SRCAP complex promotes lung cancer progression by reprograming the oncogenic transcription of Hippo-YAP/TAZ signaling pathway.

The activation of YAP/TAZ, a pair of paralogs of transcriptional coactivators, initiates a dysregulated transcription program, which is a key feature of human cancer cells. However, it is not fully understood how YAP/TAZ promote dysregulated transcription for tumor progression. In this study, we employed the BioID method to identify the interactome of YAP/TAZ and discovered that YAP/TAZ interact with multiple components of SRCAP complex, a finding that was further validated through endogenous and exogenous co-immunoprecipitation, as well as immunofluorescence experiments. CUT&Tag analysis revealed that SRCAP complex facilitates the deposition of histone variant H2A.Z at target promoters. The depletion of SRCAP complex resulted in a decrease in H2A.Z occupancy and the oncogenic transcription of YAP/TAZ target genes. Additionally, the blockade of SRCAP complex suppressed YAP-driven tumor growth. In a genetically engineered lung adenocarcinoma mouse model and non-small cell lung cancer patients, SRCAP complex and H2A.Z deposition were found to be upregulated. This upregulation was statistically correlated with YAP expression, pathological stages, and poor survival in lung cancer patients. Together, our study uncovers that SRCAP complex plays a critical role in YAP/TAZ oncogenic transcription by coordinating H2A.Z deposition during cancer progression, providing potential targets for cancer diagnosis and prevention.

LATS2 condensates organize signalosomes for Hippo pathway signal transduction.

Biomolecular condensates have been proposed to mediate cellular signaling transduction. However, the mechanism and functional consequences of signal condensates are not well understood. Here we report that LATS2, the core kinase of the Hippo pathway, responds to F-actin cytoskeleton reduction and forms condensates. The proline-rich motif (PRM) of LATS2 mediates its condensation. LATS2 partitions with the main components of the Hippo pathway to assemble a signalosome for LATS2 activation and for its stability by physically compartmentalizing from E3 ligase FBXL16 complex-dependent degradation, which in turn mediates yes-associated protein (YAP)-transcriptional coactivator with PDZ-binding motif (TAZ) recruitment and inactivation. This oncogenic FBXL16 complex blocks LATS2 condensation by binding to the PRM region to promote its degradation. Disruption of LATS2 condensation leads to tumor progression. Thus, our study uncovers that the signalosomes assembled by LATS2 condensation provide a compartmentalized and reversible platform for Hippo signaling transduction and protein stability, which have potential implications in cancer diagnosis and therapeutics.

Tiam1 methylation by NSD2 promotes Rac1 signaling activation and colon cancer metastasis.

Metastasis is a major cause of cancer therapy failure and mortality. However, targeting metastatic seeding and colonization remains a significant challenge. In this study, we identified NSD2, a histone methyltransferase responsible for dimethylating histone 3 at lysine 36, as being overexpressed in metastatic tumors. Our findings suggest that NSD2 overexpression enhances tumor metastasis both in vitro and in vivo. Further analysis revealed that NSD2 promotes tumor metastasis by activating Rac1 signaling. Mechanistically, NSD2 combines with and activates Tiam1 (T lymphoma invasion and metastasis 1) and promotes Rac1 signaling by methylating Tiam1 at K724. In vivo and in vitro studies revealed that Tiam1 K724 methylation could be a predictive factor for cancer prognosis and a potential target for metastasis inhibition. Furthermore, we have developed inhibitory peptide which was proved to inhibit tumor metastasis through blocking the interaction between NSD2 and Tiam1. Our results demonstrate that NSD2-methylated Tiam1 promotes Rac1 signaling and cancer metastasis. These results provide insights into the inhibition of tumor metastasis.

Inhibition of acylglycerol kinase sensitizes DLBCL to venetoclax via upregulation of FOXO1-mediated BCL-2 expression.

Background: Despite of the paradigm change on the treatments of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) by venetoclax, it has been less successful in the treatment of diffuse large B-cell lymphoma (DLBCL). Here, we explored whether acylglycerol kinase regulates the sensitivity of DLBCLs to venetoclax and its mechanism in both cell lines and preclinical animal models. Methods: The expression of AGK and sensitivity to venetoclax of seven DLBCL cell lines were determined. Upon knockdown and overexpression of AGK by lentivirus in DLBCL cells, the venetoclax-induced apoptosis and PTEN-FOXO1-BCL-2 signaling axis were evaluated in vitro. The efficacy of venetoclax and PTEN-FOXO1-BCL-2 signaling axis were evaluated in immunodeficient NCG mice that were implanted with control or shAGK stably transduced SU-DHL4 cells. The expressions of AGK, BCL-2 and FOXO1 were evaluated in tumor tissues of DLBCL patients. Results: AGK expression was inversely correlated with sensitivity of DLBCL to venetoclax. Inhibition of AGK rendered the DLBCL cells more sensitive to venetoclax. Mechanistically, AGK phosphorylated and inactivated PTEN, which led to AKT activation and reduced FOXO1 nuclear translocation. Inhibition of AGK also led to enhanced efficacy of venetoclax for suppression of DLBCL tumor growth in vivo, which was dependent on FOXO1. In human DLBCL tumor tissues, the expression of AGK inversely correlated with BCL-2 expression, as well as the amounts of nuclear FOXO1. Conclusions: Our data demonstrated that AGK regulates venetoclax response in DLBCL via PTEN-FOXO1-BCL-2 signaling axis. Targeting AGK may enhance the efficacy of venetoclax for the treatment of DLBCL patients.

Transcription factor EB coordinates environmental cues to regulate T regulatory cells' mitochondrial fitness and function.

T regulatory (Treg) cells are essential for self-tolerance whereas they are detrimental for dampening the host anti-tumor immunity. How Treg cells adapt to environmental signals to orchestrate their homeostasis and functions remains poorly understood. Here, we identified that transcription factor EB (TFEB) is induced by host nutrition deprivation or interleukin (IL)-2 in CD4+ T cells. The loss of TFEB in Treg cells leads to reduced Treg accumulation and impaired Treg function in mouse models of cancer and autoimmune disease. TFEB intrinsically regulates genes involved in Treg cell differentiation and mitochondria function while it suppresses expression of proinflammatory cytokines independently of its established roles in autophagy. This coordinated action is required for mitochondria integrity and appropriate lipid metabolism in Treg cells. These findings identify TFEB as a critical regulator for orchestrating Treg generation and function, which may contribute to the adaptive responses of T cells to local environmental cues.

Abnormal global alternative RNA splicing in COVID-19 patients.

Viral infections can alter host transcriptomes by manipulating host splicing machinery. Despite intensive transcriptomic studies on SARS-CoV-2, a systematic analysis of alternative splicing (AS) in severe COVID-19 patients remains largely elusive. Here we integrated proteomic and transcriptomic sequencing data to study AS changes in COVID-19 patients. We discovered that RNA splicing is among the major down-regulated proteomic signatures in COVID-19 patients. The transcriptome analysis showed that SARS-CoV-2 infection induces widespread dysregulation of transcript usage and expression, affecting blood coagulation, neutrophil activation, and cytokine production. Notably, CD74 and LRRFIP1 had increased skipping of an exon in COVID-19 patients that disrupts a functional domain, which correlated with reduced antiviral immunity. Furthermore, the dysregulation of transcripts was strongly correlated with clinical severity of COVID-19, and splice-variants may contribute to unexpected therapeutic activity. In summary, our data highlight that a better understanding of the AS landscape may aid in COVID-19 diagnosis and therapy.

Increased Expression of Tim-3 Is Associated With Depletion of NKT Cells In SARS-CoV-2 Infection.

In the ongoing coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), natural killer T (NKT) cells act as primary initiators of immune responses. However, a decrease of circulating NKT cells has been observed in COVID-19 different stages, of which the underlying mechanism remains to be elucidated. Here, by performing single-cell RNA sequencing analysis in three large cohorts of COVID-19 patients, we found that increased expression of Tim-3 promotes depletion of NKT cells during the progression stage of COVID-19, which is associated with disease severity and outcome of patients with COVID-19. Tim-3+ NKT cells also expressed high levels of CD147 and CD26, which are potential SARS-CoV-2 spike binding receptors. In the study, Tim-3+ NKT cells showed high enrichment of apoptosis, higher expression levels of mitochondrial genes and caspase genes, with a larger pseudo time value. In addition, Tim-3+ NKT cells in COVID-19 presented a stronger capacity to secrete IFN-γ, IL-4 and IL-10 compared with healthy individuals, they also demonstrated high expression of co-inhibitory receptors such as PD-1, CTLA-4, and LAG-3. Moreover, we found that IL-12 secreted by dendritic cells (DCs) was positively correlated with up-regulated expression of Tim-3 in NKT cells in COVID-19 patients. Overall, this study describes a novel mechanism by which up-regulated Tim-3 expression induced the depletion and dysfunction of NKT cells in COVID-19 patients. These findings not only have possible implications for the prediction of severity and prognosis in COVID-19 but also provide a link between NKT cells and future new therapeutic strategies in SARS-CoV-2 infection.

Aorta Regulatory T Cells with a Tissue-Specific Phenotype and Function Promote Tissue Repair through Tff1 in Abdominal Aortic Aneurysms.

In addition to maintaining immune tolerance, Foxp3+ regulatory T cells (Tregs) perform specialized functions in tissue homeostasis and remodeling. However, whether Tregs in aortic aneurysms have a tissue-specific phenotype and function is unclear. Here, a special group of Tregs that potentially inhibit abdominal aortic aneurysm (AAA) progression are identified and functionally characterized. Aortic Tregs gradually increase during the process of AAA and are mainly recruited from peripheral circulation. Single-cell TCR sequencing and bulk RNA sequencing demonstrate their unique phenotype and highly expressed trefoil factor 1 (Tff1). Foxp3cre/cre Tff1flox/flox mice are used to clarify the role of Tff1 in AAA, suggesting that aortic Tregs secrete Tff1 to regulate smooth muscle cell (SMC) survival. In vitro experiments confirm that Tff1 inhibits SMC apoptosis through the extracellular signal-regulated kinase (ERK) 1/2 pathway. The findings reveal a tissue-specific phenotype and function of aortic Tregs and may provide a promising and novel approach for the prevention of AAA.

Depletion and Dysfunction of Dendritic Cells: Understanding SARS-CoV-2 Infection.

Uncontrolled severe acute respiratory syndrome-coronavirus (SARS-CoV)-2 infection is closely related to disorders of the innate immune and delayed adaptive immune systems. Dendritic cells (DCs) "bridge" innate immunity and adaptive immunity. DCs have important roles in defending against SARS-CoV-2 infection. In this review, we summarize the latest research concerning the role of DCs in SARS-CoV-2 infection. We focus on the complex interplay between DCs and SARS-CoV-2: pyroptosis-induced activation; activation of the renin-angiotensin-aldosterone system; and activation of dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin. We also discuss the decline in DC number, the impaired antigen-presentation capability, and the reduced production of type-I interferon of DCs in severe SARS-CoV-2 infection. In addition, we discuss the potential mechanisms for pathological activation of DCs to understand the pattern of SARS-CoV-2 infection. Lastly, we provide a brief overview of novel vaccination and immunotherapy strategies based on DC targeting to overcome SARS-CoV-2 infection.

Pathogenic Tconvs promote inflammatory macrophage polarization through GM-CSF and exacerbate abdominal aortic aneurysm formation.

Abdominal aortic aneurysms (AAAs) elicit massive inflammatory leukocyte recruitment to the aorta. CD4+ T cells, which include regulatory T cells (Tregs) and conventional T cells (Tconvs), are involved in the progression of AAA. Tregs have been reported to limit AAA formation. However, the function and phenotype of the Tconvs found in AAAs remain poorly understood. We characterized aortic Tconvs by bulk RNA sequencing and discovered that Tconvs in aortic aneurysm highly expressed Cxcr6 and Csf2. Herein, we determined that the CXCR6/CXCL16 signaling axis controlled the recruitment of Tconvs to aortic aneurysms. Deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF), encoded by Csf2, markedly inhibited AAA formation and led to a decrease of inflammatory monocytes, due to a reduction of CCL2 expression. Conversely, the exogenous administration of GM-CSF exacerbated inflammatory monocyte infiltration by upregulating CCL2 expression, resulting in worsened AAA formation. Mechanistically, GM-CSF upregulated the expression of interferon regulatory factor 5 to promote M1-like macrophage differentiation in aortic aneurysms. Importantly, we also demonstrated that the GM-CSF produced by Tconvs enhanced the polarization of M1-like macrophages and exacerbated AAA formation. Our findings revealed that GM-CSF, which was predominantly derived from Tconvs in aortic aneurysms, played a pathogenic role in the progression of AAAs and may represent a potential target for AAA treatment.

Ferroptosis Markers Predict the Survival, Immune Infiltration, and Ibrutinib Resistance of Diffuse Large B cell Lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common hematological malignancy in adults. Ferroptosis is an iron-dependent programmed cell death caused by lipid peroxidation. However, the potential functions of ferroptosis in the DLBCL prognosis, immune infiltration, and drug resistance remain unknown. Data of DLBCL patients were downloaded from public GEO databases and TCGA cohort. R software was used for analysis. Ferroptosis-related risk score model was constructed using LASSO Cox regression analysis. The prognosis of the model and its association with immune cells infiltration and ibrutinib-resistance were studied by single-sample gene set enrichment analysis (ssGSEA) and correlation analysis. Ferroptosis-related risk score model was constructed with 11 ferroptosis-related genes. DLBCL patients can be divided into high- or low-risk groups with this model. High-risk patients had significant shorter survival (p < 0.001). The area under curve at 3-year was 0.779. Functional enrichment analysis was mainly associated with the immune response. High score patients were positively correlated with immunosuppressive cell infiltration, including macrophages and regulatory T cells, and immunoevasion checkpoints, such as CTLA4, PD-L1, LAG-3, and TIM-3. We also found that tumors with high risk would resist to ibrutinib treatment and uncovered that acetaminophen, as a ferroptosis inducer, inhibited the defined high-risk gene expression in the ibrutinib-resistant DLBCL cell lines. Ferroptosis-related risk score model can predict the overall survival (OS) of DLBCL patients and ibrutinib resistance of ABC-DLBCL cells, which was associated with immunosuppression status within the tumor microenvironment.

EZH2-triggered methylation of SMAD3 promotes its activation and tumor metastasis.

SMAD3 plays a central role in cancer metastasis, and its hyperactivation is linked to poor cancer outcomes. Thus, it is critical to understand the upstream signaling pathways that govern SMAD3 activation. Here, we report that SMAD3 underwent methylation at K53 and K333 (K53/K333) by EZH2, a process crucial for cell membrane recruitment, phosphorylation, and activation of SMAD3 upon TGFB1 stimulation. Mechanistically, EZH2-triggered SMAD3 methylation facilitated SMAD3 interaction with its cellular membrane localization molecule (SARA), which in turn sustained SMAD3 phosphorylation by the TGFB receptor. Pathologically, increased expression of EZH2 expression resulted in the accumulation of SMAD3 methylation to facilitate SMAD3 activation. EZH2-mediated SMAD3 K53/K333 methylation was upregulated and correlated with SMAD3 hyperactivation in breast cancer, promoted tumor metastasis, and was predictive of poor survival outcomes. We used 2 TAT peptides to abrogate SMAD3 methylation and therapeutically inhibit cancer metastasis. Collectively, these findings reveal the complicated layers involved in the regulation of SMAD3 activation coordinated by EZH2-mediated SMAD3 K53/K333 methylation to drive cancer metastasis.

The incidence, clinical characteristics, and outcome of polytrauma patients with the combination of pulmonary contusion, flail chest and upper thoracic spinal injury.

BACKGROUND: Chest trauma was the third most common cause of death in polytrauma patients, accounting for 25% of all deaths from traumatic injury. Chest trauma involves in injury to the bony thorax, intrathoracic organs and thoracic medulla. This study aimed to investigate the incidence, clinical characteristics, and outcome of polytrauma patients with pulmonary contusion, flail chest and upper thoracic spinal injury. METHODS: Patients who met inclusion criteria were divided into groups: Pulmonary contusion group (PC); Pulmonary contusion and flail chest group (PC + FC); Pulmonary contusion and upper thoracic spinal cord injury group (PC + UTSCI); Thoracic trauma triad group (TTT): included patients with flail chest, pulmonary contusion and the upper thoracic spinal cord injury coexisted. Outcomes were determined, including 30-day mortality and 6-month mortality. RESULTS: A total 84 patients (2.0%) with TTT out of 4176 polytrauma patients presented to Tongji trauma center. There was no difference in mean ISS among PC + FC group, PC + UTSCI group and TTT group. Patients with TTT had a longer ICU stay (21.4 days vs. 7.5 and 6.2; p<0.01), relatively higher 30-day mortality (40.5% vs. 6.0% and 4.3%; p<0.01), and especially higher 6-month mortality (71.4% vs. 6.5%, 13.0%; p<0.01), compared to patients with PC + FC or with PC + UTSCI. The leading causes of death for patients with TTT were ARDS (44.1%) and pulmonary infection (26.5%) during first 30 days after admission. For those patients who died later than 30 days during the 6 months, the predominant underlying cause of death was MOF (53.8%). CONCLUSIONS: Lethal triad of thoracic trauma (LTTT) were described in this study, which consisting of pulmonary contusion,flail chest and the upper thoracic spine cord injury. Like the classic "lethal triad", there was a synergy between the factors when they coexist, resulting in especially high mortality rates. Polytrauma patients with LTTT were presented relatively high 30-day mortality and 6 months mortality. We should pay much more attention to the patients with LTTT for further minimizing complications and mortality.

Clinical characteristics and risk factors of COVID-19 patients with chronic hepatitis B: a multi-center retrospective cohort study.

The Coronavirus disease 2019 (COVID-19) has spread globally. Although mixed liver impairment has been reported in COVID-19 patients, the association of liver injury caused by specific subtype especially chronic hepatitis B (CHB) with COVID-19 has not been elucidated. In this multi-center, retrospective, and observational cohort study, 109 CHB and 327 non-CHB patients with COVID-19 were propensity score matched at an approximate ratio of 3:1 on the basis of age, sex, and comorbidities. Demographic characteristics, laboratory examinations, disease severity, and clinical outcomes were compared. Furthermore, univariable and multivariable logistic and Cox regression models were used to explore the risk factors for disease severity and mortality, respectively. A higher proportion of CHB patients (30 of 109 (27.52%)) developed into severe status than non-CHB patients (17 of 327 (5.20%)). In addition to previously reported liver impairment markers, such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin, we identified several novel risk factors including elevated lactate dehydrogenase (⩾ 245 U/L, hazard ratio (HR) = 8.639, 95% confidence interval (CI) = 2.528-29.523; P < 0.001) and coagulation-related biomarker D-dimer (⩾ 0.5 µg/mL, HR = 4.321, 95% CI = 1.443-12.939; P = 0.009) and decreased albumin (< 35 g/L, HR = 0.131, 95% CI = 0.048-0.361; P < 0.001) and albumin/globulin ratio (< 1.5, HR = 0.123, 95% CI = 0.017-0.918; P = 0.041). In conclusion, COVID-19 patients with CHB were more likely to develop into severe illness and die. The risk factors that we identified may be helpful for early clinical surveillance of critical progression.

Genetic association analysis between IL9 and coronary artery disease in a Chinese Han population.

Interleukin-9 (IL-9) plays important role in coronary artery disease (CAD). However, the exact relationship between them is not explored yet. Here, four tag SNPs covering IL9 (rs31563, rs2069868, rs2069870 and rs31564) were selected to conduct case-control association analyses in a total of 3704 individuals from Chinese Han population (1863 CAD vs 1841 control). Results showed that: first, rs2069868 was associated with CAD combined with hypertension (Padj = 0.027); second, IL9 haplotype (CGAT) was associated with CAD (Padj = 0.035), and the combination genotype of "rs31563_CC/rs31564_TT" would remarkably decrease the risk of CAD (Padj = 0.001); third, significant associations were found between rs2069870 and decreased LDL-c levels and decreased total cholesterol levels, and between rs31563 and increased HDL-c levels (Padj < 0.05). Therefore, we conclude that IL9 might play a causal role in CAD by interacted with CAD traditional risk factors, which might confer a new way to improve the prevention and treatment of CAD.

Interleukin-7 Biology and Its Effects on Immune Cells: Mediator of Generation, Differentiation, Survival, and Homeostasis.

Interleukin-7 (IL-7), a molecule known for its growth-promoting effects on progenitors of B cells, remains one of the most extensively studied cytokines. It plays a vital role in health maintenance and disease prevention, and the congenital deficiency of IL-7 signaling leads to profound immunodeficiency. IL-7 contributes to host defense by regulating the development and homeostasis of immune cells, including T lymphocytes, B lymphocytes, and natural killer (NK) cells. Clinical trials of recombinant IL-7 have demonstrated safety and potent immune reconstitution effects. In this article, we discuss IL-7 and its functions in immune cell development, drawing on a substantial body of knowledge regarding the biology of IL-7. We aim to answer some remaining questions about IL-7, providing insights essential for designing new strategies of immune intervention.

Lactate in the tumour microenvironment: From immune modulation to therapy.

Disordered metabolic states, which are characterised by hypoxia and elevated levels of metabolites, particularly lactate, contribute to the immunosuppression in the tumour microenvironment (TME). Excessive lactate secreted by metabolism-reprogrammed cancer cells regulates immune responses via causing extracellular acidification, acting as an energy source by shuttling between different cell populations, and inhibiting the mechanistic (previously 'mammalian') target of rapamycin (mTOR) pathway in immune cells. This review focuses on recent advances in the regulation of immune responses by lactate, as well as therapeutic strategies targeting lactate anabolism and transport in the TME, such as those involving glycolytic enzymes and monocarboxylate transporter inhibitors. Considering the multifaceted roles of lactate in cancer metabolism, a comprehensive understanding of how lactate and lactate-targeting therapies regulate immune responses in the TME will provide insights into the complex relationships between metabolism and antitumour immunity.

Bispecific antibody targeting TROP2xCD3 suppresses tumor growth of triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) is a subtype of breast cancers with poor prognosis and targeted drug therapies are limited. To develop novel and efficacious therapies for TNBC, we developed a bispecific antibody F7AK3 that recognizes both trophoblast cell surface antigen 2 (TROP2) and CD3 and evaluated its antitumor activities both in vitro and in vivo. METHODS: The binding affinities of F7AK3 to the two targets, TROP2 and CD3, were evaluated by surface plasmon resonance. Binding of F7AK3 to TNBC cells and T cells were evaluated by flow cytometry. Immunofluorescent staining was performed to demonstrate the interactions between T cells with TNBC cells. The cytotoxicity of T cells against TNBC cell lines and primary tumor cells mediated by F7AK3 were determined in vitro. In vivo antitumor activity of F7AK3 was investigated in a xenograft TNBC tumor model, using immunodeficient mice that were reconstituted with human peripheral blood mononuclear cells. RESULTS: We demonstrated that F7AK3 binds specifically to human TROP2 and CD3 antigens, as well as TNBC cell lines and primary tumor cells. Human T cells can only be activated by F7AK3 in the presence of target tumor cells. F7AK3 recruits T cells to TROP2+ tumor cells in vitro and into tumor tissues in vivo. Antitumor growth activity of F7AK3 is observed in a xenograft TNBC tumor model. CONCLUSION: This study showed the antitumor potential of an anti-TROP2xCD3 bispecific antibody F7AK3 to TNBC tumor cells both in vitro and in vivo. These data demonstrate that F7AK3 has the potential to treat TNBC patients, which warrants further preclinical and clinical evaluation of the F7AK3 in advanced or metastatic TNBC patients.

Iron deprivation restrains the differentiation and pathogenicity of T helper 17 cell.

Iron plays a critical role in immune responses. However, its role in T helper cell differentiation and function remains poorly understood. In this study, it is shown that the restraint of iron availability through blocking CD71-mediated iron endocytosis impaired the differentiation and pathogenicity of TH 17 cells. Administrations of anti-CD71 mAb could relieve the development of experimental autoimmune encephalomyelitis (EAE). Mechanistically, the iron deficiency due to the blocking of CD71 enhanced IL-2 expression, which further restrained the differentiation of TH 17 cells. Meanwhile, CD71 blockade impaired histone modifications of Il17 gene and reduced the recruitment of RORγt to Il17a locus. In sum, the findings reveal that iron plays a pivotal role in regulating TH 17 cell differentiation and function in autoimmune diseases.

Clinical characteristics and risk factors of fatal patients with COVID-19: a retrospective cohort study in Wuhan, China.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has caused a global pandemic, resulting in considerable mortality. The risk factors, clinical treatments, especially comprehensive risk models for COVID-19 death are urgently warranted. METHODS: In this retrospective study, 281 non-survivors and 712 survivors with propensity score matching by age, sex, and comorbidities were enrolled from January 13, 2020 to March 31, 2020. RESULTS: Higher SOFA, qSOFA, APACHE II and SIRS scores, hypoxia, elevated inflammatory cytokines, multi-organ dysfunction, decreased immune cell subsets, and complications were significantly associated with the higher COVID-19 death risk. In addition to traditional predictors for death risk, including APACHE II (AUC = 0.83), SIRS (AUC = 0.75), SOFA (AUC = 0.70) and qSOFA scores (AUC = 0.61), another four prediction models that included immune cells subsets (AUC = 0.90), multiple organ damage biomarkers (AUC = 0.89), complications (AUC = 0.88) and inflammatory-related indexes (AUC = 0.75) were established. Additionally, the predictive accuracy of combining these risk factors (AUC = 0.950) was also significantly higher than that of each risk group alone, which was significant for early clinical management for COVID-19. CONCLUSIONS: The potential risk factors could help to predict the clinical prognosis of COVID-19 patients at an early stage. The combined model might be more suitable for the death risk evaluation of COVID-19.