BACKGROUND: Increasing evidence indicates that oxidative stress and interferon γ (IFNγ)-driven cellular immune responses are responsible for the pathogenesis of vitiligo. However, the connection between oxidative stress and the local production of IFNγ in early vitiligo remains unexplored. The aim of this study was to identify the mechanism underlying the production of IFNγ by mast cells and its impact on vitiligo pathogenesis. METHODS: Skin specimens from the central, marginal, and perilesional skin areas of active vitiligo lesions were collected to characterize changes of mast cells, CD8 + T cells, and IFNγ-producing cells. Cell supernatants from hydrogen peroxide (H 2 O 2 )-treated keratinocytes (KCs) were harvested to measure levels of soluble stem cell factor (sSCF) and matrix metalloproteinase (MMP)-9. A murine vitiligo model was established using Mas-related G protein-coupled receptor-B2 (MrgB2, mouse ortholog of human MrgX2) conditional knockout (MrgB2 -/- ) mice to investigate IFNγ production and inflammatory cell infiltrations in tail skin following the challenge with tyrosinase-related protein (Tyrp)-2 180 peptide. Potential interactions between the Tyrp-2 180 peptide and MrgX2 were predicted using molecular docking. The siRNAs targeting MrgX2 and the calcineurin inhibitor FK506 were also used to examine the signaling pathways involved in mast cell activation. RESULTS: IFNγ-producing mast cells were closely aligned with the recruitment of CD8 + T cells in the early phase of vitiligo skin. sSCF released by KCs through stress-enhanced MMP9-dependent proteolytic cleavage recruited mast cells into sites of inflamed skin (Perilesion vs . lesion, 13.00 ± 4.00/high-power fields [HPF] vs . 26.60 ± 5.72/HPF, P <0.05). Moreover, IFNγ-producing mast cells were also observed in mouse tail skin following challenge with Tyrp-2 180 (0 h vs . 48 h post-recall, 0/HPF vs . 3.80 ± 1.92/HPF, P <0.05). The IFNγ + mast cell and CD8 + T cell counts were lower in the skin of MrgB2 -/- mice than in those of wild-type mice (WT vs . KO 48 h post-recall, 4.20 ± 0.84/HPF vs . 0.80 ± 0.84/HPF, P <0.05). CONCLUSION Mast cells activated by MrgX2 serve as a local IFNγ producer that bridges between innate and adaptive immune responses against MCs in early vitiligo. Targeting MrgX2-mediated mast cell activation may represent a new strategy for treating vitiligo.
Vitiligo/metabolism* ; Mast Cells/immunology* ; Animals ; Interferon-gamma/metabolism* ; Mice ; Humans ; Melanocytes/metabolism* ; Receptors, G-Protein-Coupled/genetics* ; Mice, Knockout ; Mice, Inbred C57BL ; Male ; Female ; Matrix Metalloproteinase 9/metabolism* ; Stem Cell Factor/metabolism*

Tumors exhibit abnormal glucose metabolism, consuming excessive glucose and excreting lactate, which constructs a tumor microenvironment that facilitates cancer progression and disrupts immunotherapeutic efficacy. Currently, tumor glucose metabolic dysregulation to reshape the immunosuppressive microenvironment and enhance immunotherapy efficacy is emerging as an innovative therapeutic strategy. However, glucose metabolism modulators lack specificity and still face significant challenges in overcoming tumor delivery barriers, microenvironmental complexity, and metabolic heterogeneity, resulting in poor clinical benefit. Nanomedicines, with their ability to selectively target tumors or immune cells, respond to the tumor microenvironment, co-deliver multiple drugs, and facilitate combinatorial therapies, hold significant promise for enhancing immunotherapy through tumor glucose metabolic reprogramming. This review explores the complex interactions between tumor glucose metabolism-specifically metabolite transport, glycolysis processes, and lactate-and the immune microenvironment. We summarize how nanomedicine-mediated reprogramming of tumor glucose metabolism can enhance immunotherapy efficacy and outline the prospects and challenges in this field.

From September 26 to 28,2024,the 11th Korean International Gastric Cancer Week(KINGCA WEEK 2024),a prestigious academic conference in the field of gastric cancer,was held in Seoul.Organized by the Korean Gastric Cancer Association,the conference featured one main venue,18 sub-venues,and 16 thematic symposiums,including 100 invited presentations and four keynote speeches,attracting 788 experts and scholars from around the world.Additionally,the conference set 16 themes and received 425 submissions from 24 countries,including Republic of Korea,China,Japan,and the United States.After a review process,365 submissions were accepted,which included eight plenary oral presentations,78 oral reports,and 279 poster presentations.The conference covered many hot topics in gastric cancer diagnosis and treatment,with a particular focus on surgical-related areas such as treatment strategies for metastatic gastric cancer,an international consensus meeting on the conversion therapy for stage Ⅳgastric cancer,future research directions of the Korean Laparoendoscopic Gastrointestinal Surgery Study Group,the development of new surgical instruments and equipment,and key issues in lymph node dissection,resection,and reconstruction during minimally invasive gastric cancer surgeries.Furthermore,our team was invited to present two oral reports on"the application of artificial intelligence in minimally invasive gastric cancer surgery".This report aims to detail the dynamics and hotspots related to surgical treatment for gastric cancer,providing valuable references and insights for domestic surgical peers.

Lung cancer remains the leading cause of cancer deaths worldwide and is the most common cancer in males. Immune-checkpoint inhibitors (ICIs) that target programmed cell death protein-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) have achieved impressive efficacy in the treatment of non-small-cell lung cancer (NSCLC) (Pardoll, 2012; Champiat et al., 2016; Gao et al., 2022). Although ICIs are usually well tolerated, they are often accompanied by immune-related adverse events (irAEs) (Doroshow et al., 2019). Non-specific activation of the immune system produces off-target immune and inflammatory responses that can affect virtually any organ or system (O'Kane et al., 2017; Puzanov et al., 2017). Compared with adverse events caused by chemotherapy, irAEs are often characterized by delayed onset and prolonged duration and can occur in any organ at any stage of treatment, including after cessation of treatment (Puzanov et al., 2017; von Itzstein et al., 2020). They range from rash, pneumonitis, hypothyroidism, enterocolitis, and autoimmune hepatitis to cardiovascular, hematological, renal, neurological, and ophthalmic irAEs (Nishino et al., 2016; Kumar et al., 2017; Song et al., 2020). Hence, we conducted a retrospective study to identify validated factors that could predict the magnitude of the risk of irAEs in patients receiving PD-1/PD-L1 inhibitors; our approach was to analyze the correlation between the clinical characteristics of patients at the start of treatment and relevant indicators such as hematological indices and the risk of developing irAEs. Then, we developed an economical, practical, rapid, and simple model to assess the risk of irAEs in patients receiving ICI treatment, as early as possible.
Male ; Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Lung Neoplasms/drug therapy* ; Immune Checkpoint Inhibitors/adverse effects* ; Programmed Cell Death 1 Receptor ; Retrospective Studies ; Apoptosis

Single-cell transcriptome sequencing (scRNA-seq) can resolve the expression characteristics of cells in tissues with single-cell precision, enabling researchers to quantify cellular heterogeneity within populations with higher resolution, revealing potentially heterogeneous cell populations and the dynamics of complex tissues. However, the presence of a large number of technical zeros in scRNA-seq data will have an impact on downstream analysis of cell clustering, differential genes, cell annotation, and pseudotime, hindering the discovery of meaningful biological signals. The main idea to solve this problem is to make use of the potential correlation between cells and genes, and to impute the technical zeros through the observed data. Based on this, this paper reviewed the basic methods of imputing technical zeros in the scRNA-seq data and discussed the advantages and disadvantages of the existing methods. Finally, recommendations and perspectives on the use and development of the method were provided.
Cluster Analysis ; Transcriptome

Acute pancreatitis (AP) is a devastating disease characterized by an inflammatory disorder of the pancreas. P-selectin glycoprotein ligand-1 (PSGL-1) plays a crucial role in the initial steps of the adhesive at process to inflammatory sites, blockade of PSGL-1 might confer potent anti-inflammatory effects. In this study, we generated two non-human primate derived monoclonal antibodies capable of efficiently targeting human PSGL-1, RH001-6 and RH001-22, which were screened from immunized rhesus macaques. We found that RH001-6, can effectively block the binding of P-selectin to PSGL-1, and abolish the adhesion of leukocytes to endothelial cells in vitro. In vivo, we verified that RH001-6 relieved inflammatory responses and pancreatic injury in both caerulein and l-arginine induced AP models. We also evaluated the safety profile after RH001-6 treatment in mice, and verified that RH001-6 did not cause any significant pathological damages in vivo. Taken together, we developed a novel non-human primate derived PSGL-1 blocking antibody with high-specificity, named RH001-6, which can interrupt the binding of PSGL-1 and P-selectin and attenuate inflammatory responses during AP. Therefore, RH001-6 is highly potential to be further developed into therapeutics against acute inflammatory diseases, such as AP.

Objective:To explore the short-term and long-term prognostic outcomes of anatomical liver resection(AR)for patients with perihilar cholangio-carcinoma. Methods:This is a retrospective study.All data were obtained from 4 centers,including The First Affiliated Hospital of Army Medical University,Eastern Hepatobiliary Hospital of Naval Medical University,Sichuan Provincial People's Hospital and Affiliated Hospital of Qinghai University,of a multi-center database.A total of 305 consecutive perihilar cholangiocarcinoma patients receiving radical resection between January 2013 and June 2021 were included in this study.According to the method of liver resection,all patients were divided into the AR group(n=205)and the non-anatomical liver resection(NAR)group(n=100).The baseline characteristics,short-term prognosis and long-term prognosis of the 2 groups were compared. Results:The perioperative transfusion rate and the 30-day complication rate were significantly lower in the AR group than those in the NAR group(P＜0.05).There was no statistically significant difference in the survival rates between the AR and the NAR groups(P＞0.05). Conclusion:The 2 hepatic resection modalities had no obvious effect on the long-term prognosis of perihilar cholangiocarcinoma patients after radical resection,but choosing AR tends to achieve a better short-term prognosis and is worth promoting in clinical practice.

Objective:To analyze the immunology-related risk factors for short-term prognosis in patients with demyelinating diseases of central nervous system, and to evaluate their predictive value.Methods:From January 2012 to October 2022 in Beijing Tiantan Hospital of Capital Medical University and General Hospital of Tianjin Medical University, the clinical data of 362 patients with demyelinating diseases of central nervous system were analyzed, including neuromyelitis optic spectrum disease (NMOSD) 181 cases, multiple sclerosis (MS) 129 cases, anti-myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) 38 cases, acute disseminated encephalomyelopathy (ADEM) 14 cases. According to the expanded disability status scale (EDSS) score at discharge, the patients were divided into good prognosis group (EDSS≤3 scores, 267 cases) and poor prognosis group (EDSS>3 scores, 95 cases). The clinical data, admission severity (admission EDSS score), treatment, autoantibodies and immunoglobulin level and serum inflammatory factor level were compared between two groups. Multivariate Logistic regression was used to analyze the independent risk factors of short-term prognosis in patients with demyelinating diseases of central nervous system; and the predictive efficacy was evaluated by receiver operating characteristic (ROC) curve.Results:Compared with the good prognosis group, the admission EDSS score in the poor prognosis group was significantly higher: 2.5 (1.5) scores vs. 6.5 (3.5) scores. The positive rates of autoimmune disease-related antibody, systemic autoantibody, anti-nuclear antibody, anti-extractable nuclear antigen antibody, thyroid peroxidase antibody and thyroid globulin antibody were significantly higher: 89.5% (85/95) vs. 59.6% (159/267), 75.8% (72/95) vs. 52.1% (139/267), 65.3% (62/95) vs. 38.6% (103/267), 42.1% (40/95) vs. 23.2% (62/267), 40.0% (38/95) vs. 19.1% (51/267) and 42.1% (40/95) vs. 19.9% (53/267). The serum IgM was significantly lower: 0.84 (0.78) g/L vs. 1.00 (0.75) g/L. The serum tumor necrosis factor-α, interleukin-2 receptor and cerebrospinal fluid IgG were significantly higher: 8 055 (3 118) pg/L vs. 6 830 (3 515) pg/L, 348 (175) kU/L vs. 314 (146) kU/L and 47.50 (46.50) g/L vs. 33.00 (24.00) g/L. And there were statistical differences ( P<0.01 or <0.05). Multivariate Logistic regression analysis result showed that the admission EDSS score and anti-nuclear antibody positive were the independent risk factors of short-term prognosis in patients with demyelinating diseases of central nervous system ( OR = 5.034 and 6.942, 95% CI 3.289 to 7.705 and 2.250 to 21.422, P<0.01). ROC curve analysis result showed that the area under the curve of anti-nuclear antibody positive combined with admission EDSS score predicted the short-term prognosis in patients with demyelinating diseases of central nervous system was 0.972, with a sensitivity of 90.5%, and a specificity of 92.5%. Conclusions:The admission EDSS score and anti-nuclear antibody positive are the independent risk factors for poor prognosis in patients with demyelinating diseases of central nervous system. And the combination of two indexes can better predict the short-term prognosis.

OBJECTIVE: To discuss the development of a multifunctional and multipoint fixed support drainage device for the digestive tract, as well as the effect of its application on animal experimental models and patients. METHODS: The digestive tract multifunctional and multipoint fixed support drainage device is designed according to the requirements of the various gastrointestinal surgery and interventional procedures. It has metal flaps and airbags to achieve multi point fixation. The cuffs and shears are used to achieve endoscopic removal. And through different tube diameters and lengths, surgeons can achieve different surgical purposes. RESULTS: A multifunctional and multipoint fixed support drainage device for the digestive tract was successfully designed and developed. The application experiment of the winged pancreatico-intestinal supporting drainage tube on animal models and patients, showed lower drainage fluid amylase level, faster amylase recovery speed, and better perioperative safety. CONCLUSIONS The support drainage device has the characteristics of simple operation, firm fixation, and good controllability of removal. It is an ideal choice among support drainage tubes in gastrointestinal surgery and interventional operations.
Drainage ; Gastrointestinal Tract ; Endoscopy

Objective:To investigate whether it is by regulating interleukin 1β ( IL-1β) gene expression that androgen receptor (AR) in macrophages affects hyperphosphate-induced vascular smooth muscle cell calcification. Methods:The chromatin immunoprecipitation (ChIP) experiment was used to determine whether AR was bound to the androgen receptor element (ARE) sequence of IL-1β promoter in THP-1 cells. Whether the AR regulated IL-1β gene expression was detected by luciferase assay experiments. AR of THP-1 cells was silenced and transfected by lentivirus with vector or shRNA. Flow cytometry was used to select positive transfected cells THP-1ARsc (control) and THP-1ARsi (AR silencing) with fluorescent markers. Western blotting was used to detect AR protein levels of THP-1ARsc (control) and THP-1ARsi cells (AR silencing in monocytes). Macrophages MФARsc (control) or MФARsi (AR silencing) were induced by 50 ng/ml phorbol ester. Enzyme-linked immunosorbent assay was used to detect IL-1β expression levels of MФARsc or MФARsi conditioned medium. The human aortic smooth muscle cells (HASMC) were cultured in MФARsc or MФARsi conditioned medium with phosphate (2.5 mmol/L final concentration of sodium dihydrogen phosphate), and Alizarin red S staining was used to analyze HASMC calcification degree. Western blotting was used to detect the expression levels of RUNX2 (osteoblast marker) and SM22α (HASMC marker), and neutralization assay was performed to test IL-1β-mediating effect of macrophages AR on HASMC calcification. Results:AR was bound to ARE sequence of IL-1β promoter and regulated IL-1β gene expression. The expression level of IL-1β protein in conditioned medium of MФARsi cells decreased significantly compared to MФARsc cells ( P<0.001). Compared with MФARsc conditioned medium group, HASMC calcium deposition in MФARsi conditioned medium group decreased significantly, RUNX2 protein decreased and SM22α protein increased (all P<0.05). The degree of HASMC calcification in the MФARsi conditioned medium+IgG antibody group decreased than that in the MФARsc conditioned medium+IgG antibody group significantly, and the degree of HASMC calcification in the MФARsc conditioned medium+IL-1β antibody group decreased significantly than that in the MФARsc conditioned medium+IgG antibody group; while the degree of HASMC calcification in the MФARsi conditioned medium+IgG antibody group and MФARsi conditioned medium+IL-1β antibody group decreased than that in the MФARsc conditioned medium+IL-1β antibody group (all P<0.05). Conclusions:Macrophage AR regulates IL-1β expression by binding to ARE sequence within IL-1β promoter, and IL-1β mediates the effect of macrophage AR on hyperphosphate-induced HASMC calcification.