) and January 2013-June 2013 (post-intervention period). Educational initiatives to GPs were completed in July 2012-December 2012. Pre-test/post-test analysis (2013 vs. 2012) was performed, also using predicted 2013 data (P < 0.01 for statistical significance)., Results: Despite the slight increase in poly-therapy rate (16% in 2013, +1.5% from 2011), we found a stable or slightly declining number of potential DDIs for each elderly poly-treated patient (~1.5). In 2013, 11 DDIs exceeded 5% of prevalence rate: antidiabetics-β-adrenoceptor blockers ranked first (20.3%), followed by ACE Inhibitors (ACEIs)/sartans-non steroidal anti-inflammatory drugs (NSAIDs) (16.4%), diuretics-NSAIDs (13.6%), selective serotonin re-uptake inhibitors (SSRIs)-NSAIDs/acetyl salicylic acid (ASA) (12.7%) and corticosteroids-NSAIDs/ASA (9.7%). A remarkable reduction emerged for NSAID-related DDIs (diuretics-NSAIDs peaked -14.5%; P < 0.01), whereas prevalence of antidiabetics-β-adrenoceptor blockers increased (+7.9%; P < 0.01). When using predicted values, the statistical significance disappeared for antidiabetics-β-adrenoceptor blockers (+1.3%; P = 0.04), whereas it persisted for almost all NSAIDs-related DDIs: ACEIs/sartans-NSAIDs (-3.0%), diuretics-NSAIDs (-6.0%), SSRIs-NSAIDs/ASA (-5.9%)., Conclusions: This campaign contained the burden of DDIs in poly-treated elderly patients by 1) reducing most prevalent DDIs, especially NSAIDs-related DDIs and 2) balancing the observed rise in poly-therapy rate with stable rate in overall prescriptions of potentially interacting drugs per patient., (© 2015 The British Pharmacological Society.)

Cancer of the colon does not always present with the familiar symptoms. Perforation and penetration of adjacent organs, with abscess formation as the initial presentation, is uncommon. Splenic abscess is a rare clinical entity. The four causes of a splenic abscess described are: primary pyogenic infection, splenic trauma, hemoglobinopathies and contiguous disease. In this paper we report a case of splenic abscess from colon cancer in an 50-year-old man who had a left lower chest contusion two-week before and review pertinent literature. Only 11 reported cases of splenic abscess from colorectal cancer were found in Medline.

Backgrounds and Objective: Aim of the present study was to evaluate the clinical correlates of small bowel CT patterns in patients with Crohn's disease (CD), as compared to barium studies and endoscopic findings, as far as parameters of disease activity are concerned., Material and Methods: Thirty five patients with pathologically proven CD were studied by means of helical single detector CT (13) or multidetector CT (22), after administration of low density contrast by mouth (13) or by nasojeunal tube (22). Eight hours later, all patients were studied with barium administered by mouth (13) or with barium and methilcellulose administered by nasojeunal tube (22). Clinical activity was assessed by CDAI score, ESR, CRP, alpha1 glycoprotein and fibrinogen levels. In twenty one patients, colonoscopy was also performed., Results: Sensitivity of small bowel CT versus endoscopy was of 88% while sensitivity of barium studies was of 77% versus endoscopic findings, and it reached 100% for the combination of both exams. We found positive correlations between the detection at CT of "target sign" and a CDAI score > 150 or abnormal values of CRP, ESR, alpha1 glycoprotein. Abnormal ESR or fibrinogen levels were correlated with the detection of fistulas at CT scans. The diameter of enlarged mesenteric lymph nodes was correlated with alpha1 glycoprotein values. No similar correlations were detected for contrast radiology findings., Discussion: This study underscores the clinical usefulness of performing small bowel CT in adjunct to conventional diagnostic studies in Crohn's disease patients. CT findings (either by oral route or nasojeunal tube) correlate with parameters of disease activity.

A case of early cutaneous involvement by an acute myeloid leukemia in a Caucasian man, previously affected by a "classical" Kaposi's sarcoma is reported. The diagnoses were based upon histologic examinations and appropriate hematologic investigations. After reviewing extensively the literature about the association of lymphoreticular system malignancies and Kaposi's sarcoma, possible implications and hypothetical etiopathogenetic mechanisms are discussed.