Association of dietary intake and serum concentration of omega-3 fatty acids on celiac disease: evidence from observational study and Mendelian randomization.

OBJECTIVE: The association between omega-3 fatty acids (O3FA) and celiac disease lacks sufficient investigation. METHODS: Utilizing data gleaned from the 2009 to 2014 National Health and Nutrition Examination Survey (NHANES), this research comprises a sample of 13 403 adults, each aged 20 years and above. We conducted a multivariable logistic regression analysis to assess the association between dietary intake of O3FA and celiac disease. Subsequently, a two-sample Mendelian randomization was performed to estimate the unconfounded causal relationship between serum O3FA and celiac disease. The principal analytical strategy utilized the inverse-variance weighted methodology. RESULTS: In this cross-sectional study, 48 occurrences (0.36%) of celiac disease were encompassed. In the multivariable model, there was no association between dietary intake of O3FA and cases of celiac disease (odds ratio: 1.12, 95% confidence interval: 0.47-2.66, P = 0.792). However, serum levels of O3FA determined by genetic assay were correlated with celiac disease (inverse-variance weighted, ß = 0.2439, P = 0.0287), with no evidence of horizontal pleiotropy (P = 0.3689). CONCLUSION: The dietary consumption of O3FA did not exhibit an association with the risk of celiac disease in this cross-sectional investigation. However, a correlation between celiac disease and serum levels of O3FA was observed in the Mendelian randomization. Further investigations, including human clinical trials, are warranted.

Ultra-high order mode-assisted optical differentiator for edge detection with high tunability.

An optical spatial differentiator based on the photonic spin Hall effect (PSHE) with high tunability is presented. By utilizing the characteristics of ultra-high order modes in the symmetrical metal cladding waveguide, the Fresnel reflection coefficient spectrum exhibits a narrow peak width and low trough at the resonant incident angles, resulting in high sensitivity to changes in the incident angle-induced spatial shift caused by the PSHE (the highest ∂(|r s/r p|)/∂ θ value can reach 107). After polarization transformation and extinction, the output field demonstrates differential operation with respect to the input field. When applied to edge detection, our differentiator can achieve tunable resolution edge images by adjusting the incident angle. Our proposed edge detection scheme has potential applications for cellular and molecular imaging through two-dimensional extension via the target rotation.

A Novel Multi-modal Population-graph based Framework for Patients of Esophageal Squamous Cell Cancer Prognostic Risk Prediction.

Prognostic risk prediction is pivotal for clinicians to appraise the patient's esophageal squamous cell cancer (ESCC) progression status precisely and tailor individualized therapy treatment plans. Currently, CT-based multi-modal prognostic risk prediction methods have gradually attracted the attention of researchers for their universality, which is also able to be applied in scenarios of preoperative prognostic risk assessment in the early stages of cancer. However, much of the current work focuses only on CT images of the primary tumor, ignoring the important role that CT images of lymph nodes play in prognostic risk prediction. Additionally, it is important to consider and explore the inter-patient feature similarity in prognosis when developing models. To solve these problems, we proposed a novel multi-modal population-graph based framework leveraging CT images including primary tumor and lymph nodes combined with clinical, hematology, and radiomics data for ESCC prognostic risk prediction. A patient population graph was constructed to excavate the homogeneity and heterogeneity of inter-patient feature embedding. Moreover, a novel node-level multi-task joint loss was proposed for graph model optimization through a supervised-based task and an unsupervised-based task. Sufficient experimental results show that our model achieved state-of-the-art performance compared with other baseline models as well as the gold standard on discriminative ability, risk stratification, and clinical utility. The core code is available at https://github.com/wuchengyu123/MPGSurv.

Indisulam synergizes with melphalan to inhibit Multiple Myeloma malignancy via targeting TOP2A.

Multiple myeloma (MM) is the second most prevalent hematologic malignancy which remains uncurable. Numerous drugs have been discovered to inhibit MM cells. Indisulam, an aryl sulfonamide, has a potent anti-myeloma activity in vitro and in vivo. This study aims to explore the new mechanism of indisulam and investigate its potential use in combination with melphalan. We examined DNA damage in MM cells through various methods such as western blotting (WB), immunofluorescence, and comet assay. We also identified the role of topoisomerase IIα (TOP2A) using bioinformatic analyses. The impact of indisulam on the RNA and protein levels of TOP2A was investigated through qPCR and WB. Cell proliferation and apoptosis were assessed using CCK-8 assays, Annexin V/PI assays and WB. We predicted the synergistic effect of the combination treatment based on calculations performed on a website, and further explored the effect of indisulam in combination with melphalan on MM cell lines and xenografts. RNA sequencing data and basic experiments indicated that indisulam caused DNA damage and inhibited TOP2A expression by decreasing transcription and promoting degradation via the proteasome pathway. Functional experiments revealed that silencing TOP2A inhibited cell proliferation and induced apoptosis and DNA damage. Finally, Indisulam/melphalan combination treatment demonstrated a strong synergistic anti-tumor effect compared to single-agent treatments in vitro and in vivo. These findings suggest that combination therapies incorporating indisulam and melphalan have the potential to enhance treatment outcomes for MM.

IRF4-BLOC1S5: the first rearrangement gene identified in TEMPI syndrome.

Not available.

PGKD-Net: Prior-guided and Knowledge Diffusive Network for Choroid Segmentation.

The thickness of the choroid is considered to be an important indicator of clinical diagnosis. Therefore, accurate choroid segmentation in retinal OCT images is crucial for monitoring various ophthalmic diseases. However, this is still challenging due to the blurry boundaries and interference from other lesions. To address these issues, we propose a novel prior-guided and knowledge diffusive network (PGKD-Net) to fully utilize retinal structural information to highlight choroidal region features and boost segmentation performance. Specifically, it is composed of two parts: a Prior-mask Guided Network (PG-Net) for coarse segmentation and a Knowledge Diffusive Network (KD-Net) for fine segmentation. In addition, we design two novel feature enhancement modules, Multi-Scale Context Aggregation (MSCA) and Multi-Level Feature Fusion (MLFF). The MSCA module captures the long-distance dependencies between features from different receptive fields and improves the model's ability to learn global context. The MLFF module integrates the cascaded context knowledge learned from PG-Net to benefit fine-level segmentation. Comprehensive experiments are conducted to evaluate the performance of the proposed PGKD-Net. Experimental results show that our proposed method achieves superior segmentation accuracy over other state-of-the-art methods. Our code is made up publicly available at: https://github.com/yzh-hdu/choroid-segmentation.

RNA-binding proteins in breast cancer: Biological implications and therapeutic opportunities.

RNA-binding proteins (RBPs) refer to a class of proteins that participate in alternative splicing, RNA stability, polyadenylation, localization and translation of RNAs, thus regulating gene expression in post-transcriptional manner. Dysregulation of RNA-RBP interaction contributes to various diseases, including cancer. In breast cancer, disorders in RBP expression and function influence the biological characteristics of tumor cells. Targeting RBPs has fostered the development of innovative therapies for breast cancer. However, the RBP-related mechanisms in breast cancer are not completely clear. In this review, we summarize the regulatory mechanisms of RBPs and their signaling crosstalk in breast cancer. Specifically, we emphasize the potential of certain RBPs as prognostic factors due to their effects on proliferation, invasion, apoptosis, and therapy resistance of breast cancer cells. Most importantly, we present a comprehensive overview of the latest RBP-related therapeutic strategies and novel therapeutic targets that have proven to be useful in the treatment of breast cancer.

Development and validation of prognostic models for small cell lung cancer patients with liver metastasis: a SEER population-based study.

BACKGROUND: This study was to establish and validate prediction models to predict the cancer-specific survival (CSS) and overall survival (OS) of small-cell lung cancer (SCLC) patients with liver metastasis. METHODS: In the retrospective cohort study, SCLC patients with liver metastasis between 2010 and 2015 were retrospectively retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were randomly divided into the training group and testing group (3: 1 ratio). The Cox proportional hazards model was used to determine the predictive factors for CSS and OS in SCLC with liver metastasis. The prediction models were conducted based on the predictive factors. The performances of the prediction models were evaluated by concordance indexes (C-index), and calibration plots. The clinical value of the models was evaluated by decision curve analysis (DCA). RESULTS: In total, 8,587 patients were included, with 154 patients experiencing CSS and 154 patients experiencing OS. The median follow-up was 3 months. Age, gender, marital status, N stage, lung metastases, multiple metastases surgery of metastatic site, chemotherapy, and radiotherapy were independent predictive factors for the CSS and OS of SCLC patients with liver metastasis. The prediction models presented good performances of CSS and OS among patients with liver metastasis, with the C-index for CSS being 0.724, whereas the C-index for OS was 0.732, in the training set. The calibration curve showed a high degree of consistency between the actual and predicted CSS and OS. DCA suggested that the prediction models provided greater net clinical benefit to these patients. CONCLUSION: Our prediction models showed good predictive performance for the CSS and OS among SCLC patients with liver metastasis. Our developed nomograms may help clinicians predict CSS and OS in SCLC patients with liver metastasis.

Pathogenicity and horizontal transmission evaluation of a novel isolated African swine fever virus strain with a three-large-fragment-gene deletion.

African swine fever has caused substantial economic losses to China`s pig industry in recent years. Currently, the highly pathogenic African swine fever virus strain of genotype II is predominantly circulating in China, accompanied by a series of emerging isolates displaying unique genetic variations. The pathogenicity of these emerging strains is still unclear. Recently, a novel ASFV strain with a distinguishable three-large-fragment gene deletion was obtained from the field specimens, and its in vivo pathogenicity and transmission were evaluated in this study. The animal experiment involved inoculating a high dose of YNFN202103 and comparing its effects with those of the highly pathogenic strain GZ201801_2. Results showed that pigs infected by YNFN202103 exhibited significantly prolonged onset and survival time, lower viremia levels, and less severe histopathological lesions compared to GZ201801_2. These findings contributed valuable insights into the pathogenicity and transmission of ASFV and its prevention and eradication strategies in practical settings.

Integrative analysis of an endoplasmic reticulum stress-related signature in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a malignancy in which plasma cells proliferate abnormally, and it remains incurable. The cells are characterized by high levels of endoplasmic reticulum stress (ERS) and depend on the ERS response for survival. Thus, we aim to find an ERS-related signature of MM and assess its diagnostic value. METHODS: We downloaded three datasets of MM from the Gene Expression Omnibus database. After identifying ERS-related differentially expressed genes (ERDEGs), we analyzed them using Gene Ontology enrichment analysis. A protein-protein interaction network, a transcription factor-mRNA network, a miRNA-mRNA network and a drug-mRNA network were constructed to explore the ERDEGs. The clinical application of these genes was identified by calculating the infiltration of immune cells and using receiver operating characteistic analyses. Finally, qPCR was performed to further confirm the roles of ERDEGs. RESULTS: We obtained nine ERDEGs of MM. Gene Ontology enrichment indicated that the ERDEGs played a role in the endoplasmic reticulum membrane. Additionally, the protein-protein interaction network showed interaction among the ERDEGs, and there were 20 proteins, 107 transcription factors, 42 drugs or molecular compounds and 51 miRNAs which were likely to interact with the nine genes. In addition, immune cell infiltration analyses showed that there was a strong correlation between the nine genes and immune cells, and these potential biomarkers exhibited good diagnostic values. Finally, the expression of ERDEGs in MM cells was different from that in healthy donor samples. CONCLUSION: The nine ERS-related genes, CR2, DHCR7, DNAJC3, KDELR2, LPL, OSBPL3, PINK1, VCAM1 and XBP1 are potential biomarkers of MM, and this supports further clinical development of the diagnosis and treatment of MM.

Microvascular activation and exocytosis after exposure to the serum from mismatched recipients by using donor microvascular cultures.

BACKGROUND: Microvascular injury resulting from activation and exocytosis are early signs of tissue damage caused by allografting. However, humoral anti-graft reactions are not easily detectable in transplant biopsies. The aim of this study was to establish a bioassay to recapitulate this process in a prospective approach. METHODS: The study was executed by using our previously established protocol to isolate and freeze the donors' microvascular endothelial cells (MVEC) at the transplantation (34 living-related donors and 26 cadaver donors); and to collect sera from the recipients before the transplantation, one-, three- and six-months after transplantation. The activation and exocytosis of the MVEC were determined by incubating the donors' cultures with the recipients' sera. We determined if there was any endothelial activation by quantifying the releases of monocyte chemotactic protein-1 (MCP-1) and interleukin 8 (IL-8) in supernatants and the expressions of membrane intercellular adhesion molecule-1 (CD54) and intercellular adhesion molecule-1 (CD106) by flow cytometry. Endothelial exocytosis was determined by quantifying soluble E-selectin (CD62E) and cytoplasmic von Willebrand Factor (vWF) in supernatants. Endothelial activation or exocytosis was considered positive when the fold change (≧1.5) of post-transplantation to pre-transplantation was reached. We also monitored serum PRA and cytokines using Luminex multiple-plex and cytometric bead-based assay respectively. RESULTS: We found 41.2% recipients (14 out of 34, ranging from 1.5 to 5.2 folds, p < 0.05) exhibited positive MVEC activation in the first month after transplantation as determined by IL-8 levels; 26.5% recipients (9 out of 34, ranging from 1.5 to 11.8 folds, p < 0.05) by MCP-1 levels. In the group of three months post-transplantation, 70.6% patients were positive (12 out of 17, ranging from 1.8 to 87.1 folds, p < 0.05) by IL-8 increased levels; 24% recipients (4 out of 17, ranging from 1.8 to 50.5 folds, p < 0.05) measured by MCP-1 levels. However, these changes disappeared six months after transplantation. Flow cytometric data showed that a time-dependent of CD54+ and CD106+ expressions existed over the course of six months. Most CD54+ and CD106+ cells were CD31- (platelet-endothelial cell adhesion molecule-1), though CD31+/CD106+ (37.5%, 3 out of 8) and CD31+/CD106+ (25%. 2 out of 8) were seen. When comparing donor MVEC activation to their recipient's proinflammatory cytokine levels or PRA status, we could not draw a conclusion regarding the connections between them. The sera collected from recipients at either one- or three-months after allografting did not significantly induce the release of either soluble CD62E or vWF (p > 0.05), indicating exocytosis was not significantly involved in the acute phase of allografting. CONCLUSIONS: This bioassay enables us to detect the activation and exocytosis of donor MVEC elicited by respective sera from mismatched kidney recipients.

Fibroblast growth factor 10 reverses cigarette smoke- and elastase-induced emphysema and pulmonary hypertension in mice.

BACKGROUND: COPD is an incurable disease and a leading cause of death worldwide. In mice, fibroblast growth factor (FGF)10 is essential for lung morphogenesis, and in humans, polymorphisms in the human FGF10 gene correlate with an increased susceptibility to develop COPD. METHODS: We analysed FGF10 signalling in human lung sections and isolated cells from healthy donor, smoker and COPD lungs. The development of emphysema and PH was investigated in Fgf10+/- and Fgfr2b+/- (FGF receptor 2b) mice upon chronic exposure to cigarette smoke. In addition, we overexpressed FGF10 in mice following elastase- or cigarette smoke-induced emphysema and pulmonary hypertension (PH). RESULTS: We found impaired FGF10 expression in human lung alveolar walls and in primary interstitial COPD lung fibroblasts. In contrast, FGF10 expression was increased in large pulmonary vessels in COPD lungs. Consequently, we identified impaired FGF10 signalling in alveolar walls as an integral part of the pathomechanism that leads to emphysema and PH development: mice with impaired FGF10 signalling (Fgf10+/- and Fgfr2b+/- ) spontaneously developed lung emphysema, PH and other typical pathomechanistic features that generally arise in response to cigarette smoke exposure. CONCLUSION: In a therapeutic approach, FGF10 overexpression successfully restored lung alveolar and vascular structure in mice with established cigarette smoke- and elastase-induced emphysema and PH. FGF10 treatment triggered an initial increase in the number of alveolar type 2 cells that gradually returned to the basal level when the FGF10-mediated repair process progressed. Therefore, the application of recombinant FGF10 or stimulation of the downstream signalling cascade might represent a novel therapeutic strategy in the future.

Theoretical calculations and experimental investigation toward the π-conjugated modulation in arylamine derivative-based hole transporting materials for perovskite solar cells.

Excellent hole transporting materials (HTMs) are beneficial to promote the performance of perovskite solar cells (PSCs). Herein, starting from the modulation of the π-conjugated groups of carbazole-diphenylamine derivatives, HTMs CY1 and CY2 were designed and investigated using density functional theory and Marcus theory. Theoretical simulations show that CY1 and CY2 exhibit appropriate HOMO/LUMO energy levels, small recombination energy, good optical properties and molecular stability. Compared with CY1, CY2 with a larger π-conjugated group on its side chain can yield a higher hole mobility and better charge separation. The experimental results confirm that CY2 in PSCs exhibits superior properties such as good hole transporting ability, good film morphology, and efficient charge extraction and dissociation at perovskite/HTM inerfaces. Therefore, a PSC device with CY2 yields a higher efficiency than those of CY1- and Spiro-OMeTAD-based devices. Hence, the results demonstrate that the strategy of the extended π-π conjugation on a side chain is a practicable approach to design potential HTMs for application in PSCs.

Imaging analysis reveals budding of filamentous human metapneumovirus virions and direct transfer of inclusion bodies through intercellular extensions.

IMPORTANCE: Human metapneumovirus is an important respiratory pathogen that causes significant morbidity and mortality, particularly in the very young, the elderly, and the immunosuppressed. However, the molecular details of how this virus spreads to new target cells are unclear. This work provides important new information on the formation of filamentous structures that are consistent with virus particles and adds critical new insight into the structure of extensions between cells that form during infection. In addition, it demonstrates for the first time the movement of viral replication centers through these intercellular extensions, representing a new mode of direct cell-to-cell spread that may be applicable to other viral systems.

Vegetarian diets and the risk of gastrointestinal cancers: a meta-analysis of observational studies.

The systematic review aimed to assess the association between vegetarian diet and the risk of gastrointestinal tumorigenesis. PubMed, Embase, Cochrane Library, and Web of Science were searched from inception to August 2022 for observational studies on vegetarian diets and the risk of gastrointestinal tumorigenesis. The primary outcome was morbidity due to gastrointestinal cancer. The Newcastle-Ottawa Scale was used to assess the quality of included studies. Pooled effects were analyzed using a random-effects model. The study protocol was registered in PROSPERO (no. CRD42022310187). Eight original studies (seven cohorts and one case-control), involving 686 691 participants, were included. Meta-analysis showed a negative correlation between vegetarian diets and gastrointestinal tumorigenesis risk [relative risk (RR) equals 0.77, 95% confidence interval (CI) is (0.65-0.90)], compared with non-vegetarian diets. Subgroup analysis indicated that vegetarian diets were negatively correlated with the risks of gastric cancer [RR = 0.41, 95% CI (0.28-0.61)] and colorectal cancer [RR = 0.85, 95% CI (0.76-0.95)], but not with that of upper gastrointestinal cancer (excluding stomach) [RR = 0.93, 95% CI (0.61-1.42)]. Vegetarian diets were negatively correlated with the risk of gastrointestinal tumorigenesis in men [RR = 0.57, 95% CI (0.36-0.91)], but were uncorrelated in women [RR = 0.89, 95% CI (0.71-1.11)]. Vegetarian diets were negatively correlated with the risk of gastrointestinal tumorigenesis in North American [RR = 0.76, 95% CI (0.61-0.95)] and Asian populations [RR = 0.43, 95% CI (0.26-0.72)] and were uncorrelated in the European population [RR = 0.83, 95% CI (0.68-1.01)]. Adhering to vegetarian diets reduces the risk of gastrointestinal tumorigenesis. More data from well-conducted cohort and other studies are needed.

Toward controllable and predictable synthesis of high-entropy alloy nanocrystals.

High-entropy alloy (HEA) nanocrystals have attracted extensive attention in catalysis. However, there are no effective strategies for synthesizing them in a controllable and predictable manner. With quinary HEA nanocrystals made of platinum-group metals as an example, we demonstrate that their structures with spatial compositions can be predicted by quantitatively knowing the reduction kinetics of metal precursors and entropy of mixing in the nanocrystals under dropwise addition of the mixing five-metal precursor solution. The time to reach a steady state for each precursor plays a pivotal role in determining the structures of HEA nanocrystals with homogeneous alloy and core-shell features. Compared to the commercial platinum/carbon and phase-separated counterparts, the dendritic HEA nanocrystals with a defect-rich surface show substantial enhancement in catalytic activity and durability toward both hydrogen evolution and oxidation. This quantitative study will lead to a paradigm shift in the design of HEA nanocrystals, pushing away from the trial-and-error approach.

CEACAM6 as a Novel Therapeutic Target to Boost HO-1-mediated Antioxidant Defense in COPD.

Rationale: Tobacco smoking and air pollution are primary causes of chronic obstructive pulmonary disease (COPD). However, only a minority of smokers develop COPD. The mechanisms underlying the defense against nitrosative/oxidative stress in nonsusceptible smokers to COPD remain largely unresolved. Objectives: To investigate the defense mechanisms against nitrosative/oxidative stress that possibly prevent COPD development or progression. Methods: Four cohorts were investigated: 1) sputum samples (healthy, n = 4; COPD, n = 37), 2) lung tissue samples (healthy, n = 13; smokers without COPD, n = 10; smoker+COPD, n = 17), 3) pulmonary lobectomy tissue samples (no/mild emphysema, n = 6), and 4) blood samples (healthy, n = 6; COPD, n = 18). We screened 3-nitrotyrosine (3-NT) levels, as indication of nitrosative/oxidative stress, in human samples. We established a novel in vitro model of a cigarette smoke extract (CSE)-resistant cell line and studied 3-NT formation, antioxidant capacity, and transcriptomic profiles. Results were validated in lung tissue, isolated primary cells, and an ex vivo model using adeno-associated virus-mediated gene transduction and human precision-cut lung slices. Measurements and Main Results: 3-NT levels correlate with COPD severity of patients. In CSE-resistant cells, nitrosative/oxidative stress upon CSE treatment was attenuated, paralleled by profound upregulation of heme oxygenase-1 (HO-1). We identified carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) as a negative regulator of HO-1-mediated nitrosative/oxidative stress defense in human alveolar type 2 epithelial cells (hAEC2s). Consistently, inhibition of HO-1 activity in hAEC2s increased the susceptibility toward CSE-induced damage. Epithelium-specific CEACAM6 overexpression increased nitrosative/oxidative stress and cell death in human precision-cut lung slices on CSE treatment. Conclusions: CEACAM6 expression determines the hAEC2 sensitivity to nitrosative/oxidative stress triggering emphysema development/progression in susceptible smokers.

Oral Ionic Liquid for Transdermal Delivery and Obesity Treatment.

Obesity is currently a prerequisite for more than 70% of adults, including chronic obesity and long-term obesity. With the increase of diabetes patients in the world, it is urgent to develop effective oral drugs to replace insulin. However, the gastrointestinal tract is a main obstacle to oral drug preparations. Here, a highly effective oral drug was developed, mainly formulated as an ionic liquid (IL) prepared by l-(-)-carnitine and geranic acid. Density functional theory (DFT) calculations showed that l-(-)-carnitine and geranic acid can exist stably through hydrogen bonding. IL can significantly enhance the transdermal transport of drugs. In vitro study of intestinal permeability showed that particles formed by IL can prevent the absorption of intestinal fat. Compared with the control group, oral administration of IL (10 mL kg-1) significantly reduced blood glucose, white adipose tissue in the liver and epididymis, and the expression of SREBP-1c and ACC in IL. Therefore, these results and high-throughput sequencing analysis showed that IL can effectively reduce the intestinal absorption of adipose tissue to reduce blood glucose. IL has good biocompatibility and stability. Therefore, IL has a certain application value in the field of oral drug-delivery carriers, which provides an effective means for the treatment of diabetes and is a potential tool to solve the epidemic of obesity.

Nicotine promotes e-cigarette vapour-induced lung inflammation and structural alterations.

BACKGROUND: Electronic cigarette (e-cigarette) vapour is gaining popularity as an alternative to tobacco smoking and can induce acute lung injury. However, the specific role of nicotine in e-cigarette vapour and its long-term effects on the airways, lung parenchyma and vasculature remain unclear. RESULTS: In vitro exposure to nicotine-containing e-cigarette vapour extract (ECVE) or to nicotine-free e-cigarette vapour extract (NF ECVE) induced changes in gene expression of epithelial cells and pulmonary arterial smooth muscle cells (PASMCs), but ECVE in particular caused functional alterations (e.g. a decrease in human and mouse PASMC proliferation by 29.3±5.3% and 44.3±8.4%, respectively). Additionally, acute inhalation of nicotine-containing e-cigarette vapour (ECV) but not nicotine-free e-cigarette vapour (NF ECV) increased pulmonary endothelial permeability in isolated lungs. Long-term in vivo exposure of mice to ECV for 8 months significantly increased the number of inflammatory cells, in particular lymphocytes, compared to control and NF ECV in the bronchoalveolar fluid (BALF) (ECV: 853.4±150.8 cells·mL-1; control: 37.0±21.1 cells·mL-1; NF ECV: 198.6±94.9 cells·mL-1) and in lung tissue (ECV: 25.7±3.3 cells·mm-3; control: 4.8±1.1 cells·mm-3; NF ECV: 14.1±2.2 cells·mm-3). BALF cytokines were predominantly increased by ECV. Moreover, ECV caused significant changes in lung structure and function (e.g. increase in airspace by 17.5±1.4% compared to control), similar to mild tobacco smoke-induced alterations, which also could be detected in the NF ECV group, albeit to a lesser degree. In contrast, the pulmonary vasculature was not significantly affected by ECV or NF ECV. CONCLUSIONS: NF ECV components induce cell type-specific effects and mild pulmonary alterations, while inclusion of nicotine induces significant endothelial damage, inflammation and parenchymal alterations.

The adenosinergic machinery in cancer: In-tandem insights from basic mechanisms to therapy.

Extracellular adenosine (eADO) signaling has emerged as an increasingly important regulator of immune responses, including tumor immunity. eADO is mainly produced from extracellular ATP (eATP) hydrolysis. eATP is rapidly accumulated in the extracellular space following cell death or cellular stress triggered by hypoxia, nutrient starvation, or inflammation. eATP plays a pro-inflammatory role by binding and activating the P2 purinergic receptors (P2X and P2Y), while eADO has been reported in many studies to mediate immunosuppression by activating the P1 purinergic receptors (A1, A2A, A2B, and A3) in diverse immune cells. Consequently, the hydrolysis of eATP to eADO alters the immunosurveillance in the tumor microenvironment (TME) not only by reducing eATP levels but also by enhancing adenosine receptor signaling. The effects of both P1 and P2 purinergic receptors are not restricted to immune cells. Here we review the most up-to-date understanding of the tumor adenosinergic system in all cell types, including immune cells, tumor cells, and stromal cells in TME. The potential novel directions of future adenosinergic therapies in immuno-oncology will be discussed.