Spleen Tyrosine Kinase (SYK) is a critical immune signaling molecule and therapeutic target. We identified damaging monoallelic SYK variants in six patients with immune deficiency, systemic disease such as colitis, arthritis and skin inflammation, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling indicating gain-of-function. A knock-in (SYK S544Y ) mouse model of a patient variant (p.S550Y) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wildtype mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease.

Background: This study aimed to investigate independent risk factors of postoperative hypoxemia in patients with acute type A aortic dissection (ATAAD).Methods: A single-center retrospective study was conducted with enrolled 75 ATAAD patients following surgery, which were stratified into three groups on the basis of the postoperative PaO 2 /FiO 2 ratio: severe hypoxemia group (PaO 2 /FiO 2 ratio ≤100 mmHg); moderate hypoxemia group (100 mmHg < PaO 2 /FiO 2 ratio ≤200 mmHg); and non-hypoxemia group (PaO 2 /FiO 2 ratio >200 mmHg). The patient's demography, perioperative laboratory results, operative details, clinical outcomes were collected and analyzed. Univariable and multivariable analyses were performed and logistic regression model was established. Results:The incidence of postoperative severe hypoxemia and hypoxemia was 32% and 52%, respectively. Among the three groups, severe hypoxemia group exhibited a high significance of body mass index (BMI) and preoperative white blood cell (WBC) and main distribution of hypertension; meanwhile, Marfan syndrome was mainly distributed in non-hypoxemia group. On intensive care unit (ICU) admission, severe hypoxemia group exhibited a high significance of Acute Physiology and Chronic Health Evaluation (APACHE II) score of postoperative patients, and more patients would present shock. Moreover, severe hypoxemia group patients had a higher incidence of postoperative acute kidney injury (AKI) and usage of renal replacement therapy, longer length of stay (LOS) of ICU, and shorter 28 days ventilator-free days (VFDs). Conclusions:The incidence of postoperative hypoxemia was high in ATAAD patients owing to comprehensive high-risk factors. Besides, postoperative complications negatively impacted their clinical outcomes.

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Heparin is a soluble glycosaminoglycan largely used as an anti-coagulant drug and with well known anti‑inflammatory effects. However, heparin is currently not used as an anti‑inflammatory agent in the clinic due to a risk of bleeding as well as its complex mechanism of action. The underlying mechanism of the anti‑inflammatory action of heparin and its effector targets have remained to be fully elucidated. The present study confirmed the anti‑inflammatory effects of heparin in lipopolysaccharide (LPS)‑induced murine peritoneal macrophages through decreasing the levels of the inflammatory cytokines tumor necrosis factor alpha (TNF‑α), interleukin 6 (IL‑6), IL‑8 and IL‑1β. Caveolin‑1 participated in the anti‑inflammatory process and it was able to be induced by heparin. Transfection of small interfering RNA of caveolin‑1 into murine peritoneal macrophages attenuated the anti‑inflammatory effects of heparin. Furthermore, following caveolin‑1 silencing, the p38/mitogen‑activated protein kinase (MAPK) pathway was still able to be activated by heparin, while the extracellular signal‑regulated kinase and c‑Jun N‑terminal kinase pathways were inhibited. In conclusion, these results suggested that heparin inhibits LPS‑induced inflammation via inducing caveolin‑1 and activating the p38/MAPK pathway in murine peritoneal macrophages. Revealing the anti‑inflammatory mechanisms of heparin will aid in its development for clinical treatment in the future.

Heparin is a potent blood anticoagulant that has been demonstrated to attenuate inflammatory responses in sepsis. Sepsis is considered to be a microcirculation-mitochondrial distress syndrome. Azurocidin (AZU), a protein with strong heparin-binding potential that induces inflammatory responses and apoptosis, has been shown to increase the permeability of endothelial cells and induce the prognosis of sepsis. However, the function of AZU in mitochondrial oxygen metabolism has yet to be reported. The aim of the present study was to investigate whether heparin exhibits an antagonistic effect on AZU-induced mitochondrial dysfunction in human umbilical vein endothelial cells (HUVECs) and to further investigate the possible underlying mechanisms. HUVECs were randomly assigned into blank control, AZU, heparin plus AZU and heparin groups. The blank control group were incubated with phosphate-buffered saline for 12 h, while the AZU group were incubated with 1 μg/ml AZU for 12 h. The heparin plus AZU group were incubated with 100 μg/ml heparin for 2 h, followed by the addition of 1 μg/ml AZU and incubation for 12 h. The heparin group were incubated with 100 μg/ml heparin for 12 h. Flow cytometry was used to determine the mitochondrial membrane potential, while electron microscopy was used to determine the mitochondrial morphology. Western blotting and quantitative polymerase chain reaction were used to determine the protein and mRNA expression levels of Cox II in the mitochondria, respectively. Western blotting was also used to evaluate the concentration of AZU in cytoplasm, along with immunofluorescence analysis. AZU was revealed to decrease the mitochondrial membrane potential, reduce cytochrome c oxidase subunit II expression and destroy the morphology of the mitochondria. Heparin exhibited an antagonistic function on these processes and inhibited the endocytosis of AZU by HUVECs. In conclusion, the results indicated that AZU inhibited the oxygen metabolic function in mitochondria, and this function was effectively antagonized by heparin via the inhibition of AZU endocytosis by HUVECs. Therefore, heparin may be a potential therapeutic agent for treating mitochondrial dysfunction in the future.

KRAS mutations are causally linked to pro-tumor inflammation and identified as driving factors in tumorigenesis. Here, using multi-omics data gathered from a large set of patients, we showed that KRAS mutation was associated with a specific landscape of alternative mRNA splicing that connected to myeloid inflammation in intrahepatic cholangiocarcinoma (iCCA). Then, we identified a negative feedback mechanism in which the upregulation of interleukin 1 receptor antagonist (IL1RN)-201/203 due to alternative splicing confers vital anti-inflammatory effects in KRAS mutant iCCA. In KRAS mutant iCCA mice, both IL1RN-201/203 upregulation and anakinra treatment ignited a significant anti-tumor immune response by altering neutrophil recruitment and phenotypes. Furthermore, anakinra treatment synergistically enhanced anti-PD-1 therapy to activate intratumoral GZMB+ CD8+ T cells in KRAS mutant iCCA mice. Clinically, we found that high IL1RN-201/203 levels in KRAS mutant iCCA patients were significantly associated with superior response to anti-PD-1 immunotherapy.

Background: To investigate the conversion ratio of tacrolimus switching from intravenous infusion to oral administration in patients after lung transplantation. Methods: We retrospectively recruited patients received lung transplantation in the First Affiliated Hospital of Guangzhou Medical Hospital from January 2015 to June 2019. The blood concentration of tacrolimus administrated through intravenous infusion and oral administration were collected. The blood concentration, concentration/dose ratio (C/D), and (C/Dpo)/(C/Div) ratio were analyzed to explore the conversion ratio of tacrolimus switching from intravenous infusion to oral administration, as combined medication of tacrolimus and caspofungin were used. Results: The concentration of intravenously administered tacrolimus was significantly higher than that of oral administration; the C/D ratio of intravenously administrated tacrolimus (C/Div) was significantly higher than that of the oral administration (C/Dpo). There was a significant correlation between C/Dpo and C/Div (R 2 =0.774, P<0.001). The conversion ratio of tacrolimus from intravenous administration to oral administration was 1:7.4, as combined medication of tacrolimus and caspofungin were used. Conclusions: The conversion ratio of tacrolimus switching from intravenous to oral administration is 1:7.4 in the combination treatment of tacrolimus and caspofungin after lung transplantation.