Objective: To investigate the effect of injectable tetra-polyethylene glycol (PEG) hydrogels loaded with sitagliptin (STG) (abbreviated as PEG-STG hydrogels) on skin wound healing in diabetic mice, providing an experimental basis for the subsequent development of local therapeutic materials for primary healing of oral and maxillofacial skin and soft tissue wounds in patients with diabetes. Methods: PEG hydrogels were fabricated via the reaction of four-arm PEG succinimidyl glutarate (PEG-SG) and four-arm PEG amine (PEG-NH2). Subsequently, PEG hydrogels loaded with STG were prepared. The microstructure, gelation, injectability, compression properties, swelling, degradation, and in vitro drug release profiles were characterized. In vitro cellular experiments were conducted using the mouse fibroblast cell line L929 and human umbilical vein endothelial cells (HUVECs), which were divided into four groups: an NC group (normal medium control), Glu group (30 mmol/L high glucose medium), PEG group (high glucose medium with PEG hydrogel extracts), and PEG-STG group (high glucose medium with PEG-STG hydrogel extracts). Biocompatibility was evaluated via CCK-8 assays, live/dead staining, and hemolysis tests. The impact of the PEG-STG hydrogels on cellular function under hyperglycemic conditions was assessed using scratch assays, Transwell migration assays, qRT-PCR, and western blotting. Furthermore, approved by the Institutional Animal Care and Use Committee of the affiliated institution, a diabetic C57BL/6J mouse skin defect model was established and divided into three groups: an NC group (normal mice control), Glu group (diabetic model control), and PEG-STG group (treated with PEG-STG hydrogel in situ). Wound healing was evaluated through gross observation, wound healing rate analysis, and histological assessment via H&E staining. Results: The PEG-STG hydrogels exhibited rapid gelation at room temperature, excellent injectability, and a uniform porous structure. Compared with the PEG hydrogels, the PEG-STG hydrogels showed a significantly increased maximum compressive strength, swelling ratio, and degradation rate (P < 0.05). In vitro release profiles indicated an initial burst release of STG followed by a sustained release phase. Biocompatibility assessments confirmed that the PEG-STG hydrogels possessed good cytocompatibility and hemocompatibility. In vitro cellular experiments demonstrated that high glucose significantly inhibited the migration of the HUVECs and L929 cells, which was not ameliorated by the PEG group but was notably improved by the PEG-STG group. Moreover, the PEG-STG hydrogels upregulated the mRNA expression levels of platelet-endothelial cell adhesion molecule-1 (PECAM-1/CD31), vascular endothelial growth factor (VEGF), and von Willebrand factor in HUVECs, along with increased protein expression of VEGF and CD31. In vivo results revealed that at 14 days post-operation, the PEG-STG group exhibited significantly enhanced wound closure compared with the Glu and NC groups. H&E staining showed improved re-epithelialization, increased granulation tissue formation, and better tissue structure restoration in the PEG-STG group. Conclusion PEG-STG hydrogels possess favorable injectability and biocompatibility. They can improve endothelial cell and fibroblast function under hyperglycemic conditions and promote diabetic skin wound healing, providing a experimental basis for developing localized therapeutic materials for oral and maxillofacial wounds in patients with diabetes.

Objective To explore the effect and mechanism of Gegen Qinlian decoction (GQD) on myocardial injury induced by high-fat diet combined with streptozotocin in type 2 diabetic mice through network pharmacology and animal experiments. MethodsNetwork pharmacology was applied to screen the potential signaling pathways of GQD in the intervention of diabetic heart disease (DHD). A total of 36 specific pathogen-free (SPF) male C57BL/6J mice aged 8 weeks were acclimatized for 1 week and randomly divided into a normal control group (n=6) and a model group (n=30). Mice in the model group were fed a 60% high-fat diet and 5% glucose water for 4 weeks, and were intraperitoneally injected with 100 mg/kg streptozotocin after 12 h of fasting to establish the type 2 diabetes model. Mice in the normal control group were given a conventional diet and drinking water, and were intraperitoneally injected with an equal volume of citrate buffer after 12 h of fasting at the same time point. After successful establishment of the diabetic mouse model, the model mice were randomly divided into five groups according to body weight: model control group, GQD low-dose group, GQD medium-dose group, GQD high-dose group, and metformin positive control group, with 6 mice in each group. After 6 weeks of intragastric administration of corresponding doses of GQD, metformin, and ddH₂O respectively, all mice in the six groups (one normal control group and five model groups) were anesthetized with inhaled 2% isoflurane, blood samples were collected via eyeball enucleation, and heart tissues were harvested after euthanasia by cardiac exsanguination. Hematoxylin-eosin (HE) staining and wheat germ agglutinin (WGA) staining were performed to observe the pathological damage of myocardial tissues and measure the cross-sectional area of cardiomyocytes. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of pro-inflammatory cytokines in serum. Immunohistochemical staining was adopted to determine the protein expression levels of receptor for advanced glycation end products (RAGE), nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3), and phosphorylated nuclear factor-κB p65 (p-p65) in myocardial tissues. ResultsNetwork pharmacology analysis revealed that the targets of GQD against DHD were significantly enriched in inflammatory pathways, including the advanced glycation end products (AGEs)-RAGE axis, tumor necrosis factor (TNF) and interleukin-17 (IL-17) signaling pathways. HE and WGA staining results showed that, compared with the normal control group, the model control group exhibited myocardial fiber rupture, cardiomyocyte swelling, and significantly increased cardiomyocyte cross-sectional area (P<0.05). Compared with the model control group, GQD intervention significantly ameliorated the pathological changes, including myocardial fiber rupture, cell swelling, and cardiomyocyte hypertrophy. The results of immunohistochemical staining and ELISA indicated that compared with the model control group, GQD intervention markedly downregulated the protein expression of RAGE, NLRP3, and p-p65 in myocardial tissues, as well as the levels of serum pro-inflammatory cytokines (P<0.05). ConclusionGQD can effectively alleviate myocardial pathological injury in diet-induced type 2 diabetic mice, and its mechanism may be related to inhibiting the activation of the RAGE/p-p65/NLRP3 signaling pathway and reducing myocardial inflammatory response.

Objective To summarize the clinical features and prognosis of children suffered from malignant solid tumors of head and neck.Methods The clinical data of children with primary malignant solid tumors located in the head and neck was retrospectively analyzed from January 2007 to December 2021 in the Department of Oncology,Beijing Children's Hospital,Capital Medical University,and the clinical features,prognostic factors were summarized.Results A total of 234 children with malignant solid tumors of head and neck were included,with a male to female ratio of 1∶0.7,aged from 3 months to 17 years and 6 months(median age 51 months).173 cases(73.9％)were treated with local painless masses.Other symptoms included snoring and facial paralysis.The proportion of rhabdomyosarcoma(RMS)was the highest(145 cases,62.0％),followed by neuroblastoma(NB)(25 cases,10.7％),Ewing sarcoma(19 cases,8.1％),etc.A total of 47 cases(20.1％)had distant metastasis.The patients received surgery,chemotherapy and radiotherapy under the mode of multidisciplinary treatment(MDT).The 3-year and 5-year overall survival(OS)were 80.8％and 75.8％,respectively,and the 3-year and 5-year progression free survival(PFS)were 64.0％and 58.9％,respectively.Tumor survivors had abnormal appearance or facial motor function(49 cases,41.2％),developmental problems or abnormal tooth loss(18 cases,15.1％),and other long-term complications that may be related to the tumor or treatment.Conclusion There are various pathologic types of pediatric head and neck malignant solid tumors,RMS and NB are the most common.Local painless mass was the most common complaint.Distant metastasis is an independent risk factor for the prognosis of head and neck malignant solid tumors.Under the MDT model,the prognosis of malignant solid tumors of the head and neck in our center was generally good.In the treatment of the tumors,the side effects and sequelae should be controlled as small as possible under the premise of long-term survival.

Objective:To investigate the expression of ephrin type-A receptor 2 (EPHA2) in psoriatic lesions and its effect on the proliferation and differentiation of normal human epidermal keratinocytes (NHEKs) .Methods:The GDS4602 dataset from the Gene Expression Omnibus (GEO) database was analyzed to determine EPHA2 gene expression changes in psoriatic lesions. Skin tissue samples were collected from 3 psoriasis patients and 3 healthy controls, and EPHA2 expression was determined in the skin tissues by immunofluorescence staining. Twelve female BALB/c mice were randomly divided into 3 groups (4 mice in each group) : a normal control group (receiving no treatment), an imiquimod group (topically treated with 62.5 mg of imiquimod 5% cream), and an imiquimod + ALWⅡ-41-27 group (topically treated with 62.5 mg of imiquimod 5% cream, followed by intraperitoneal injections of the EPHA2 inhibitor ALWⅡ-41-27 at a dose of 20 mg·kg -1·d -1) ; after 6 days of treatment, dorsal skin samples were harvested for hematoxylin-eosin (HE) staining, immunofluorescence staining was performed to determine the expression of EPHA2 and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), and real-time fluorescence-based quantitative PCR (qPCR) was conducted to determine the mRNA expression of the nuclear proliferation antigen Ki67, involucrin (Ivl), loricrin (Lor), and keratin 10 (Krt10). In vitro cultured NHEKs were divided into a control group (receiving no treatment), an M5 group (treated with 10 ng/ml M5 cytokines [including interleukin-17A, interleukin-22, interleukin-1α, oncostatin M and tumor necrosis factor-α]), an ALWⅡ-41-27 group (treated with 1 μmol/L ALWⅡ-41-27), and an M5 + ALWⅡ-41-27 group (treated with 10 ng/ml M5 and 1 μmol/L ALWⅡ-41-27) ; after 24 hours of treatment, the 5-ethynyl-2′-deoxyuridine (EdU) assay was performed to assess cellular proliferative activity, Western blot analysis to determine the expression of EPHA2, ERK and their phosphorylated proteins, and qPCR to determine the mRNA expression of KI67, IVL, LOR, and KRT10. One-way analysis of variance, Dunnett's T3 test, two-independent-sample t test, and paired t test were used for statistical analysis. Results:GEO database analysis revealed upregulated EPHA2 expression in psoriatic lesions compared with normal skin tissues from healthy controls ( t = 21.07, P < 0.001). Immunofluorescence staining showed increased EPHA2 expression in skin tissues from psoriasis patients and mouse models of psoriasis compared with those from healthy controls and normal control mice, respectively (both P < 0.01). In the animal experiments, the imiquimod group showed thicker epidermis, increased Ki67 mRNA expression, decreased mRNA expression of Ivl, Lor, and Krt10, and elevated p-ERK1/2 expression compared with the normal control group and imiquimod + ALWⅡ-41-27 group (all P < 0.05). In the cell experiments, the M5 group showed an increased proportion of EdU-positive cells (35.61% ± 1.18% vs. 24.83% ± 0.60% and 12.49% ± 1.52%, t = 8.12, 12.00, P = 0.015, 0.001, respectively), increased KI67 mRNA expression, and decreased mRNA expression of IVL, LOR, and KRT10 compared with the control group and M5 + ALWⅡ-41-27 group (all P < 0.05) ; Western blot analysis revealed that the expression levels of EPHA2, p-EPHA2, and p-ERK1/2 in NHEKs were significantly higher in the M5 group than in the control group and M5 + ALWⅡ-41-27 group (all P < 0.05), but there was no significant difference in the ERK1/2 protein expression among groups ( P > 0.05) . Conclusion:EPHA2 expression was upregulated in psoriatic lesions, which may promote keratinocyte proliferation and inhibit its differentiation, possibly via the ERK pathway.

Objective To report a rare clinical case of Rickettsia sibirica infection complicated with left ventricular apical thrombus,and to explore its pathogenesis,diagnosis and treatment strategies,as well as the significance of anticoagulant intervention.Methods Clinical analysis was performed on a 71-year-old female patient.The patient presented with fever,coma,and multiple organ damage.Combined with the presence of eschar on the left ankle and a history of contact with pet dogs,the diagnosis of Rickettsia sibirica infection was confirmed by blood metagenomic next-generation sequencing(mNGS).The patient was treated with doxycycline combined with vancomycin for anti-infection,and rivaroxaban for anticoagulation.Inflammatory indicators,coagulation function,cardiac ultrasound,and organ function were dynamically monitored.Results Blood mNGS detected Rickettsia sibirica(11 sequences,relative abundance 29.73%).The diagnosis was confirmed in combination with eschar,skin rash,and shock manifestations.After 4 days of anti-rickettsial treatment,the patient regained consciousness,body temperature and blood pressure returned to normal,and inflammatory and coagulation indicators improved significantly.Cardiac ultrasound showed a left ventricular apical thrombus(3.8 cm×2.4 cm).The thrombus persisted but remained asymptomatic after anticoagulant treatment.Rickettsia-induced vascular endothelial damage,hypercoagulable state,and reduced left ventricular systolic function[ejection fraction(EF)was 0.40]collectively contributed to the formation of the apical thrombus.Conclusions Rickettsia sibirica infection can lead to intracardiac thrombus(the first reported case),with mechanisms related to endothelial damage,hypercoagulable state,and cardiac insufficiency.mNGS has key value in the rapid identification of pathogens in patients with fever of unknown origin accompanied by shock.Doxycycline is a core effective drug for rickettsial infections,and early anticoagulant intervention is required for patients with complicated thrombus.A history of pet contact and skin eschar are important epidemiological clues,which need to be strengthened in clinical identification.

Turning to critical illness is a common stage of various diseases and injuries before death. Patients usually have complex health conditions, while the treatment process involves a wide range of content, along with high requirements for doctor′s professionalism and multi-specialty teamwork, as well as a great demand for time-sensitive treatments. However, this is not matched with critical care professionals and the current state of medical care in China. Telemedicine, which shortens the distance of medical professionals and the gap of disease diagnosis and treatments in various regions through electronic information, can effectively solve the current problem. Therefore, there is an urgent need to develop a standardized, high-quality visualization telemedicine round system .Therefore, experts have been organized to search domestic and foreign literature on telemedicine round for critically ill patients and to form this consensus based on clinical experiences so as to further improve the level of critical care treatments in regions.

Objective:To explore the clinical efficacy of the posterior to anterior malleolar extended lateral approach (PAMELA) in the treatment of quadrimalleolar fractures.Methods:A retrospective study was conducted to analyze the clinical data of 12 patients with quadrimalleolar fracture who had been admitted to Foot and Ankle Surgery Department, Henan Luoyang Orthopaedic & Traumatological Hospital from June 2022 to June 2023. There were 5 males and 7 females, with an age of (37.3±12.2) years and a duration from injury to surgery of (8.8±3.5) d. Open reduction and internal fixation of displaced Chaput tubercle fractures, lateral and posterior malleolar fractures were conducted through the PAMELA for all patients. The incision exposure, operation time, intraoperative bleeding, and incision healing were noted. Postoperatively, the fracture reduction was evaluated using the Burwell-Charnley criteria. The clinical efficacy was evaluated at the final follow-up using the ankle-hindfoot score of American Orthopaedic Foot & Ankle Society (AOFAS), visual analogue scale (VAS), and range of motion (ROM) of the ankle joint.Results:Good exposure of the Chaput tubercle, anterolateral tibiotalar joint, and lateral and posterior malleoli was achieved during surgery in all patients. The follow-up time for the 12 patients was (14.3±1.8) months, the operation time (152.5±26.0) minutes, and the intraoperative bleeding (137.5±44.1) mL. All incisions healed at the first stage postoperatively without any complications. According to the Burwell-Charnley criteria, anatomic reduction was achieved in all patients. CT scans showed good reduction of the distal tibiofibular syndesmosis. At the final follow-up, their AOFAS score was (94.1±8.3) points, VAS 0 (0, 1) point, and ankle joint ROM 17.5°±9.0° for dorsiflexion and 35.2°±9.6° for plantarflexion.Conclusions:In the treatment of quadrimalleolar fractures, because the PAMELA can lead to good exposure of the anterolateral ankle joint, distal tibiofibular syndesmosis, and lateral and posterior malleolar fractures, it results in a high rate of anatomic reduction of the fractures, safe incisions and limited soft tissue complications. Therefore, it is a safe, simple, and effective surgical approach.

Background and purpose:Gallic acid(GA)induces tumor cells apoptosis and inhibits angiogenesis.Beyond directly attacking tumor cells,another crucial aspect of GA is its ability to modulate and enhance immune system function.For example,it can improve T cell metabolism,alleviate T cell exhaustion,and promote the formation of memory T cell phenotypes.Although several chimeric antigen receptor T(CAR-T)cells products have gained market approval,the technology still faces significant challenges.These limitations include off-target effects,a predisposition to T cell exhaustion and so on.Moreover,similar to exhaustion,cellular senescence is a major hindrance that impairs T cell function.This study aimed to investigate the effects of GA on the anti-tumor function of CAR-T cells both in vitro and in vivo.We further evaluated the impact of GA on CAR-T cells senescence and memory phenotypes,as well as the impact of GA and CAR-T cells on immune cell infiltration within the tumor microenvironment(TME).Methods:Second-generation CAR targeting mouse glypican 3(GPC3)and human epidermal growth factor receptor 2(HER2)were constructed to generate CAR-T cells.CAR-T cells were co-cultured with GA at a concentration of 5 μg/mL,and flow cytometry was used to assess the senescence status and memory phenotype of CAR-T cells and their killing ability against tumor cells at different effector-to-target ratios.Senescence markers included p53,p21,γ-H2AX and senescence-associated β-galactosidase(SA-β-gal),while CCR7 served as the memory phenotype marker.A subcutaneous tumor model was established to explore the effects of GA on the anti-tumor function of CAR-T cells and immune cell infiltration within the TME.Results:We successfully generated human HER2 and murine GPC3 CAR-T cells,achieving a purity of 30%-50%.GA enhanced the in vitro killing ability of CAR-T cells targeting mouse GPC3 and human HER2(P＜0.001)at different E:T ratios,delayed the senescence of mouse GPC3 CAR-T cells(p53,p21,γ-H2AX,P＜0.05;SA-β-gal,P＜0.001;CCR7,P＜0.001).And GA promoted the differentiation of CAR-T cells toward a memory phenotype(P＜0.001).Additionally,GPC3 CAR-T cells inhibited tumor cell growth(P＜0.05),prolonged mouse survival(P＜0.001),and enhanced the infiltration capacity of CAR-cells(P＜0.001)and endogenous immune cells[CD4+T cells,P＜0.05;CD8+T cells,P＜0.01;natural killer(NK)cells,P＜0.01].Conclusion:GA can enhance the cytotoxic activity of CAR-T cells in vitro,and delay the senescence of CAR-T cells.Furthermore,by modulating TME,GA improved immune cell infiltration,thereby augmenting the overall anti-tumor efficacy of CAR-T cells.

Objective To investigate the intervention effects and mechanism of Danggui Shaoyao power on spontaneous abortion rats.Methods A total of 60 first-day pregnant rats were randomly divided into normal group,model group,dydrogesterone group and Danggui Shaoyao power low,middle,and high dose groups,with 10 rats in each group.The low,middle,and high dose groups were given Danggui Shaoyao power 5.175 g·kg-1,10.35 g·kg-1,20.7 g·kg-1,respectively,from 1 to 12 days of gestation,and the dydrogesterone group was given dydrogesterone tablet solution 2 mg·kg-1 once a day.On the 13th day of gestation,rats model of spontaneous abortion was established by intragastric administration of 5 mg·kg-1 of mifepristone tablet solution except for the normal group.Serum levels of GnRH,FSH,LH,E2 were measured,and abortion rates and uterine coefficients were calculated.The pathological changes of pregnant uterus were observed by haematoxylin-eosin(HE)staining.The differential proteins in rats pregnant uterus were detected by Label-Free shotgun proteomic technique,and the PPI,Gene Ontology(GO),and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathways analysis of the differential proteins were analyzed.Immunohistochemistry was used to verify the expression levels of differential proteins.Results Compared with normal group,the serum levels of GnRH,FSH,LH,E2 and uterine coefficients were decreased,and the abortion rates were increased in model group(P<0.05).There were abortion lesions of spontaneous abortion in model group.Compared with model group,the serum levels of GnRH,FSH,LH,E2 and uterine coefficients were increased(P<0.05),and the abortion rates were decreased(P<0.05)in dydrogesterone group and Danggui Shaoyao power low,middle,and high dose groups.Proteomic results showed that a total of 550 proteins were quantified in this study.PPI analysis showed that a total of 159 proteins interacted with other proteins as hubs;the results of GO and KEGG enrichment analysis showed that the intervention effect of Danggui Shaoyao power on spontaneous abortion is related to the focal adhesion pathway,and involved upregulation of Akt2,Col6a1,Col6a2 and downregulation of Pten.Immunohistochemistry results showed that compared with normal group,the expression level of Akt2,Col6a1 and Col6a2 were decreased(P<0.05),and the expression level of Pten was increased(P<0.05)in model group.Compared with model group,the expression level of Akt2,Col6a1 and Col6a2 were increased(P<0.05),and the expression level of Pten was decreased(P<0.05)in dydrogesterone group and Danggui Shaoyao power low,middle,and high dose groups.Conclusions Danggui Shaoyao power has the intervention effect on spontaneous abortion,and its mechanism may be related to by demoting the protein expressions of Pten,and promoting the protein expressions of Akt2,Col6a1 and Col6a2.