Characteristics and outcomes of COVID-19 in Chinese immune thrombocytopenia patients: A prospective cohort study.

The coronavirus disease 2019 (COVID-19) pandemic has a significant impact on the immune system. This is the first and largest study on pre-existing immune thrombocytopenia (ITP) patients infected with COVID-19 in China. We prospectively collected ITP patients infected with COVID-19 enrolled in the National Longitudinal Cohort of Hematological Diseases (NICHE, NCT04645199) and followed up for at least 1 month after infection. One thousand and one hundred forty-eight pre-existing ITP patients were included. Two hundred and twelve (18.5%) patients showed a decrease in the platelet (PLT) count after infection. Forty-seven (4.1%) patients were diagnosed with pneumonia. Risk factors for a decrease in the PLT count included baseline PLT count <50 × 109/L (OR, 1.76; 95% CI, 1.25-2.46; p = 0.001), maintenance therapy including thrombopoietin receptor agonists (TPO-RAs) (OR, 2.27; 95% CI, 1.60-3.21; p < 0.001) and previous splenectomy (OR, 1.98; 95% CI, 1.09-3.61; p = 0.03). Risk factors for pneumonia included age ≥40 years (OR, 2.45; 95% CI, 1.12-5.33; p = 0.02), ≥2 comorbidities (OR, 3.47; 95% CI, 1.63-7.64; p = 0.001), maintenance therapy including TPO-RAs (OR, 2.14; 95% CI, 1.17-3.91; p = 0.01) and immunosuppressants (OR, 3.05; 95% CI, 1.17-7.91; p = 0.02). In this cohort study, we described the characteristics of pre-existing ITP patients infected with COVID-19 and identified several factors associated with poor outcomes.

Semiparametric probit regression model with misclassified current status data.

Current status data arise when each subject under study is examined only once at an observation time, and one only knows the failure status of the event of interest at the observation time rather than the exact failure time. Moreover, the obtained failure status is frequently subject to misclassification due to imperfect tests, yielding misclassified current status data. This article conducts regression analysis of such data with the semiparametric probit model, which serves as an important alternative to existing semiparametric models and has recently received considerable attention in failure time data analysis. We consider the nonparametric maximum likelihood estimation and develop an expectation-maximization (EM) algorithm by incorporating the generalized pool-adjacent-violators (PAV) algorithm to maximize the intractable likelihood function. The resulting estimators of regression parameters are shown to be consistent, asymptotically normal, and semiparametrically efficient. Furthermore, the numerical results in simulation studies indicate that the proposed method performs satisfactorily in finite samples and outperforms the naive method that ignores misclassification. We then apply the proposed method to a real dataset on chlamydia infection.

Efficacy and Safety Analysis of Combination Therapy Consisting of Intravenous Immunoglobulin and Corticosteroids versus Respective Monotherapies in the Treatment of Relapsed ITP in Adults.

Objective In this study, we aimed to evaluate the efficacy and safety of combination therapy, consisting of intravenous immunoglobulin (IVIg) and corticosteroids, in comparison to respective monotherapies in the treatment of relapsed immune thrombocytopenia (ITP) in adults. Methods A retrospective analysis of clinical data was conducted on 205 adult patients with relapsed ITP who received first-line combination therapy or monotherapy in multiple centers across China from January 2010 to December 2022. The study evaluated the patients' clinical characteristics, efficacy, and safety. Results We found that the proportion of patients with platelet counts in complete response was significantly higher in the combination group (71.83%) compared with the IVIg group (43.48%) and the corticosteroids group (23.08%). The mean PLT max in the combination group (178 × 10 9 /L) was significantly higher than that in the IVIg group (109 × 10 9 /L) and the corticosteroids group (76 × 10 9 /L). Additionally, the average time for platelet counts to reach 30 × 10 9 /L, 50 × 10 9 /L, and 100 × 10 9 /L in the combination group was significantly shorter than in the monotherapy groups. The proportion curves for reaching these platelet counts during treatment were also significantly different from those in the monotherapy groups. However, there were no significant differences in the effective rate, clinical characteristics, and adverse events among the three groups. Conclusion We concluded that combining IVIg and corticosteroids was a more effective and faster treatment for relapsed ITP in adults than using either therapy alone. The findings of this study provided clinical evidence and reference for the use of first-line combination therapy in the treatment of relapsed ITP in adults.

Increased reactive oxygen species lead to overactivation of platelets in essential thrombocythemia.

INTRODUCTION: Platelet function, rather than platelet count, plays a crucial role in thrombosis in essential thrombocythemia (ET). However, little is known about the abnormal function of platelets in ET. Here, we investigated the functional characteristics of platelets in ET hemostasis to explore the causes of ET platelet dysfunction and new therapeutic strategies for ET. MATERIALS AND METHODS: We analyzed platelet aggregation, activation, apoptosis, and reactive oxygen species (ROS) in ET patients and JAK2V617F-positive ET-like mice. The effects of ROS on platelet function and the underlying mechanism were investigated by inhibiting ROS using N-acetylcysteine (NAC). RESULTS: Platelet aggregation, activation, apoptosis, ROS, and clot retraction were elevated in ET. No significant differences were observed between ET patients with JAK2V617F or CALR mutations. Increased ROS activated the JAK-STAT pathway, which may further influence platelet function. Inhibition of platelet ROS by NAC reduced platelet aggregation, activation, and apoptosis, and prolonged bleeding time. Furthermore, NAC treatment reduced platelet count in ET-like mice by inhibiting platelet production from megakaryocytes. CONCLUSIONS: Elevated ROS in ET platelets resulted in enhanced platelet activation, function and increased risk of thrombosis. NAC offers a potential therapeutic strategy for reducing platelet count.

Imaging-Guided Biomimetic M1 Macrophage Membrane-Camouflaged Magnetic Nanorobots for Photothermal Immunotargeting Cancer Therapy.

Biohybrid micro/nanorobots have demonstrated improved therapeutic outcomes for targeting and treating diseases in preclinical trials. However, in vivo applications remain challenging due to a lack of sufficient targeting. Based on evidence that immune cells play a role in the immune modulation in the tumor microenvironment, we developed M1 macrophage membrane-coated magnetic photothermal nanocomplexes (MPN) for photoacoustic (PA) imaging-guided tumor therapy. The MPN were able to inherit the protein from the original macrophage cells and exert a targeted immunosuppression role. Integrating black phosphorus quantum dots and DOX also greatly enhanced reactive oxygen species generation and chemo-phototherapy efficacy. The results suggest that the MPN can be employed as an excellent tumor immunotargeting nanorobotic platform for modulating the tumor microenvironment under PA imaging and magnetic guidance and, thus, exert synergistic therapeutic efficacies.

The role of autophagy in idiopathic pulmonary fibrosis: from mechanisms to therapies.

Idiopathic pulmonary fibrosis (IPF) is an interstitial pulmonary disease with an extremely poor prognosis. Autophagy is a fundamental intracellular process involved in maintaining cellular homeostasis and regulating cell survival. Autophagy deficiency has been shown to play an important role in the progression of pulmonary fibrosis. This review focused on the six steps of autophagy, as well as the interplay between autophagy and other seven pulmonary fibrosis related mechanisms, which include extracellular matrix deposition, myofibroblast differentiation, epithelial-mesenchymal transition, pulmonary epithelial cell dysfunction, apoptosis, TGF-ß1 pathway, and the renin-angiotensin system. In addition, this review also summarized autophagy-related signaling pathways such as mTOR, MAPK, JAK2/STAT3 signaling, p65, and Keap1/Nrf2 signaling during the development of IPF. Furthermore, this review also illustrated the commonly used autophagy detection methods, the currently approved antifibrotic drugs pirfenidone and nintedanib, and several prospective compounds targeting autophagy for the treatment of IPF.

The neutrophil-to-lymphocyte ratio is an important indicator correlated to early neurological deterioration in single subcortical infarct patients with diabetes.

Background and purpose: This study aimed to investigate the relationship between neutrophil-to-lymphocyte ratio (NLR) and early neurological deterioration (END) among cases suffering from single subcortical infarction (SSI) and diabetes. Methods: We collected the data of patients with SSI admitted to our hospital between January 2019 and December 2020 retrospectively. A score of ≥2 elevations in overall National Institutes of Health Stroke Scale (NIHSS) score or ≥1 increase in motor NIHSS score in 5-day post-admission was considered END. Furthermore, logistic regression was used to analyze the relationship between NLR and END among SSI cases. Results: Altogether, we enrolled 235 consecutive SSI cases, of which 53 (22.5%) were diagnosed with END, while 93 (39.5%) were diabetic. In patients with diabetes, the value of NLR increased markedly among the patients with END (median, 3.59; IQR, 2.18-4.84) compared to patients without END (median, 2.64; IQR, 1.89-3.18; P = 0.032). Meanwhile, in patients without diabetes, NLR was not significantly associated with END. In the multivariate analysis, NLR values were positively related to END (adjusted odds ratio (OR), 1.768; 95% CI, 1.166-2.682, P = 0.007) upon adjusting age, SSI type, lesion diameter, initial NIHSS, fasting blood glucose (FBG), 2-h postprandial blood glucose (2hPBG), and estimated glomerular filtration rate (eGFR). The subgroup analysis showed that the relationship between NLR and END was more pronounced in the branch atheromatous disease (BAD) (adjusted OR, 1.819; 95% CI, 1.049-3.153, P = 0.033) and anterior SSI subgroups (adjusted OR, 2.102; 95% CI, 1.095-4.037, P = 0.026). Conclusion: NLR value was significantly related to END among SSI patients with diabetes and was recognized as an independent factor in predicting the risk of END.

Bibliometric analysis of studies on the treatment of hemifacial spasm.

Objective: Hemifacial spasm (HFS) is a common neurological disorder of the brain, which is difficult to treat. Most patients are distracted by it and are unable to work or study normally, which seriously affects their physical and mental health. However, there are a few bibliometric studies on it. This paper searched the articles on HFS using a bibliometric approach. Method: Articles about HFS were retrieved from the Web of Science (WoS) Core Collection database. We employed the Visualization of Similarities (VOS)viewer to analyze these publications. Results: A total of 645 reviews or articles in English were retrieved from WoS. In this study, we found that the number of publications showed a rising trend and China is the most active in searching the treatment of HFS. About keywords, neurosciences and neurology was searched (422 times) keyword, followed by hemifacial spasm (420 times) and surgery (320 times). By assessing the organizations, Shanghai Jiao Tong University published the most papers (8.68%), followed by Sungkyunkwan University (3.26%) and Baylor College Medicine (2.64%). A total of 247 journals have delivered publications on the treatment of HFS, World Neurosurgery (44 papers) published the largest number of articles. Conclusion: The annual publications have increased with a fluctuating tendency. More researchers were taking an interest in HFS. This study helped us find out the hotspot and trend in research about facial spasm treatment.

Hypoxia facilitates proliferation of smooth muscle cells derived from pluripotent stem cells for vascular tissue engineering.

Tissue-engineered blood vessels (TEBVs) show significant therapeutic potential for replacing diseased blood vessels. Vascular smooth muscle cells (VSMCs) derived from human induced pluripotent stem cells (hiPSCs) via embryoid body (EB)-based differentiation, are promising seed cells to construct TEBVs. However, obtaining sufficient high-quality hiPSC-VSMCs remains challenging. Stem cells are located in a niche characterized by hypoxia. Hence, we explored molecular and cellular functions at different induction stages from the EB formation commencement to the end of directed differentiation under normoxic and hypoxic conditions, respectively. Hypoxia enhanced the formation, adhesion and amplification rates of EBs. During directed differentiation, hiPSC-VSMCs exhibited increased cell viability under hypoxic conditions. Moreover, seeding hypoxia-pretreated cells on biodegradable scaffolds, facilitated collagen I and elastin secretion, which has significant application value for TEBV development. Hence, we proposed that hypoxic treatment during differentiation effectively induces proliferative hiPSC-VSMCs, expanding high-quality seed cell sources for TEBV construction.

Osthole Attenuates Bleomycin-Induced Pulmonary Fibrosis by Modulating NADPH Oxidase 4-Derived Oxidative Stress in Mice.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by the extensive accumulation of myofibroblasts and collagens. However, the exact mechanism that underlies this condition is unclear. Growing evidence suggests that NADPH oxidases (NOXs), especially NOX4-derived oxidative stress, play an important role in the development of lung fibrosis. Bleomycin (BLM) is a tumor chemotherapeutic agent, which has been widely employed to establish IPF animal models. Osthole (OST) is an active constituent of the fruit of Cnidium ninidium. Here, we used an in vivo mouse model and found that OST suppressed BLM-induced body weight loss, lung injury, pulmonary index increase, fibroblast differentiation, and pulmonary fibrosis. OST also significantly downregulated BLM-induced NOX4 expression and oxidative stress in the lungs. In vitro, OST could inhibit TGF-ß1-induced Smad3 phosphorylation, differentiation, proliferation, collagen synthesis, NOX4 expression, and ROS generation in human lung fibroblasts in a concentration-dependent manner. Moreover, NOX4 overexpression could prevent the above effects of OST. We came to the conclusion that OST could significantly attenuate BLM-induced pulmonary fibrosis in mice, via the mechanism that involved downregulating TGF-ß1/NOX4-mediated oxidative stress in lung fibroblasts.

High SQLE Expression and Gene Amplification Correlates with Poor Prognosis in Head and Neck Squamous Cell Carcinoma.

OBJECTIVE: Squalene epoxidase (SQLE) is considered a metabolic oncogene, but its biological function and prognostic value in head and neck squamous cell carcinoma (HNSCC) remain unclear. We aimed to evaluate the role of SQLE in the occurrence and development of HNSCC through bioinformatics analysis, and validation experiments. METHODS: Transcriptomic, genomic, and clinical data from The Cancer Genome Atlas were used for pan-cancer analysis. SQLE expression in HNSCC was evaluated using Gene Expression Omnibus datasets and immunohistochemistry. The biological significance of SQLE in the tumor microenvironment (TME) of HNSCC was determined using TISCH, HuRI, LinkedOmics, and TIMER 2.0. The prognostic value of SQLE in HNSCC was analyzed using univariate Cox regression and Kaplan-Meier survival curves. Effect of SQLE on the Cal27 HNSCC cell line was evaluated using cell counting kit 8, wound healing, and EdU assays. RESULTS: SQLE was overexpressed and amplified in various cancers, including HNSCC. High SQLE expression promoted cell proliferation, associated with T stage in HNSCC patients. Copy number amplification and DNA demethylation contributed to high SQLE expression in HNSCC, which was associated with poor prognosis. SQLE was related to HNSCC TME, and its mRNA expression/copy number alterations were negatively correlated with the infiltration of CD8+ T cells, follicular helper T cells, and regulatory T cell infiltration and mast cell activation and positively correlated with the infiltration of M0 macrophages and resting mast cells in HNSCC. CONCLUSION: SQLE was identified as a prognostic biomarker and a potential pharmaceutical target for HNSCC.

Mitochondrial quality control protects photoreceptors against oxidative stress in the H2O2-induced models of retinal degeneration diseases.

Retinal degeneration diseases (RDDs) are common and devastating eye diseases characterized by the degeneration of photoreceptors, which are highly associated with oxidative stress. Previous studies reported that mitochondrial dysfunction is associated with various neurodegenerative diseases. However, the role of mitochondrial proteostasis mainly regulated by mitophagy and mitochondrial unfolded protein response (mtUPR) in RDDs is unclear. We hypothesized that the mitochondrial proteostasis is neuroprotective against oxidative injury in RDDs. In this study, the data from our hydrogen peroxide (H2O2)-treated mouse retinal cone cell line (661w) model of RDDs showed that nicotinamide riboside (NR)-activated mitophagy increased the expression of LC3B II and PINK1, and promoted the co-localization of LC3 and mitochondria, as well as PINK1 and Parkin in the H2O2-treated 661w cells. However, the NR-induced mitophagy was remarkably reversed by chloroquine (CQ) and cyclosporine A (CsA), mitophagic inhibitors. In addition, doxycycline (DOX), an inducer of mtUPR, up-regulated the expression of HSP60 and CHOP, the key proteins of mtUPR. Activation of both mitophagy and mtUPR increased the cell viability and reduced the level of apoptosis and oxidative damage in the H2O2-treated 661w cells. Furthermore, both mitophagy and mtUPR played a protective effect on mitochondria by increasing mitochondrial membrane potential and maintaining mitochondrial mass. By contrast, the inhibition of mitophagy by CQ or CsA reversed the beneficial effect of mitophagy in the H2O2-treated 661w cells. Together, our study suggests that the mitophagy and mtUPR pathways may serve as new therapeutic targets to delay the progression of RDDs through enhancing mitochondrial proteostasis.

Scoparone alleviates Ang II-induced pathological myocardial hypertrophy in mice by inhibiting oxidative stress.

Long-term poorly controlled myocardial hypertrophy often leads to heart failure and sudden death. Activation of ras-related C3 botulinum toxin substrate 1 (RAC1) by angiotensin II (Ang II) plays a pivotal role in myocardial hypertrophy. Previous studies have demonstrated that scoparone (SCO) has beneficial effects on hypertension and extracellular matrix remodelling. However, the function of SCO on Ang II-mediated myocardial hypertrophy remains unknown. In our study, a mouse model of myocardial hypertrophy was established by Ang II infusion (2 mg/kg/day) for 4 weeks, and SCO (60 mg/kg bodyweight) was administered by gavage daily. In vitro experiments were also performed. Our results showed that SCO could alleviate Ang II infusion-induced cardiac hypertrophy and fibrosis in mice. In vitro, SCO treatment blocks Ang II-induced cardiomyocyte hypertrophy, cardiac fibroblast collagen synthesis and differentiation to myofibroblasts. Meanwhile, we found that SCO treatment blocked Ang II-induced oxidative stress in cardiomyocytes and cardiac fibroblasts by inhibiting RAC1-GTP and total RAC1 in vivo and in vitro. Furthermore, reactive oxygen species (ROS) burst by overexpression of RAC1 completely abolished SCO-mediated protection in cardiomyocytes and cardiac fibroblasts in vitro. In conclusion, SCO, an antioxidant, may attenuate Ang II-induced myocardial hypertrophy by suppressing of RAC1 mediated oxidative stress.

The Complete Mitochondrial Genomes of Four Species in the Subfamily Limenitidinae (Lepidoptera, Nymphalidae) and a Phylogenetic Analysis.

The complete mitogenomes of four species, Neptis thisbe, Neptis obscurior, Athyma zeroca, and Aldania raddei, were sequenced with sizes ranging from 15,172 bp (N. obscurior) to 16,348 bp (Al. raddei). All four mitogenomes display similar nucleotide content and codon usage of protein-coding genes (PCGs). Typical cloverleaf secondary structures are identified in 21 tRNA genes, while trnS1 (AGN) lacks the dihydrouridine (DHC) arm. The gene orientation and arrangement of the four mitogenomes are similar to that of other typical mitogenomes of Lepidoptera. The Ka/Ks ratio of 13 PCGs among 58 Limenitidinae species reveals that cox1 had the slowest evolutionary rate, while atp8 and nad6 exhibited a higher evolutionary rate. The phylogenetic analysis reveals that tribe-levels are well-supported monophyletic groups. Additionally, Maximum Likelihood analysis recovered the relationship (Parthenini + ((Chalingini + (Cymothoini + Neptini)) + (Adoliadini + Limenitidini))). However, a Bayesian analysis based on the same dataset recovered the relationship (Parthenini + (Adoliadini + ((Cymothoini + Neptini) + (Chalingini + Limenitidini)))). These results will offer valuable data for the future study of the phylogenetic relationships for Limenitidinae.

Protection of melatonin against long-term radon exposure-caused lung injury.

Radon is one of the major pathogenic factors worldwide. Recently, epidemiological studies have suggested that radon exposure plays an important role in lung injury, which could further cause cancer. However, the toxic effects and underlying mechanism on lung injury are still not clear. Here, we identified the detailed toxic effects of long-term radon exposure. Specifically, the manifestations were inflammatory response and cell apoptosis in dose- and time-dependent manners. In detail, it caused the mitochondrial dysfunction and oxidative stress as determined by the abnormal levels of mitochondrial DNA copy number, adenosine triphosphate, mitochondrial membrane potential, superoxide dismutase, and cycloxygenase-2. Furthermore, we found that melatonin treatment ameliorated mitochondrial dysfunction and attenuated the levels of oxidative stress caused by long-term radon exposure, which could further inhibit the lung tissue apoptosis as determined by the decreased levels of cleaved caspase 3. Our study would provide potential therapeutic application of melatonin on lung tissue injury caused by long-term radon exposure.

Fbxo7 and Pink1 play a reciprocal role in regulating their protein levels.

Pink1, Parkin and Fbxo7, three autosomal recessive familial genes of Parkinson's disease (PD), have been implicated in mitophagy pathways for quality control and clearance of damaged mitochondria, but the interplay of these three genes still remains unclear. Here we present that Fbxo7 and Pink1 play a reciprocal role in the regulation of their protein levels. Regardless of the genotypes of Fbxo7, the wild type and the PD familial mutants of Fbxo7 stabilize the processed form of Pink1, supporting the prior study that none of the PD familial mutations in Fbxo7 have an effect on the interaction with Pink1. On the other hand, the interaction of Fbxo7 with Bag2 further facilitates its capability to stabilize Pink1. Intriguingly, the stabilization of Fbxo7 by Pink1 is specifically observed in substantial nigra pars compacta but striatum and cerebral cortex. Taken together, our findings support the notion that Fbxo7 as a scaffold protein has a chaperon activity in the stabilization of proteins.

XIAP Protects Retinal Ganglion Cells in the Mutant ND4 Mouse Model of Leber Hereditary Optic Neuropathy.

Purpose: Leber hereditary optic neuropathy (LHON) is a genetic form of vision loss that occurs primarily owing to mutations in the nicotinamide adenine dinucleotide dehydrogenase (ND) subunits that make up complex I of the electron transport chain. LHON mutations result in the apoptotic death of retinal ganglion cells. We tested the hypothesis that gene therapy with the X-linked inhibitor of apoptosis (XIAP) would prevent retinal ganglion cell apoptosis and reduce disease progression in a vector-induced mouse model of LHON that carries the ND4 mutation. Methods: Adeno-associated virus (AAV) encoding full length hemagglutinin-tagged XIAP (AAV2.HA-XIAP) or green fluorescent protein (AAV2.GFP) was injected into the vitreous of DBA/1J mice. Two weeks later, the LHON phenotype was induced by AAV delivery of mutant ND4 (AAV2.mND4FLAG) to the vitreous. Retinal function was assessed by pattern electroretinography. Optic nerves were harvested at 4 months, and the effects of XIAP therapy on nerve fiber layer and optic nerve integrity were evaluated using immunohistochemistry, transmission electron microscopy and magnetic resonance imaging. Results: During LHON disease progression, retinal ganglion cell axons are lost. Apoptotic cell bodies are seen in the nuclei of astrocytes or oligodendrocytes in the optic nerve, and there is thinning of the optic nerve and the nerve fiber layer of the retina. At 4 months after disease onset, XIAP gene therapy protects the nerve fiber layer and optic nerve architecture by preserving axon health. XIAP also decreases nuclear fragmentation in resident astrocytes or oligodendrocytes and decreases glial cell infiltration. Conclusions: XIAP therapy improves optic nerve health and delays disease progression in LHON.

Astragaloside IV alleviates doxorubicin induced cardiomyopathy by inhibiting NADPH oxidase derived oxidative stress.

Doxorubicin (DOX) is a classic anti-tumor chemotherapeutic used to treat a wide range of tumors. One major downfall of DOX treatment is it can induce fatal cardiotoxicity. Astragaloside IV (AS-IV) is one of the primary active ingredients that can be isolated from the traditional Chinese herbal medicine, Astragalus membranaceus. This study uses both in vitro and in vivo tools to investigate whether AS-IV alleviates DOX induced cardiomyopathy. We found that AS-IV supplementation alleviates body weight loss, myocardial injury, apoptosis of cardiomyocytes, cardiac fibrosis and cardiac dysfunction in DOX-treated mice. Also, DOX-induced cardiomyocyte injury and apoptosis were effectively improved by AS-IV treatment in vitro. NADPH oxidase (NOX) plays an important role in the progress of the oxidative signal transduction and DOX-induced cardiomyopathy. In this study, we found that AS-IV treatment relieves DOX-induced NOX2 and NOX4 expression and oxidative stress in cardiomyocytes. In conclusion, AS-IV, an antioxidant, attenuates DOX-induced cardiomyopathy through the suppression of NOX2 and NOX4.

Radon induced mitochondrial dysfunction in human bronchial epithelial cells and epithelial-mesenchymal transition with long-term exposure.

Radon is a naturally occurring radionuclide, which has a wide environmental distributed. It emits multiple high linear energy transfer (LET) alpha particles during radiative decay, and has been regarded as a human carcinogen by the International Agency for Research on Cancer. Currently, residential radon exposure is considered as the second highest cause of lung cancer and the leading cause among nonsmokers. Radon exposure leads to genomic instability, which causes the accumulation of multiple genetic changes and leads to cancer development. However, the molecular basis underlying carcinogenesis, especially the radon-induced changes to mitochondria, has not been fully elucidated. The aim of this study was to explore the dynamic changes in mitochondria along with the cell transformations induced by long-term radon exposure. A malignant transformation model of BEAS-2B cells was established with upto 40 times the usual radon exposure (20 000 Bq m-3, 30 min each time every 3 days). Long-term radon exposure induced EMT-like transformation of epithelial cells in our study, evidenced by decrease in epithelial markers and increase in mesenchymal markers, as well as the loss of cell-cell adhesion and alterations to the morphology of cells from compact shape to a spindle shaped, fibroblast-like morphology. Additionally, the proliferation and migration of cells were increased and apoptosis was decreased with long-term radon exposure. Furthermore, mitochondrial function was up-regulated and the levels of oxidative stress were repressed with long-term radon exposure. Our work explored the dynamic changes of mitochondrial in radon induced malignant transformation of lung bronchial epithelial cells, which could partially elucidate the role of mitochondria in radon induced cell malignancy.

Control of Treg cell homeostasis and immune equilibrium by Lkb1 in dendritic cells.

To balance immunity and tolerance, the endogenous pool of Foxp3+ regulatory T (Treg) cells is tightly controlled, but the underlying mechanisms of this control remain poorly understood. Here we show that the number of Treg cells is negatively regulated by the kinase Lkb1 in dendritic cells (DCs). Conditional knockout of the Lkb1 gene in DCs leads to excessive Treg cell expansion in multiple organs and dampens antigen-specific T cell immunity. Lkb1-deficient DCs are capable of enhancing, compared with wild-type DCs, Treg cell proliferation via cell-cell contact involving the IKK/IKBα-independent activation of the NF-κB/OX40L pathway. Intriguingly, treating wild-type mice with lipopolysaccharide selectively depletes Lkb1 protein in DCs, resulting in Treg cell expansion and suppressed inflammatory injury upon subsequent challenge. Loss of Lkb1 does not obviously upregulate proinflammatory molecules expression on DCs. We thus identify Lkb1 as a regulatory switch in DCs for controlling Treg cell homeostasis, immune response and tolerance.