Cyclo(L-Pro-L-Trp) from Chilobrachys jingzhao alleviates formalin-induced inflammatory pain by suppressing the inflammatory response and inhibiting TRAF6-mediated MAPK and NF-κB signaling pathways.

Chronic pain has emerged as a significant public health issue, seriously affecting patients' quality of life and psychological well-being, with a lack of effective pharmacological treatments. Numerous studies have indicated that macrophages play a crucial role in inflammatory pain, and targeting neuro-immune interactions for drug development may represent a promising direction for pain management. Chilobrachys jingzhao (C. jingzhao) is used as a folk medicine of the Li nationality with the efficacy of eliminating swelling, detoxicating, and relieving pain, and the related products are widely used in the market. However, the chemical constituents of C. jingzhao have not been reported, and the pharmacodynamic substance and the precise functional mechanism are unrevealed. Here we isolated a cyclic dipeptide, cyclo(L-Pro-L-Trp) (CPT) from C. jingzhao for the first time. CPT remarkably alleviated formalin-induced inflammatory pain and significantly inhibited inflammatory responses. In vivo, CPT attenuated neutrophil infiltration and plantar tissue edema and suppressed the mRNA expression of pro-inflammatory molecules. In vitro, CPT suppressed inflammation triggered by lipopolysaccharide (LPS) in both RAW 264.7 and iBMDM cells, reducing expressions of inducible nitric oxide synthase (iNOS), superoxide, and pro-inflammatory molecules. A mechanistic study revealed that CPT exerted an anti-inflammatory activity by blocking the mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, as well as alleviating the ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6). Our results elucidated the pharmacodynamic material basis of C. jingzhao, and CPT can be a promising lead for alleviating inflammation and inflammatory pain.

Recombinant human adenovirus type 5 promotes anti-tumor immunity via inducing pyroptosis in tumor endothelial cells.

Recombinant human type 5 adenovirus (H101) is an oncolytic virus used to treat nasopharyngeal carcinoma. Owing to the deletion of the E1B-55kD and E3 regions, H101 is believed to selectively inhibit nasopharyngeal carcinoma. Whether H101 inhibits other type of tumors via different mechanisms remains unclear. In this study we investigated the effects of H101 on melanomas. We established B16F10 melanoma xenograft mouse model, and treated the mice with H101 (1 × 108 TCID50) via intratumoral injection for five consecutive days. We found that H101 treatment significantly inhibited B16F10 melanoma growth in the mice. H101 treatment significantly increased the infiltration of CD8+ T cells and reduced the proportion of M2-type macrophages. We demonstrated that H101 exhibited low cytotoxicity against B16F10 cells, but the endothelial cells were more sensitive to H101 treatment. H101 induced endothelial cell pyroptosis in a caspase-1/GSDMD-dependent manner. Furthermore, we showed that the combination of H101 with the immune checkpoint inhibitor PD-L1 antibody (10 mg/kg, i.p., every three days for three times) exerted synergic suppression on B16F10 tumor growth in the mice. This study demonstrates that, in addition to oncolysis, H101 inhibits melanoma growth by promoting anti-tumor immunity and inducing pyroptosis of vascular endothelial cells.

Comparison of totally robotic and totally laparoscopic gastrectomy for gastric cancer: a propensity score matching analysis.

BACKGROUND: With the improvements in laparoscopic or robotic surgical techniques and instruments, a growing number of surgeons have attempted to complete all digestive tract reconstruction intracorporeally; these procedures include totally robotic gastrectomy (TRG) and totally laparoscopic gastrectomy (TLG). This study aimed to evaluate the safety and feasibility of the TRG and compare the short-term outcomes of the TRG and TLG in patients with gastric cancer. METHODS: Between January 2018 and June 2023, 346 consecutive patients who underwent TRG or TLG at a high-volume academic gastric cancer specialty center were included. 1:1 propensity score matching (PSM) was performed to reduce confounding bias. The surgical outcomes, postoperative morbidity, and surgical burden were compared in PSM cohort. RESULTS: After PSM, a well-balanced cohort of 194 patients (97 in each group) was included in the analysis. The total operation time of the TRG group was significantly longer than that of the TLG group (244.9 vs. 213.0 min, P < 0.001). There was no significant difference in the effective operation time between the 2 groups (217.8 vs. 207.2 min, P = 0.059). The digestive tract reconstruction time of the TRG group was significantly shorter than that of the TLG group (39.4 vs. 46.7 min, P < 0.001). The mean blood loss in the TRG group was less than that in the TLG group (101.1 vs. 126.8 mL, P = 0.014). The TRG group had more retrieved lymph nodes in the suprapancreatic area than that in the TLG group (16.6 vs 14.2, P = 0.002). The TRG group had a lower surgery task load index (38.9 vs. 43.1, P < 0.001) than the TLG group. No significant difference was found in terms of postoperative morbidity between the 2 groups (14.4% vs. 16.5%, P = 0.691). CONCLUSION: This study demonstrated that TRG is a safe and feasible procedure, and is preferable to TLG in terms of invasion and ergonomics. The TRG may maximize the superiority of robotic surgical systems and embodies the theory of minimally invasive surgery.

Novel Mutation in the Moesin (MSN) Gene Leads to Immunodeficiency with Epstein-Barr Virus (EBV) Infection and Dermatomyositis-Like Symptoms.

PURPOSE: Moesin (MSN) deficiency is a recently reported combined immunodeficiency, and few cases have been reported to date. We describe a Chinese patient with a novel mutation causing MSN deficiency and a novel phenotype. METHODS: Clinical and immunological data were collected. Whole-exome sequencing was performed to identify gene mutations. MSN protein expression and T cell proliferation and activation were determined by flow cytometry. Cell migration was confirmed with a Transwell assay. Autoantibody levels were analyzed using antigen microarrays. RESULTS: The patient was a 10-year-old boy who presented with recurrent fever, oral ulcers and dermatomyositis-like symptoms, such as periorbital edema, facial swelling, elevated creatine kinase levels, and abnormal electromyography and muscle biopsy results. Epstein-Barr virus (EBV) DNA was detected in the serum, cells and tissues of this patient. He further developed nasal-type NK/T-cell lymphoma. A novel hemizygous mutation (c.68 A > G, p.N23S) in the MSN gene was found. The immunological phenotype of this patient included persistent decreases in T and B lymphocyte counts but normal immunoglobulin IgG levels. The patient had attenuated MSN protein expression and impaired T-cell proliferation and migration. The proportions of Tfh cells and CD21low B cells in the patient were higher than those in the controls. Moreover, 82 IgG and 102 IgM autoantibodies were more abundant in the patient than in the healthy controls. CONCLUSIONS: The novel mutation N23S is pathogenic and leads to a severe clinical phenotype. EBV infection, tumor, and dermatomyositis-like autoimmune symptoms may be associated with MSN deficiency, further expanding the understanding of the disease.

DLG1 functions upstream of SDCCAG3 and IFT20 to control ciliary targeting of polycystin-2.

Polarized vesicular trafficking directs specific receptors and ion channels to cilia, but the underlying mechanisms are poorly understood. Here we describe a role for DLG1, a core component of the Scribble polarity complex, in regulating ciliary protein trafficking in kidney epithelial cells. Conditional knockout of Dlg1 in mouse kidney causes ciliary elongation and cystogenesis, and cell-based proximity labeling proteomics and fluorescence microscopy show alterations in the ciliary proteome upon loss of DLG1. Specifically, the retromer-associated protein SDCCAG3, IFT20, and polycystin-2 (PC2) are reduced in the cilia of DLG1-deficient cells compared to control cells. This phenotype is recapitulated in vivo and rescuable by re-expression of wild-type DLG1, but not a Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)-associated DLG1 variant, p.T489R. Finally, biochemical approaches and Alpha Fold modelling suggest that SDCCAG3 and IFT20 form a complex that associates, at least indirectly, with DLG1. Our work identifies a key role for DLG1 in regulating ciliary protein composition and suggests that ciliary dysfunction of the p.T489R DLG1 variant may contribute to CAKUT.

A mini case report: Klebsiella pneumoniae-induced metastatic neck abscess following laparoscopic appendectomy.

Common complications following laparoscopic appendectomy include wound infection, bleeding, intra-abdominal abscess, small bowel obstruction, stump leakage, and stump appendicitis. Here, we presented a case reporting detailing a rare complication following laparoscopic appendectomy: the development of a metastatic neck abscess induced by Klebsiella pneumoniae(K. pneumoniae). A 49-year-old male underwent emergency laparoscopic surgery with prophylactic antibiotic administration for acute appendicitis. Subsequently, he experienced persistent neck pain and fever postoperatively, prompting further investigation. Pus and blood cultures revealed K. pneumoniae, with magnetic resonance imaging confirming the presence of a neck abscess. Antibiotic therapy was adjusted, and surgical drainage of the abscess was performed after multidisciplinary consultation. The patient was discharged without complications. While rare, metastatic abscesses following appendectomy warrant consideration, particularly in K. pneumoniae infections. Comprehensive clinical assessment, imaging, and laboratory evaluation are crucial for timely diagnosis and management of such complications.

MTCH2 stimulates cellular proliferation and cycles via PI3K/Akt pathway in breast cancer.

The MTCH2 protein is located on the mitochondrial outer membrane and regulates mitochondria-related cell death. This study set out to investigate the role of MTCH2 in the underlying pathophysiological mechanisms of breast cancer (BC). MTCH2 expression levels in BC were analyzed using bioinformatics prior to verification by cell lines in vitro. Experiments of over-expression and siRNA-mediated knockdown of MTCH2 were conducted to assess its biological functions, including its effects on cellular proliferation and cycle progression. Xenografts were utilised for in vivo study and signaling pathway alterations were examined to identify the mechanisms driven by MTCH2 in BC proliferation and cell-cycle regulation. MTCH2 was up-regulated in BC and correlated with patients' overall survival. Over-expression of MTCH2 promoted cellular proliferation and cycle progression, while silencing MTCH2 had the opposite effect. Xenograft experiments were utilised to confirm the in vitro cellular findings and it was identified that the PI3K/Akt signaling pathway was activated by MTCH2 over-expression and suppressed by its silencing. Moreover, the activation of IGF-1R rescued cellular growth and cycle arrest induced by MTCH2-silencing. Overall, this study reveals that expression of MTCH2 in BC is upregulated and potentiates cellular proliferation and cycle progression via the PI3K/Akt pathway.

Evaluation of factors influencing long-term and textbook outcomes in laparoscopic gastrectomy.

BACKGROUND: Textbook outcome (TO) in gastric cancer surgery is a multidimensional measure of surgical quality. However, its impact on long-term survival after laparoscopic gastrectomy (LG) is unclear. This study aims to evaluate TO in LG, assess its hospital-level relevance, and examine its association with long-term survival. METHODS: In this retrospective cohort study, we analyzed 2278 consecutive gastric cancer patients who underwent laparoscopic gastrectomy (LG) from January 2004 to December 2017. We determined TO achievement rates, compared preoperative and intraoperative variables between TO and non-TO groups, identified independent predictors of TO, and assessed long-term oncologic outcomes using Kaplan-Meier analysis and Cox regression. RESULTS: A total of 1540 LG patients were analyzed, with 994 (64.5%) achieving TO. The least frequently achieved metric was 'hospital stays ≤21 days' (83.4%), followed by 'lymph nodes retrieved ≥15' (84.0%). Factors independently associated with reduced TO likelihood included age ≥65 years, BMI ≥25, ASA III, conversion to open surgery, operation time ≥260 min, and estimated blood loss ≥150 ml. Furthermore, TO was independently linked to improved 5-year overall survival (OS) and disease-free survival (DFS) (HR 0.519 [0.443-0.609] and HR 0.517 [0.443-0.604], respectively). CONCLUSION: Implementing the TO concept in LG provides a benchmark for achieving improved prognoses and empowers surgeons to devise strategies for enhancing surgical care quality.

Long-term oncological outcomes of robotic versus laparoscopic gastrectomy for gastric cancer: multicentre cohort study.

BACKGROUND: The aim of this multicentre cohort study was to compare the long-term oncological outcomes of robotic gastrectomy (RG) and laparoscopic gastrectomy (LG) for patients with gastric cancer. METHODS: Patients with gastric cancer who underwent radical gastrectomy by robotic or laparoscopic approaches from 1 March 2010 to 31 December 2018 at 10 high-volume centres in China were selected from institutional databases. Patients receiving RG were matched 1 : 1 by propensity score with patients undergoing LG. The primary outcome was 3-year disease-free survival. Secondary outcomes were overall survival and disease recurrence. RESULTS: Some 2055 patients who underwent RG and 4309 patients who had LG were included. The propensity score-matched cohort comprised 2026 RGs and 2026 LGs. Median follow-up was 41 (i.q.r. 39-58) months for the RG group and 39 (38-56) months for the LG group. The 3-year disease-free survival rates were 80.8% in the RG group and 79.5% in the LG group (log rank P = 0.240; HR 0.92, 95% c.i. 0.80 to 1.06; P = 0.242). Three-year OS rates were 83.9 and 81.8% respectively (log rank P = 0.068; HR 0.87, 0.75 to 1.01; P = 0.068) and the cumulative incidence of recurrence over 3 years was 19.3% versus 20.8% (HR 0.95, 0.88 to 1.03; P = 0.219), with no difference between groups. CONCLUSION: RG and LG in patients with gastric cancer are associated with comparable disease-free and overall survival.

DLG1 functions upstream of SDCCAG3 and IFT20 to control ciliary targeting of polycystin-2.

Polarized vesicular trafficking directs specific receptors and ion channels to cilia, but the underlying mechanisms are poorly understood. Here we describe a role for DLG1, a core component of the Scribble polarity complex, in regulating ciliary protein trafficking in kidney epithelial cells. Conditional knockout of Dlg1 in mouse kidney caused ciliary elongation and cystogenesis, and cell-based proximity labelling proteomics and fluorescence microscopy showed alterations in the ciliary proteome upon loss of DLG1. Specifically, the retromer-associated protein SDCCAG3, IFT20 and polycystin-2 (PC2) were reduced in cilia of DLG1 deficient cells compared to control cells. This phenotype was recapitulated in vivo and rescuable by re-expression of wildtype DLG1, but not a Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)-associated DLG1 variant, p.T489R. Finally, biochemical approaches and Alpha Fold modelling suggested that SDCCAG3 and IFT20 form a complex that associates, at least indirectly, with DLG1. Our work identifies a key role for DLG1 in regulating ciliary protein composition and suggests that ciliary dysfunction of the p.T489R DLG1 variant may contribute to CAKUT.

Constructing a nomogram based on the distribution of thyroid nodules and suspicious lateral cervical lymph nodes in fine-needle aspiration biopsies to predict metastasis in papillary thyroid carcinoma.

Purpose: Elevated concentrations of thyroglobulin eluent is a risk factor for lateral cervical lymph node metastasis (LLNM) in patients with papillary thyroid cancer (PTC). We aimed to develop a practical nomogram based on the distribution of thyroid nodules and the presence of suspicious lateral cervical lymph nodes in fine-needle aspiration biopsies (LN-FNABs), including the cytopathology and the suspicious lateral cervical lymph node (LLN) thyroglobulin eluent (Tg), to predict the possibility of LLNM preoperatively in patients with PTC. Methods: The clinical data of PTC patients who were admitted to the Third Affiliated Hospital of Soochow University from January 2022 to May 2023 to undergo fine-needle aspiration biopsy (FNAB) were included in this study. A total of 208 patients in 2022 served as the training set (70%), and 89 patients in 2023 served as the validation set (30%). The clinical characteristics and LN-FNAB results were collected to determine the risk factors of LLNM. A preoperative nomogram was developed for predicting LLNM based on the results of the univariate and multivariate analyses. Internal calibration, external calibration, and decision curve analysis (DCA) were performed for these models. Results: The multivariate logistic regression analysis showed that the maximum thyroid nodule diameter (Odds Ratio (OR) 2.323, 95% CI 1.383 to 3.904; p = 0.001), Tg level (OR 1.007, 95% CI 1.005 to 1.009; p = 0.000), Tg divided by serum thyroglobulin, (Tg/sTg) [odds ratio (OR) 1.005, 95% CI 1.001 to 1.008; p = 0.009], and cytopathology (OR 9.738, 95% CI 3.678 to 25.783; p = 0.000) (all p < 0.05) had a significant impact on the LLNM of patients with suspicious LLNs. The nomogram showed a better predictive value in both the training cohort [area under the curve, (AUC) 0.937, 95% CI 0.895 to 0.966] and the validation cohort (AUC 0.957, 95% CI 0.892 to 0.989). The nomogram also showed excellent internal and external calibration in predicting LLNM. According to the DCA, the diagnostic performance of this model was dependent on the following variables: maximum thyroid nodule diameter, Tg level, Tg/sTg, and cytopathology. Conclusion: Based on the aforementioned risk factors, we believe that it is necessary to establish a personalized LLNM model for patients with PTC. Using this practical nomogram, which combines clinical and Tg risk factors, surgeons could accurately predict the possibility of LLNM preoperatively. The nomogram will also help surgeons to establish personalized treatment plans before surgery.

Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis.

Fibrocystin/Polyductin (FPC), encoded by PKHD1, is associated with autosomal recessive polycystic kidney disease (ARPKD), yet its precise role in cystogenesis remains unclear. Here we show that FPC undergoes complex proteolytic processing in developing kidneys, generating three soluble C-terminal fragments (ICDs). Notably, ICD15, contains a novel mitochondrial targeting sequence at its N-terminus, facilitating its translocation into mitochondria. This enhances mitochondrial respiration in renal epithelial cells, partially restoring impaired mitochondrial function caused by FPC loss. FPC inactivation leads to abnormal ultrastructural morphology of mitochondria in kidney tubules without cyst formation. Moreover, FPC inactivation significantly exacerbates renal cystogenesis and triggers severe pancreatic cystogenesis in a Pkd1 mouse mutant Pkd1V/V in which cleavage of Pkd1-encoded Polycystin-1 at the GPCR Proteolysis Site is blocked. Deleting ICD15 enhances renal cystogenesis without inducing pancreatic cysts in Pkd1V/V mice. These findings reveal a direct link between FPC and a mitochondrial pathway through ICD15 cleavage, crucial for cystogenesis mechanisms.

Assessment of early anthracycline-induced cardiotoxicity using segmental strain of cardiac magnetic resonance compared with global strain and functional parameters: an animal study.

Background: The identification of anthracycline-induced cardiotoxicity holds significant importance in guiding subsequent treatment strategies, and recent research has demonstrated the efficacy of cardiac magnetic resonance (CMR) global strain analysis for its diagnosis. On the other hand, it is noteworthy that abnormal global myocardial strain may exhibit a temporal delay due to different cardiac movement in each segment of the left ventricle. To address this concern, this study aims to assess the diagnostic utility of CMR segmental strain analysis as an early detection method for cardiotoxicity. Methods: A serials of CMR scans were performed in 18 adult males New Zealand rabbits at baseline time (n=15), followed by scans at week 2 (n=15), week 4 (n=9), week 6 (n=6), and week 8 (n=5) after each week's anthracycline injection. Additionally, following each CMR scan, two to three rabbits were euthanized for pathological comparison. Cardiac functional parameters, global peak strain parameters, segmental peak strain parameters of the left ventricle, and the presence of myocardial cells damage were obtained. A mixed linear model was employed to obtain the earliest CMR diagnostic time. Receiver operating characteristic (ROC) analysis was performed to get the parameter threshold indicative of cardiotoxicity. Results: The left ventricular ejection fraction decreased at week 8 (P=0.002). There were no statistical differences in global strain throughout the experiment period (P>0.05). Regarding segmental strain analysis, the peak segmental radial strain of the apical lateral wall exhibited a decrease starting from week 2 and reached its lowest point at this week (P=0.011). Conversely, peak segmental circumferential strain of the apical anterior wall showed an increase at week 2 and reached its peak at week 6 (P=0.026). The cutoff strain value by ROC analysis for these two walls were 46.285 and -16.920, with the respective areas under the curve (AUC) 0.593 [specificity =0.267, sensitivity =1.000, 95% confidence interval (CI): 0.471-0.777] and 0.764 (specificity =0.733, sensitivity =0.784, 95% CI: 0.511-0.816). Peak segmental longitudinal strain of the apical anterior and apical lateral wall showed relatively delayed changes, occurring in the 4th week (P=0.030 and P=0.048), the cutoff values for these strains were -12.415 and -15.960, with corresponding AUCs of 0.645 (specificity =0.333, sensitivity =0.955, 95% CI: 0.495-0.795) and 0.717 (specificity =0.433, sensitivity =0.955, 95% CI: 0.566-0.902), respectively. Notably, the myocardial injury was also observed at the corresponding periods. Conclusions: Based on experimental evidence, the peak segmental strain of the apical lateral and anterior wall, as determined by CMR, demonstrated an earlier detection of anthracycline-induced cardiotoxicity compared to peak global strain and cardiac function.

Lomerizine attenuates LPS-induced acute lung injury by inhibiting the macrophage activation through reducing Ca2+ influx.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening lung diseases with high mortality rates, predominantly attributable to acute and severe pulmonary inflammation. Lomerizine (LMZ) is a calcium channel blocker previously used in preventing and treating migraine. Here, we found that LMZ inhibited inflammatory responses and lung pathological injury by reducing pulmonary edema, neutrophil infiltration and pro-inflammatory cytokine production in lipopolysaccharide (LPS)-induced ALI mice. In vitro experiments, upon treating with LMZ, the expression of interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α was attenuated in macrophages. The phosphorylation of p38 MAPK, ERK1/2, JNK, and NF-κB p65 was inhibited after LMZ treatment. Furthermore, LPS-induced Ca2+ influx was reduced by treating with LMZ, which correlated with inhibition of pro-inflammatory cytokine production. And L-type Ca2+ channel agonist Bay K8644 (BK) could restore cytokine generation. In conclusion, our study demonstrated that LMZ alleviates LPS-induced ALI and is a potential agent for treating ALI/ARDS.

Safety, immunogenicity, and efficacy of an mRNA COVID-19 vaccine (RQ3013) given as the fourth booster following three doses of inactivated vaccines: a double-blinded, randomised, controlled, phase 3b trial.

Background: Heterologous vaccine schedules have been recommended to provide superior immunity and protection against emergent SARS-CoV-2 variants of concern. We aimed to evaluate the safety, immunogenicity, and efficacy of an mRNA COVID-19 vaccine RQ3013 compared with adenoviral vectored vaccine Ad5-nCoV and protein subunit vaccine ZF2001 as the fourth dose in adults primed with three doses of inactivated vaccines in China. Methods: We conducted a double-blinded, randomised, controlled, phase 3b trial among healthy Chinese adults at Lancang County, Yunnan, China. Adults who had received three doses of inactivated COVID-19 vaccines at least 6 months prior were randomly allocated (3:1:1) to receive heterologous boosters with RQ3013, Ad5-nCoV, or ZF2001. We assessed safety within 28 days post boost and the serum geometric mean titres (GMTs) of neutralising antibodies (NAbs) against the live SARS-CoV-2 omicron variant BA.5 on day 14 post-boost. We used Poisson regression to assess the vaccine efficacy against the first episode of virologically confirmed symptomatic COVID-19 occurring at least 7 days post boost. Subgroup analyses categorized by age and sex were also performed for safety and immunogenicity outcomes. This trial has been registered with the Chinese Clinical Trial Registry (ChiCTR2200065281) and is now complete. Findings: Between December 12 and December 18, 2022, a total of 1382 adults were screened, and 1250 were enrolled and randomly assigned to receive one dose of RQ3013 (n = 750), Ad5-nCoV (n = 250), or ZF2001 (n = 250). Although solicited adverse reactions within 28 days post boost were more frequent in the RQ3013 group (175 [23.3%]) compared to the control groups (24 [9.6%] in both the Ad5-nCOV and ZF2001 groups, P < 0.05), incidences of Grade 3 events were low (9 [0.7%]) and comparable across three groups (P > 0.05). On day 14 post-boost, RQ3013 (GMT 69.14, 95% CI 47.90-99.81) elicited 4.8-fold and 5.6-fold higher concentrations of NAbs against BA.5 than did Ad5-nCoV (14.37, 7.78-26.56) and ZF2001 (12.21, 5.13-29.06), respectively. On day 28 post-boost, RQ3013 demonstrated a relative efficacy of 62.2% (95% CI 13.7-83.1, P = 0.02) compared to Ad5-nCoV, and of 69.0% (33.5-85.7, P = 0.002) compared to ZF2001. Interpretation: The administrations of all the three heterologous boosters were well tolerated. The heterologous prime-boost regimen with RQ3013 elicited superior immune responses and demonstrated better protection against symptomatic SARS-CoV-2 infections compared with Ad5-nCoV or ZF2001, supporting the use of RQ3013 as a booster vaccination in adults. Funding: Yunnan Province Science and Technology Department (grant no.202302AA310047).

Clinical and histological features of patients with chronic hepatitis B virus infection in the grey zone.

Chronic HBV infection patients who do not conform to any of the usual immune states are regarded as 'grey zone' patients. We aimed to investigate the proportion of chronic HBV infection patients in the grey zone, and evaluate the clinical characteristics and liver pathological changes in grey zone patients. Clinical data of 1391 treatment-naive chronic HBV infection patients with liver biopsy were collected. Natural history of HBV infection was determined based on European Association for the Study of the Liver (EASL) 2017, American Association for the Study of Liver Diseases (AASLD) 2018 and Chinese 2019 guidelines for the prevention and treatment of chronic HBV infection. Significant liver histological changes and associated risk factors of normal ALT grey zone patients were analysed. According to EASL, AASLD and Chinese criteria, there were 50.0%, 28% and 37.4% chronic HBV infection patients in the grey zone. Among the 353 grey zone patients with normal ALT, 72.4% had significant liver histological changes. ALT (optimal cut-off value 25 IU/L) and HBV DNA (optimal cut-off value 18,000 IU/mL) were independent risk factors of significant liver histological abnormalities. In conclusion, a substantial proportion of grey zone patients with normal ALT have significant liver histological changes that can be predicted by levels of serum ALT and HBV DNA. These results provide guidance of antiviral treatment in grey zone patients.

IL-36α inhibits melanoma by inducing pro-inflammatory polarization of macrophages.

Interleukin-36α (IL-36α) is essential for various inflammatory conditions, such as psoriasis and rheumatoid arthritis, whereas its role in tumor immunity is unclear. In this study, it was demonstrated that IL-36α could activate the NF-κB and MAPK signaling pathways in macrophages, leading to the expression of IL-1ß, IL-6, TNF-α, CXCL1, CXCL2, CXCL3, CXCL5 and iNOS. Importantly, IL-36α has significant antitumor effects, altering the tumor microenvironment and promoting the infiltration of MHC IIhigh macrophages and CD8+ T cells while decreasing the levels of monocyte myeloid-derived suppressor cells, CD4+ T cells and regulatory T cells. This ultimately results in the inhibition of tumor growth and migration. Furthermore, IL-36α synergized with the PD-L1 antibody increased the immune cells infiltration and enhanced the anti-tumor effect of the PD-L1 antibody on melanoma. Collectively, this study reveals a new role for IL-36α in promoting anti-tumor immune responses in macrophages and suggests its potential for cancer immunotherapy.

Functional ß-TCP/MnO2 /PCL artificial periosteum promoting osteogenic differentiation of BMSCs by reducing locally reactive oxygen species level.

Segmental bone defects caused by trauma, tumor resection or congenital malformations are often reconstructed with autologous, allogeneic bone grafts or artificial bone materials, of which, about 5% ~ 10% will have delayed healing or even nonunion of fractures. The loss of periosteum and excessive accumulation of ROS in fracture site leads to the aging of osteoblasts and the decline of their proliferation and differentiation, thus affecting the fracture healing process. In this study, we prepared a functional modified artificial periosteum ß-TCP/MnO2 /PCL(ß-TMP) by electrospinning with a function of catalyzing decomposition of H2 O2 . We examined the surface morphology of ß-TMP, the concentration of Ca, P and Mn of ß-TMP, as well as the diameter distribution range of nanofibers on ß-TMP. Through X-ray diffraction patterns and Fourier transform infrared spectra, ß-TMP was characterized and its hydrophilicity was tested. The release of Mn2+ and Ca2+ of 0.1 and 0.05% ß-TMP in different pH values (7.4 and 5.5) determined by ICP. We also identified that ß-TMP could reduce the level of ROS in cells by lowering the level of H2 O2 . 0%, 0.05% and 0.1% ß-TMP displayed good cell compatibility, cell adhesion and cellular morphology in the condition with or without H2 O2 . 0.5% ß-TMP showed compromised cell compatibility in normal condition, however, the compromised phenotypes could be partially rescued in the present of H2 O2 . Compared with 0%, 0.05% and 0.1% ß-TMP displayed higher osteoblastic differentiation with or without H2 O2 in BMSCs as well as in MG-63. In sum, ß-TMP helped osteogenesis and promoted repair of bone defects.

Ependyma in Neurodegenerative Diseases, Radiation-Induced Brain Injury and as a Therapeutic Target for Neurotrophic Factors.

The neuron loss caused by the progressive damage to the nervous system is proposed to be the main pathogenesis of neurodegenerative diseases. Ependyma is a layer of ciliated ependymal cells that participates in the formation of the brain-cerebrospinal fluid barrier (BCB). It functions to promotes the circulation of cerebrospinal fluid (CSF) and the material exchange between CSF and brain interstitial fluid. Radiation-induced brain injury (RIBI) shows obvious impairments of the blood-brain barrier (BBB). In the neuroinflammatory processes after acute brain injury, a large amount of complement proteins and infiltrated immune cells are circulated in the CSF to resist brain damage and promote substance exchange through the BCB. However, as the protective barrier lining the brain ventricles, the ependyma is extremely vulnerable to cytotoxic and cytolytic immune responses. When the ependyma is damaged, the integrity of BCB is destroyed, and the CSF flow and material exchange is affected, leading to brain microenvironment imbalance, which plays a vital role in the pathogenesis of neurodegenerative diseases. Epidermal growth factor (EGF) and other neurotrophic factors promote the differentiation and maturation of ependymal cells to maintain the integrity of the ependyma and the activity of ependymal cilia, and may have therapeutic potential in restoring the homeostasis of the brain microenvironment after RIBI or during the pathogenesis of neurodegenerative diseases.