Clinically Applicable AI System for Accurate Diagnosis, Quantitative Measurements, and Prognosis of COVID-19 Pneumonia Using Computed Tomography.

Many COVID-19 patients infected by SARS-CoV-2 virus develop pneumonia (called novel coronavirus pneumonia, NCP) and rapidly progress to respiratory failure. However, rapid diagnosis and identification of high-risk patients for early intervention are challenging. Using a large computed tomography (CT) database from 3,777 patients, we developed an AI system that can diagnose NCP and differentiate it from other common pneumonia and normal controls. The AI system can assist radiologists and physicians in performing a quick diagnosis especially when the health system is overloaded. Significantly, our AI system identified important clinical markers that correlated with the NCP lesion properties. Together with the clinical data, our AI system was able to provide accurate clinical prognosis that can aid clinicians to consider appropriate early clinical management and allocate resources appropriately. We have made this AI system available globally to assist the clinicians to combat COVID-19.

m6A-mediated upregulation of miRNA-193a aggravates cardiomyocyte apoptosis and inflammatory response in sepsis-induced cardiomyopathy via the METTL3/ miRNA-193a/BCL2L2 pathway.

The impact of N6-methyladenosine (m6A) modification on pri-miRNA in sepsis-induced cardiomyopathy (SICM), and its underlying regulatory mechanism, have not been fully elucidated. We successfully constructed a SICM mice model through cecal ligation and puncture (CLP). In vitro, a lipopolysaccharide (LPS)-induced HL-1 cells model was also established. The results showed that sepsis frequently resulted in excessive inflammatory response concomitant with impaired myocardial function in mice exposed to CLP, as indicated by decreases in ejection fraction (EF), fraction shortening (FS), and left ventricular end diastolic diameters (LVDd). miR-193a was enriched in CLP mice heart and in LPS-treated HL-1 cells, while overexpression of miR-193a significantly increased the expression levels of cytokines. Sepsis-induced enrichment of miR-193a significantly inhibited cardiomyocytes proliferation and enhanced apoptosis, while this was reversed by miR-193a knockdown. Furthermore, under our experimental conditions, enrichment of miR-193a in SICM could be considered excessively maturated on pri-miR-193a by enhanced m6A modification. This modification was catalyzed by sepsis-induced overexpression of methyltransferase-like 3 (METTL3). Moreover, mature miRNA-193a bound to a predictive sequence within 3'UTRs of a downstream target, BCL2L2, which was further validated by the observation that the BCL2L2-3'UTR mutant failed to decrease luciferase activity when co-transfected with miRNA-193a. The interaction between miRNA-193a and BCL2L2 resulted in BCL2L2 downregulation, subsequently activating the caspase-3 apoptotic pathway. In conclusion, sepsis-induced miR-193a enrichment via m6A modification plays an essential regulatory role in cardiomyocyte apoptosis and inflammatory response in SICM. The detrimental axis of METTL3/m6A/miR-193a/BCL2L2 is implicated in the development of SICM.

Metformin alleviates allergic airway inflammation and increases Treg cells in obese asthma.

Obesity increases the morbidity and severity of asthma, with poor sensitivity to corticosteroid treatment. Metformin has potential effects on improving asthma airway inflammation. Regulatory T cells (Tregs) play a key role in suppressing the immunoreaction to allergens. We built an obese asthmatic mouse model by administering a high-fat diet (HFD) and ovalbumin (OVA) sensitization, with daily metformin treatment. We measured the body weight and airway inflammatory status by histological analysis, qRT-PCR, and ELISA. The percentage of Tregs was measured by flow cytometry. Obese asthmatic mice displayed more severe airway inflammation and more significant changes in inflammatory cytokines. Metformin reversed the obese situation and alleviated the airway inflammation and remodelling with increased Tregs and related transcript factors. The anti-inflammatory function of metformin may be mediated by increasing Tregs.

miR-142-5p and miR-130a-3p regulate pulmonary macrophage polarization and asthma airway remodeling.

Macrophages are key regulators of the development and progression of asthma, facilitating deleterious airway remodeling in affected patients. Immune cell function is tightly regulated by microRNAs (miRNAs), but how these miRNAs impact macrophage-mediated airway remodeling in the context of asthma remains to be determined. In this study, we utilized an ovalbumin (OVA)-based murine model of asthma to evaluate the importance of miRNAs within these macrophages. We found that macrophages from mice that had been sensitized with and exposed to OVA expressed higher levels of M2-like phenotypic markers and exhibited significantly altered expression of both miR-142-5p and miR-130a-3p. When these isolated pulmonary macrophages were cultured in vitro, we determined that transfecting them with miR-142-5p antisense oligonucleotide (ASO) or miR-130a-3p mimics was sufficient to inhibit the ability of interleukin-4 to induce M2 cytokine production. We additionally confirmed the in vivo relevance of these miRNAs in a Ccr2-/- murine model system mimicking asthma. Specifically, we determined that transfecting monocytes with miR-142-5p ASO and/or miR-130a-3p mimics was sufficient to disrupt the ability of these cells to promote airway remodeling. As such, these findings reveal that miR-142-5p and miR-130a-3p dysregulation are important factors governing the polarization of macrophages and associated airway remodeling in OVA-sensitized mice.

MiR-23b controls TGF-ß1 induced airway smooth muscle cell proliferation via direct targeting of Smad3.

BACKGROUND: MicroRNAs are small yet versatile gene tuners that regulate a variety of cellular processes, including cell growth and proliferation. Here we report that miR-23b inhibited airway smooth muscle cells (ASMCs) proliferation through directly targeting of Smad3. METHODS: We obtained ASMCs by laser capture microdissection of normal and asthmatic mice lung tissues. Mice ASMCs were cultured and induced by TGF-ß1. The implication between TGF-ß1 and miR-23b in ASMCs were detected by RT-PCR. The effects of miR-23b on ASMCs proliferation and apoptosis were assessed by transient transfection of miR-23b mimics and inhibitor. The expression of Smad3 in ASMCs were detected by RT-PCR and Western blotting analysis. Dual-Luciferase Reporter Assay System will be applied to identify whether Smad3 is a target gene of miR-23b. RESULTS: TGF-ß1 and miR-23b mRNA expression of in-situ bronchial ASMCs collected by laser capture microdissection were increased in asthmatic mice compared to non-asthma controls. This is accompanied by an increase in miR-23b mRNA expression in TGF-ß1 induced ASMCs. miR-23b up-regulation significantly inhibited TGF-ß1-induced ASMCs proliferation and promoted apoptosis. MiR-23b negatively regulates the expression of Smad3 in ASMCs. Dual-Luciferase Reporter Assay System demonstrated that Smad3 was a direct target of miR-23b. CONCLUSIONS: MiR-23b may function as an inhibitor of asthma airway remodeling by suppressing ASMCs proliferation via direct targeting of Smad3.

Airway smooth muscle cells from ovalbumin-sensitized mice show increased proliferative response to TGFß1 due to upregulation of Smad3 and TGFßRII.

OBJECTIVE: This study aimed to elucidate the role of Transforming growth factor (TGF)-ß1 signaling in the proliferation of airway smooth muscle cells (ASMCs). BACKGROUND: TGF-ß1 is an important cytokine in airway remodeling in asthma. However, results of studies focusing on the effect of TGFß1 on proliferation of ASMCs are controversial. METHODS: An allergic model that mimics airway remodeling in chronic asthma was established and primary ASMCs were cultured. Cell proliferation was detected by viable cell counting and Cell Counting Kit (CCK)-8 analysis. Expression and phosphorylation of Smad3, type 1 TGFß receptor (TGFßRI), type 2 TGFß receptor (TGFßRII), extracellular signal-regulated kinase (ERK)-1/2, p38 mitogen-activated protein kinase (MAPK), C-Jun N-terminal kinase (JNK) and AKT were detected by western blot. siRNAs were used to knock down Smad3 and TGFßRII. RESULTS: Smad3 and TGFßRII were up-regulated in primary ASMCs isolated from ovalbumin (OVA)-sensitized mice as compared with ASMCs isolated from unsensitized control mice, which persisted for at least four passages. TGFß1 stimulated proliferation of ASMCs isolated from OVA-sensitized mice, which was inhibited by specific siRNA targeting Smad3 or TGFßRII. However ASMCs from control mice showed no proliferative response to TGFß1. TGFß1-induced proliferation of ASMCs from OVA-sensitized mice was markedly attenuated by PD-98059, a specific ERK1/2 inhibitor. TGFß1 induced ERK1/2 phosphorylation within 15 minute, which was partially blocked by specific inhibitor of Smad3 (SIS3). CONCLUSIONS: ASMCs isolated from OVA-sensitized mice showed hyper-proliferation upon TGFß1 stimulation. This might have been associated with up-regulated Smad3 and TGFßRII and mediated by ERK1/2 downstream to Smad3.

Triptolide inhibits TGF-ß1-induced cell proliferation in rat airway smooth muscle cells by suppressing Smad signaling.

BACKGROUND: We have reported that triptolide can inhibit airway remodeling in a murine model of asthma via TGF-ß1/Smad signaling. In the present study, we aimed to investigate the effect of triptolide on airway smooth muscle cells (ASMCs) proliferation and the possible mechanism. METHODS: Rat airway smooth muscle cells were cultured and made synchronized, then pretreated with different concentration of triptolide before stimulated by TGF-ß1. Cell proliferation was evaluated by MTT assay. Flow cytometry was used to study the influence of triptolide on cell cycle and apoptosis. Signal proteins (Smad2, Smad3 and Smad7) were detected by western blotting analysis. RESULTS: Triptolide significantly inhibited TGF-ß1-induced ASMC proliferation (P<0.05). The cell cycle was blocked at G1/S-interphase by triptolide dose dependently. No pro-apoptotic effects were detected under the concentration of triptolide we used. Western blotting analysis showed TGF-ß1 induced Smad2 and Smad3 phosphorylation was inhibited by triptolide pretreatment, and the level of Smad7 was increased by triptolide pretreatment. CONCLUSIONS: Triptolide may function as an inhibitor of asthma airway remodeling by suppressing ASMCs proliferation via negative regulation of Smad signaling pathway.

Triptolide inhibits TGF-ß1 induced proliferation and migration of rat airway smooth muscle cells by suppressing NF-κB but not ERK1/2.

BACKGROUND: Airway remodeling contributes to increased mortality in asthma. We have reported that triptolide can inhibit airway remodeling in a mouse asthma model. In this study, we aimed to investigate the effect of triptolide on airway smooth muscle cells (ASMCs) proliferation, migration and the possible mechanism. METHODS: Rat airway smooth muscle cells were cultured and made synchronized, then pretreated with different concentrations of triptolide before stimulated by TGF-ß1. Cell proliferation was evaluated by cell counting and MTT assay. Flow cytometry was used to study the influence of triptolide on cell cycle. Migration was measured by Transwell analysis. Signal proteins (NF-κB p65 and ERK1/2) were detected by western blotting analysis. LDH releasing test and flow cytometry analysis of apoptosis were also performed to explore the potential cytotoxic or pro-apoptotic effects of triptolide. RESULTS: Triptolide significantly inhibited TGF-ß1 induced ASMC proliferation and migration (p<0.05). The cell cycle was blocked at G1/S-interphase by triptolide dose dependently. Western blotting analysis showed TGF-ß1 induced NF-κB p65 phosphorylation was inhibited by triptolide pretreatment, but ERK1/2 was not affected. No cytotoxic or pro-apoptotic effects were detected under the concentration of triptolide we used. CONCLUSIONS: Triptolide may function as an inhibitor of asthma airway remodeling by suppressing ASMCs proliferation and migration through inactivation of NF-κB pathway. This article is protected by copyright. All rights reserved.

Inhibition of TRPM7 channels reduces degranulation and release of cytokines in rat bone marrow-derived mast cells.

BACKGROUND: mast cells play an important role in airway inflammation in asthma. The transient receptor potential melastatin-like 7 (TRPM7) channel is expressed in primary human lung mast cells and plays a critical role for cell survival. This study aimed to investigate the role of TRPM7 on degranulation and release of cytokines in rat bone marrow-derived mast cells (BMMCs). METHODS: the expression levels of TRPM7 were observed by immunocytochemistry and RT-PCR between normal and asthmatic rat BMMCs. TRPM7-specific shRNA and 2-aminoethoxydiphenyl borate (2-APB) and specific shTRPM7 were used to inhibit the function of TRPM7. Degranulation levels were analyzed by beta-hexosaminidase assay. Histamine, TNF-α, IL-6 and IL-13 levels were measured by ELISA. RESULTS: the expression of TRPM7 was significantly higher in asthmatic rat BMMCs than in the normal control group. After application of 2-APB and down-regulation of TRPM7, the beta-hexosaminidase activity and secretion of histamine, IL-6, IL-13 and TNF-α were significantly decreased in the asthmatic group compared to the control group. CONCLUSION: this study indicates that TRPM7 channels may be involved in the process of degranulation and release of cytokines in rat bone marrow-derived mast cells.

Assessment of sepsis-associated encephalopathy by quantitative magnetic resonance spectroscopy in a rat model of cecal ligation and puncture.

Proton magnetic resonance spectroscopy (1H-MRS) is the only non-invasive technique to quantify neurometabolic compounds in the living brain. We used 1H-MRS to evaluate the brain metabolites in a rat model of Sepsis-associated encephalopathy (SAE) established by cecal ligation and puncture (CLP). 36 male Sprague-Dawley rats were randomly divided into sham and CLP groups. Each group was further divided into three subgroups: subgroup O, subgroup M, and subgroup N. Neurological function assessments were performed on the animals in the subgroup O and subgroup N at 24 h, 48 h, and 72 h. The animals in the subgroup M were examined by magnetic resonance imaging (MRI) at 12 h after CLP. Compared with the sham group, the ratio of N-acetylaspartate (NAA) to creatine (Cr) in the hippocampus was significantly lower in the CLP group. The respective ratios of lactate (Lac), myo-inositol (mIns), glutamate and glutamine (Glx), lipid (Lip), and choline (Cho) to Cr in the CLP group were clearly higher than those in the sham group. Cytochrome c, intimately related to oxidative stress, was elevated in the CLP group. Neurofilament light (NfL) chain and glial fibrillary acidic protein (GFAP) scores in the CLP group were significantly higher than those in the sham group, while zonula occludens-1 (ZO-1) was downregulated. Compared with the sham group, the CLP group displayed higher values of oxygen extraction fraction (OEF), central venous-arterial partial pressure of carbon dioxide (P (cv-a) CO2), and central venous lactate (VLac). In contrast, jugular venous oxygen saturation (SjvO2) declined. In the present study, 1H-MRS could be used to quantitatively assess brain injury in terms of microcirculation disorder, oxidative stress, blood-brain barrier disruption, and glial cell activation through changes in metabolites within brain tissue.

Allergic hyper-carcinoembryonic antigen syndrome: A syndrome summarized by case series.

Allergic respiratory diseases can increase serum carcinoembryonic antigen levels. We report three cases experiencing allergic symptoms that proved refractory to inhaled corticosteroids but exhibited a positive response to long-term treatment with oral corticosteroids. This response was characterized by a synchronous alteration in serum eosinophil counts and carcinoembryonic antigen levels. Immunofluorescence assays indicated localized carcinoembryonic antigen production within eosinophils. In addition, we conducted a systematic review of patients exhibiting similar characteristics on PubMed. After comprehensively reviewing this unique pathophysiological condition, we herein introduced a novel term "Allergic hyper-carcinoembryonic antigen syndrome," defined by the following criteria: (1) recurrent asthmatic attacks; (2) eosinophilia or pulmonary eosinophilic infiltrations accompanied by elevated serum carcinoembryonic antigen levels; (3) pulmonary lesions determined by imaging or biopsy; (4) exclusion of malignancy and infections; and (5) responsive to systemic corticosteroids. Allergic hyper-carcinoembryonic antigen syndrome suggests systemic corticosteroids should be introduced early when managing allergic patients with both eosinophilia and elevated serum carcinoembryonic antigen levels.

Consensus for antifungal stewardship in China (2024 edition).

Background: Invasive fungal disease (IFD) has become a serious threat to human health in China and around the world, with high mortality and morbidity. Currently, the misdiagnosis rate of IFD is extremely high, compounded with the low quality of prescription antifungals and the high incidence of adverse events associated with IFD treatment, resulting in lengthy hospitalization, low clinical response, and high disease burden, which have become serious challenges in clinical practice. Antifungal stewardship (AFS) can not only significantly increase the early diagnosis rate of IFD, reduce inappropriate utilization of antifungal drugs, improve patient prognosis, but can also improve therapeutic safety and reduce healthcare expenses. Thus, it is urgent to identify key AFS metrics suitable for China's current situation. Methods: Based on metrics recommended by international AFS consensuses, combined with the current situation of China and the clinical experience of authoritative experts in various fields, several metrics were selected, and experts in the fields of respiratory diseases, hematology, intensive care units (ICUs), dermatology, infectious diseases, microbiology laboratory and pharmacy were invited to assess AFS metrics by the Delphi method. Consensus was considered to be reached with an agreement level of ≥80% for the metric. Results: Consensus was reached for 24 metrics, including right patient metrics (n=4), right time metrics (n=3), and right use metrics (n=17). Right use metrics were further subdivided into drug choice (n=8), drug dosage (n=4), drug de-escalation (n=1), drug duration (n=2), and drug consumption (n=2) metrics. Forty-six authoritative experts assessed and reviewed the above metrics, and a consensus was reached with a final agreement level of ≥80% for 22 metrics. Conclusions: This consensus is the first to propose a set of AFS metrics suitable for China, which helps to establish AFS standards in China and is also the first AFS consensus in Asia, and may improve the standard of clinical diagnosis and treatment of IFD, and guide hospitals to implement AFS, ultimately promoting the rational use of antifungal drugs and improving patient prognosis.

Gut microbiota and risk of five common cancers: A univariable and multivariable Mendelian randomization study.

BACKGROUND: Previous studies have linked gut microbiota with cancer etiology, but the associations for specific gut microbiota are causal or owing to bias remain to be elucidated. METHODS: We performed a two-sample Mendelian randomization (MR) analysis to assess the causal effect of gut microbiota on cancer risk. Five common cancers, including breast, endometrial, lung, ovarian, and prostate cancer as well as their subtypes (sample sizes ranging from 27,209 to 228,951) were included as the outcomes. Genetic information for gut microbiota was obtained from a genome-wide association study (GWAS) comprising 18,340 participants. In univariable MR (UVMR) analysis, the inverse variance weighted (IVW) method was conducted as the primary method, with the robust adjusted profile scores, weighted median, and MR Egger used as supplementary methods for causal inference. Sensitivity analyses including the Cochran Q test, Egger intercept test, and leave-one-out analysis were performed to verify the robustness of the MR results. Multivariable MR (MVMR) was performed to evaluate the direct causal effects of gut microbiota on the risk of cancers. RESULTS: UVMR detected a higher abundance of genus Sellimonas predicted a higher risk of estrogen receptor-positive breast cancer (OR = 1.09, 95% CI 1.05-1.14, p = 2.01 × 10-5 ), and a higher abundance of class Alphaproteobacteria was associated with a lower risk of prostate cancer (OR = 0.84, 95% CI 0.75-0.93, p = 1.11 × 10-3 ). Sensitivity analysis found little evidence of bias in the current study. MVMR further confirmed that genus Sellimonas exerted a direct effect on breast cancer, while the effect of class Alphaproteobacteria on prostate cancer was driven by the common risk factors of prostate cancer. CONCLUSION: Our study implies the involvement of gut microbiota in cancer development, which provides a novel potential target for cancer screening and prevention, and might have an implication for future functional analysis.

Development and Validation of a Nomogram for Predicting Tigecycline-Related Coagulopathy: A Retrospective Cohort Study.

Background: Although tigecycline is an effective drug against drug-resistant bacteria, it demonstrated a higher all-cause mortality than comparator antibiotics and a high incidence of coagulation disorders which can be accompanied by severe bleeding. At present, a predictive model for tigecycline-related coagulopathy is not readily available, and the prognostic value of coagulopathy in tigecycline-administered patients has not been elucidated. In this paper, we investigate the association between tigecycline-related coagulopathy and in-hospital mortality to develop a nomogram for the prediction of tigecycline-related coagulopathy. Methods: This retrospective cohort study includes 311 adults prescribed with tigecycline from 2018 to 2020. The primary cohort and validation cohort were constructed by dividing the participants in a ratio of 7:3. The endpoint is tigecycline-related coagulopathy, defined as a condition with no abnormality in coagulation prior to tigecycline application but developed the following symptoms upon prescription: activated partial thromboplastin time (APTT) extended by >10 s than the upper limit of normal (ULN), prothrombin time (PT) prolonged for >3 s than the ULN or reduced serum level of fibrinogen to <2.0 g/L. A predictive nomogram based on logistic regression was subsequently constructed. Results: Tigecycline intake for over 7 days, combined other antibiotics, initial PT, initial fibrinogen and estimated glomerular filtration rate (eGFR), are independent prognostic factors of tigecycline-related coagulopathy. The primary and validation cohort each has an area under the receiver operating characteristic curve (AUC) of 0.792 (0.732-0.851) and 0.730 (0.629-0.832) for nomogram, respectively. Furthermore, the fitted calibration curve illustrated adequate fit of the model, while the decision curve analysis demonstrated good clinical value. Survival curves showed a high mortality rate among patients with tigecycline-related coagulopathy. Conclusion: This nomogram exhibited helpful clinical value in predicting tigecycline-related coagulopathy that could reduce the high mortality rate of patients prescribed with tigecycline.

Magnesium affects the cytokine secretion of CD4⁺ T lymphocytes in acute asthma.

INTRODUCTION: Magnesium (Mg) administration has been shown to promote bronchodilation and to improve lung function in asthma. It also plays an additional role in modulating the immune responses. This study was initiated to explore if Mg supplementation could affect the secretion of cytokines in acute asthmatic CD4⁺ T cells. METHODS: Total serum Mg concentrations of the acute asthmatic patients and healthy controls were determined. CD4⁺ T cells were isolated from the blood of the acute asthmatic patients. They were cultured in various concentrations of Mg-supplemented (0.8, 5, 10, 15, and 20 mmol/l) medium. Cytokine (IL-5, IL-13, and IFN-γ) levels were determined by Enzyme-Linked Immunosorbnent Assay (ELISA). RESULTS: Serum Mg concentration was lower in the acute asthmatic patients than that in the healthy controls (p < .05). The secretion of IL-5 and IL-13 was decreased, while the acute asthmatic CD4⁺ T cells were cultured in 10 and 15 mmol/l Mg-supplemented medium, respectively, as compared to the 0.8 mmol/l Mg group (p < .05). The secretion of IFN-γ increased in the 10 mmol/l Mg group (p < .05). CONCLUSION: Mg supplementation was able to modulate the immune responses of acute asthmatic CD4⁺ T cells and decrease the secretion of type 2 CD4⁺ T lymphocytes cytokines.

2-Aminoethoxydiphenyl borate reduces degranulation and release of cytokines in a rat mast cell line.

BACKGROUND AND OBJECTIVE: 2-aminoethoxydiphenyl borate (2-APB) has been reported to be a useful pharmacological tool in the study of calcium signaling. It is used either as a membrane-permeable inhibitor for inositol 1,4,5-trisphosphate (IP3) receptors or a store-operated calcium (Ca2+) entry (SOCE) inhibitor. The present study aimed to evaluate the effects of 2-APB on degranulation and cytokine production after antigen activation in a rat mast cell line, RBL-2H3 cells. MATERIALS AND METHODS: Degranulation levels were analyzed by beta-hexosaminidase assay. Intracellular calcium concentrations were measured by Fluo-3 assay. The mRNA expression of interleukin-4 (IL-4) and tumor necrosis factor (TNF)-alfa were analyzed by Real-time PCR. RESULTS: The intracellular Ca2+ levels were greatly suppressed in the absence or presence of 2 mmol/L Ca2+ in the extracellular medium when RBL-2H3 cells were pretreated with 100 micromol/L 2-APB for 15 min. The beta-hexosaminidase activity as well as the mRNA expression of IL-4 and TNF-alfa levels were significantly decreased after application of 2-APB. CONCLUSION: This study indicates that the application of 2-APB may be a useful method to inhibit mast cell activation.

Successful combinatorial therapy of sirolimus and neuraminidase inhibitors in a patient with highly pathogenic avian influenza A (H5N6) virus: a case report.

Background: Highly pathogenic avian influenza A (H5N6) virus poses a continuous threat to human health since 2014. Although neuraminidase inhibitors (NAIs) are prescribed in most patients infected with the H5N6 virus, the fatality remains high, indicating the need for an improved treatment regimen. Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), has been reported to reduce viral replication and improve clinical outcomes in severe H1N1 infections when combined with oseltamivir. Here, we report the first case of severe H5N6 pneumonia successfully treated by sirolimus and NAIs. Case Description: A 22-year-old man developed high fever and chills on September 24, 2018 (Day-0) and was hospitalized on Day-3. Influenza A (H5N6) was identified on Day-6 from a throat swab specimen. Despite the administration of NAIs and other supportive measures, the patient's clinical conditions and lung images showed continued deterioration, accompanied by persistently high viral titers. Consequently, sirolimus administration (rapamycin; 2 mg per day for 14 days) was started on Day-12. His PaO2/FiO2 values and Sequential Organ Failure Assessment (SOFA) score gradually improved, and imaging outcomes revealed the resolution of bilateral lung infiltrations. The viral titer gradually decreased and turned negative on Day-25. Sirolimus and NAIs were stopped on the same day. The patient was discharged on Day-65. Based on observations from a 2-year follow-up, the patient was found to be in a good condition without complications. Conclusions: In conclusion, sirolimus might be a novel and practical therapeutic approach to severe H5N6-associated pneumonia in humans.

Anti-galectin-3 antibodies induce skin vascular inflammation via promoting local production of IL-1ß in systemic lupus erythematosus.

Vascular inflammation could occur in all organs and tissues in patients with systematic lupus erythematosus (SLE), of which skin is the most frequent one. Our previous research identified anti-galectin-3 (Gal3) antibodies (Abs) as an important mediator of lupus cutaneous vasculopathy. Herein, we showed that anti-Gal3 Abs dysregulated the function of vascular endothelial cells with higher transcript levels of IL-1ß and increased expression of mature IL-1ß. The enhanced production of IL-1ß secreted by endothelial cells was dependent on NLRP3 inflammasome. Intradermal injection of anti-Gal3 Abs in mice induced local inflammation with perivascular infiltration of T cells and neutrophils, which was inhibited by IL-1ß blockade. Induction of anti-Gal3 Abs in circulation by immunization of Gal3 antigen not only led to histopathologic changes in the skin, including focal keratinocytes vacuolization and thickening of blood vessels, but also a systemic autoimmune phenotype that involves autoantibody production and kidney damage. Intriguingly, local overexpression of IL-1ß was primarily associated with skin lesions but not with other internal organs in mice. Finally, we showed that the serum levels of IL-1ß were comparable between SLE patients and healthy donors. Whilst the expression of IL-1ß was enriched in local area with perivascular inflammation in lupus skin lesion compared to healthy normal skin. The results strongly suggest that IL-1ß plays an important role in mediating anti-Gal3 Ab-induced skin vascular inflammation and raised the prospect for using IL-1ß blocking therapies to treat lupus cutaneous damage.

The effects of triptolide on airway remodelling and transforming growth factor-ß1/Smad signalling pathway in ovalbumin-sensitized mice.

Airway remodelling contributes to increased morbidity and mortality in asthma. We have reported that triptolide, the major component responsible for the immunosuppressive and anti-inflammatory effects of Tripterygium wilfordii Hook F, inhibited pulmonary inflammation in patients with steroid-resistant asthma. In the present study, we investigated whether triptolide inhibits airway remodelling in a mouse asthma model and observed the effects of triptolide on the transforming growth factor-ß1 (TGF-ß1)/Smad pathway in ovalbumin (OVA)-sensitized mice. BALB/c mice were sensitized to intraperitoneal OVA followed by repetitive OVA challenge for 8 weeks. Treatments included triptolide (40 µg/kg) and dexamethasone (2 mg/kg). The area of bronchial airway (WAt/basement membrane perimeter) and smooth muscle (WAm/basement membrane perimeter), mucus index and collagen area were assessed 24 hr after the final OVA challenge. Levels of TGF-ß(1) were assessed by immunohistology and ELISA, levels of TGF-ß(1) mRNA were measured by RT-PCR, and levels of pSmad2/3 and Smad7 were assessed by Western blot. Triptolide and dexamethasone significantly reduced allergen-induced increases in the thickness of bronchial airway and smooth muscle, mucous gland hypertrophy, goblet cell hyperplasia and collagen deposition. Levels of lung TGF-ß(1) , TGF-ß(1) mRNA and pSmad2/3 were significantly reduced in mice treated with triptolide and dexamethasone, and this was associated with a significant increase in levels of Smad7. Triptolide may function as an inhibitor of asthma airway remodelling. It may be a potential drug for the treatment of patients with a severe asthma airway.