BACKGROUND:Bone relies on the close connection between blood vessels and bone cells to maintain its integrity.Bones are in a physiologically hypoxic environment.Therefore,the study of angiogenesis and osteogenesis in hypoxic environment is closer to the microenvironment in vivo. OBJECTIVE:To explore the influence of Wenshen Tongluo Zhitong(WSTLZT)formula on H-type bone microvascular endothelial cell/bone marrow mesenchymal stem cell co-culture system in hypoxia environment and its related mechanism. METHODS:Enzyme digestion method and flow sorting technique were used to isolate and identify H-type bone microvascular endothelial cells.Mouse bone marrow mesenchymal stem cells were isolated and obtained by bone marrow adhesion method.H-type bone microvascular endothelial cell/bone marrow mesenchymal stem cell hypoxic co-culture system was established using Transwell chamber and anoxic culture workstation.WSTLZT formula powder was used to intervene in each group at a mass concentration of 50 and 100 μg/mL.The angiogenic function of H-type bone microvascular endothelial cells in the co-culture system was evaluated by scratch migration test and tube formation test.The osteogenic differentiation ability of bone marrow mesenchymal stem cells in the co-cultured system was evaluated by alkaline phosphatase staining and alizarin red staining.The protein and mRNA expression changes of PDGF/PI3K/AKT signal axis related molecules in H-type bone microvascular endothelial cells in the co-cultured system were detected by Western Blotting and q-PCR,respectively. RESULTS AND CONCLUSION:(1)Compared with the normal oxygen group,the scratch mobility and new blood vessel length of H-type bone microvascular endothelial cells were significantly higher(P<0.05);the osteogenic differentiation capacity of bone marrow mesenchymal stem cells was higher(P<0.05);the expression of PDGF/PI3K/AKT axis-related molecular protein and mRNA increased(P<0.05)in the hypoxia group.(2)Compared with the hypoxia group,scratch mobility and new blood vessel length were significantly increased in the H-type bone microvascular endothelial cells(P<0.05);bone marrow mesenchymal stem cells had stronger osteogenic function(P<0.05);the expression of PDGF/PI3K/AKT axis-related molecular proteins and mRNA further increased(P<0.05)after treatment with different dose concentrations of WSTLZT formula.These findings conclude that H-type angiogenesis and osteogenesis under hypoxia may be related to the PDGF/PI3K/AKT signaling axis,and WSTLZT formula may promote H-type vasculo-dependent bone formation by activating the PDGF/PI3K/AKT signaling axis,thereby preventing and treating osteoporosis.

Real-time,noninvasive programmed death-ligand 1(PD-L1)testing using molecular imaging has enhanced our understanding of the immune environments of neoplasms and has served as a guide for immunotherapy.However,the utilization of radiotracers in the imaging of human brain tumors using positron emission tomography/computed tomography(PET/CT)remains limited.This investigation involved the synthesis of[18F]AlF-NOTA-PCP2,which is a novel peptide-based radiolabeled tracer that targets PD-L1,and evaluated its imaging capabilities in orthotopic glioblastoma(GBM)models.Using this tracer,we could noninvasively monitor radiation-induced PD-L1 changes in GBM.[18F]AlF-NOTA-PCP2 exhibited high radiochemical purity(＞95％)and stability up to 4 h after synthesis.It demonstrated specific,high-affinity binding to PD-L1 in vitro and in vivo,with a dissociation constant of 0.24 nM.PET/CT imaging,integrated with contrast-enhanced magnetic resonance imaging,revealed significant accumulation of[18F]AlF-NOTA-PCP2 in orthotopic tumors,correlating with blood-brain barrier disruption.After radiotherapy(15 Gy),[18F]AlF-NOTA-PCP2 uptake in tumors increased from 9.51％±0.73％to 12.04％±1.43％,indicating enhanced PD-L1 expression consistent with immunohisto-chemistry findings.Fractionated radiation(5 Gy × 3)further amplified PD-L1 upregulation(13.9％±1.54％ID/cc)compared with a single dose(11.48％±1.05％ID/cc).Taken together,[18F]AlF-NOTA-PCP2 may be a valuable tool for noninvasively monitoring PD-L1 expression in brain tumors after radiotherapy.

Objective To review the state of research on medullary thyroid carcinoma(MTC)over the past two decades,so as to offer a quick reference for understanding the current state and future trends in this field.Methods A computer was employed to search the Web of Science Core Collection database for MTC-re-lated literature(types;articles and reviews)published between 2000 and 2022.VOS viewer 1.6.18 software was utilized to create collaboration network diagrams,heat distribution diagrams for high-yielding countries(with publication volume ≥ 90),research institutions(with publication volume ≥ 60),and authors(with publication volume ≥30),and high-frequency keyword clustering network diagrams.Cite Space 5.7.R5 soft-ware was employed to conduct cluster analysis and explosive keyword detection on co-cited literature.Results A total of 4866 MTC related literature(3688 articles and 918 reviews)were obtained.Although the annual publication volume fluctuated,the overall trend showed a gradual increase.The 4866 articles are from 87 coun-tries,involving 4250 research institutions,21 016 authors,and 963 journals.The United States(1436 arti-cles),MD Anderson Cancer Center at the University of Texas(139 articles),and Dralle H(Department of General Surgery at Halle Wittenberg University Hospital,61 articles)were the countries,research institu-tions,and authors with the highest number of publications,respectively.High frequency keywords form four clusters:RET gene expression,prognostic factors,MTC clinical management,and MTC treatment.The key-words emerging explosively in recent years were management,survival,guideline,association,etc.The key areas of focus in highly cited literature were RET proto oncogene,targeted therapy,RET gene mutation,and so on.Conclusions In the past 20 years,MTC related research has shown a gradual upward trend,with de-veloped countries led by the United States taking a leading position in this field.The current research hotspots are the treatment,diagnosis,application of inhibitors,and exploration of the pathogenesis of MTC.

Objective:To investigate the correlation between metabolic syndrome (MS), its different components and the risk of cholecystolithiasis and gallbladder polyp in Uygur population in rural areas of southern Xinjiang.Methods:This study was a prospective cohort study. A baseline survey was conducted in August 2016. A typical sampling method was used to select 10 476 Uygur people in rural areas of southern Xinjiang as the research objects. Baseline clinical data were collected, including demographic data such as age, gender, and education level, and laboratory examination indicators such as blood glucose and triglyceride levels. According to the MS diagnostic criteria of the relevant guidelines, 10 476 subjects were divided into the MS group (3 475 cases) and the non-MS group (7 001 cases). The incidence of cholecystolithiasis and gallbladder polyp was followed up in 2019, 2021 and 2023, respectively. Cox regression was used to analyze the correlation between MS, its different components and the risk of cholecystolithiasis and gallbladder polyp. Chi-square test and independent sample t test were used for statistical analysis. Results:The median follow-up time was 6.43 years in 10 476 subjects, and the overall cumulative incidence of cholecystolithiasis and gallbladder polyp was 5.43% (569/10 476). The cumulative incidence of cholecystolithiasis and gallbladder polyp in the MS group was 10.73% (373/ 3 475), which was significantly higher than that in the non-MS group (2.80% (196/7 001)); χ2= 284.62, P<0.001). The results of multivariate Cox regression analysis showed that, 41 to 59 years old ( HR=1.26, 95% confidence interval (95% CI): 1.03 to 1.54, P=0.025), ≥60 years old ( HR=1.88, 95% CI: 1.45 to 2.45, P<0.001), female ( HR=1.34, 95% CI: 1.13 to 1.60, P=0.001), MS ( HR=2.19, 95% CI: 1.59 to 3.01, P<0.001), hypertriglyceridemia ( HR=1.47, 95% CI: 1.18 to 1.83, P=0.001), hypertension ( HR=1.30, 95% CI: 1.04 to 1.62, P=0.023), and hyperglycemia ( HR=1.24, 95% CI: 1.01 to 1.52, P=0.041) were independent risk factors for cholecystolithiasis and gallbladder polyp. After the adjustment of age and gender, MS ( HR=3.39, 95% CI: 2.82 to 4.07, P<0.001), hypertriglyceridemia ( HR=2.37, 95% CI: 2.00 to 2.81, P<0.001), hypertension ( HR=2.00, 95% CI: 1.66 to 2.41, P<0.001), and hyperglycemia ( HR=1.86, 95% CI: 1.55 to 2.23, P<0.001) were still correlated with cholecystolithiasis and gallbladder polyp, and there was the srtongest correlation between MS and cholecystolithiasis and gallbladder polyp. The results of univariate Cox regression analysis showed that along with the increase of accumulated of MS components, the risk of cholecystolithiasis and gallbladder polyp significantly increased (1 to 5 components corresponding HR (95% CI) were 1.92 (1.13 to 3.24), 2.21 (1.32 to 3.69), 6.91 (4.22 to 11.30), 8.56 (5.15 to 14.22), and 10.73 (5.66 to 20.33); P=0.015, =0.002, <0.001, <0.001, and <0.001); after age and gender were adjusted, this trend still existed (1 to 5 components corresponding HR (95% CI) were 1.81(1.07 to 3.06), 1.95(1.16 to 3.27), 5.64(3.42 to 9.32), 6.69(3.97 to 11.25), and 7.76(4.04 to 14.91); P=0.028, =0.012, <0.001, <0.001, and <0.001). Conclusion:MS and its components can increase the risk of cholecystolithiasis and gallbladder polyp, and the risk of cholecystolithiasis and gallbladder polyp significantly increases along with the increase of accumulated of MS components.

Objective To compare the midterm outcomes of the Bentall procedure versus isolated aortic valve replacement(AVR)in patients with bicuspid aortic valve(BAV)complicated with severe stenosis and ascending aortic dilation in order to assess the therapeutic value of these surgical approaches for this complex cardiac condition.Methods A retrospective cohort study was conducted on 96 eligible patients who underwent surgical treatment in our institute between January 2018 and December 2022.According to surgical approaches,they were divided into an AVR group(65 cases)and a Bentall group(31 cases).Demographic features,comorbidities,preoperative status,and echocardiographic parameters were collected in all patients.Propensity score matching(PSM)was applied in a 1:1 ratio to balance baseline characteristics.Perioperative indicators and follow-up data were compared and analyzed between matched cohorts after control of cofounding factors.Results After PSM,25 matched pairs were screened out and analyzed with comparable baseline data(all P>0.05).The Bentall group demonstrated significantly more superior intraoperative effective orifice area(EOA,2.69±0.47 vs 2.35±0.47 cm2,P=0.013)and EOA index(EOAI,1.69±0.30 vs 1.47±0.29 cm2/m2,P=0.010),and obviously longer cardiopulmonary bypass time[190.00(147.00,257.00)vs 101.00(88.50,124.50)min,P<0.01]and aortic cross-clamp time[141.00(120.00,166.00)vs 66.00(55.00,81.50)min,P<0.01]when compared with the AVR group.During a median follow-up of 28 months,the AVR group had notably larger aortic sinus diameter[32.00(30.00,34.00)vs 26.80(26.00,28.00)mm,P<0.01]and ascending aortic diameter[38.00(34.50,42.00)mm vs 26.00(26.00,28.00)mm,P<0.01],with ongoing dilation in the ascending aorta,while the Bentall group maintained stable dimensions.The Bentall group also showed statistically lower peak aortic valve pressure gradients[21.00(15.50,27.00)vs 25.00(19.50,31.00)mmHg,P=0.049].Conclusion Both Bentall procedure and AVR are effective in treatment of BAV complicated with severe stenosis and ascending aortic dilation.But,Bentall procedure offers advantages in hemodynamic optimization and aortic stability.

Objective:To investigate, for multi-sensitized allergic rhinitis (AR) patients allergic to dust mites combined with other allergens (pollen, mold, animal dander, etc.), whether the single dust mite subcutaneous immunotherapy (SCIT) can improve the specific symptoms caused by other allergens in the patients, and to analyze the relationship between the effectiveness of symptom improvement in these patients and the type, quantity and severity of the allergens.Methods:A multicenter retrospective study was conducted to collect mul-sensitized AR patients from allergy or respiratory departments of 5 hospitals who received house dust mite allergen preparation SCIT for 12 to 36 months and met other inclusion and exclusion criteria from February to July 2024. General clinical data were collected and the perennial or seasonal symptoms before and after treatment were evaluated with visual analogue scale (VAS) to assess whether there was an perennial or allergen-specific symptom improvement (VAS score decrease ≥30%), by which the patients were divided into effective group and ineffective. R software was used to analyze the differences between groups by using Fisher′s exact test and Mann-Whitney U test. Results:A total of 62 patients were enrolled, and the treatment were effective in 39 of them, with an effective rate of 62.9%. For allergen-specific symptoms, the median age of the effective group was higher than that of the ineffective group (12 years old vs. 8 years old, P=0.039), and the effective rate in dust mite specific immunoglobin E (sIgE) grade ≤5 group was higher than that in sIgE grade >5 group (81.6% vs. 45.5%, P=0.008), and the effective rate of mold sIgE grade ≤2 group was higher than that of sIgE grade >2 group (83.3% vs. 28.6%, P=0.045), and there was no statistically significant correlation between the other allergen grades and the effective rate ( P>0.05). For perennial symptoms, the effective rate in the mold grade ≤2 group was higher than that in the sIgE grade >2 group (91.3% vs. 28.6%, P=0.010), and there was no statistically significant correlation between the other allergen grades and the effective rate ( P>0.05). There was no significant correlation between the treatment effectiveness of perennial or allergen-specific symptoms and the number of combined allergens, the grade of skin test, and the difference between the grade of combined allergens and that of dust mites ( P>0.05). Conclusion:Among the patients with multi-sensitized AR allergic to dust mites included in this study, single dust mite SCIT is effective in some of them, and for allergen-specific symptoms, the effective group was elder, and dust mite sIgE grade 6 and mold sIgE grade ≥2 was related to the low effective rate of SCIT. The present results are insufficient for selecting single or multiple AIT in any type of multi-sensitized patients.

Objective:To investigate the effects and underlying mechanisms of Stat3 knockout in donor T cells on acute gastrointestinal graft-versus-host disease (GI-aGVHD) .Methods:BALB/c mice were exposed to lethal irradiation and transplanted with bone marrow and spleen cells from BALB/c mice (syngeneic control group), C57BL/6 mice (wild-type T cell group, WT group), or C57BL/6J-Stat3 em1cyagen mice (Stat3 gene knockout T cell group, Stat3-KO group) via tail vein injection to establish the aGVHD model. The survival rate, body weight changes, and clinical scores of mice were monitored. Cytometric bead array (CBA) was used to detect the concentrations of serum cytokines. Lymphocytes were isolated from tissues for flow cytometric analysis. H&E staining was performed to observe intestinal pathological changes. FITC-dextran assay was conducted to assess intestinal permeability. Immunohistochemistry was used to evaluate the expression of Ki67 and Muc2. Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) was employed to analyze the gene expression levels of Olfm4, Lysozyme, and Muc2 in the small intestine. Metabolomics was conducted to detect metabolites in serum and intestinal tissues. An in vitro GI-aGVHD organoid model was established by coculturing intestinal organoids with allogeneic T cells, where the number and area of small intestinal organoids were recorded. The GVL effect was assessed using luciferase-transfected ALL cells (ALL/Luc) and bioluminescent imaging. Results:Compared with the WT group, Stat3 knockout T cells alleviated body weight loss, reduced symptoms—such as hunchback and diarrhea—in mice, improved survival rate ( P<0.05), and reduced serum interleukin (IL) -2, IL-6, interferon-γ, tumor necrosis factor-α, IL-17A, and IL-10 levels (all P<0.05), intestinal inflammatory cell infiltration ( P<0.05), and intestinal mucosal permeability. Further, Muc2 and Ki67 expression levels in the small intestine of the Stat3 knockout group were markedly increased, and Olfm4, Lysozyme, and Muc2 gene expression levels were significantly increased (all P<0.05). In vitro, the Stat3 knockout group demonstrated better organoid development than the WT group. Metabolomic analyses indicated that Stat3 knockout in T cells may affect the pathways associated with bile acid secretion and unsaturated fatty acids. ALL/Luc cells in the GVL mouse model proliferated rapidly in the TCD-BM group; however, 80% of the mice in the Stat3-KO group survived tumor-free for >100 days ( P<0.05) . Conclusion:Knocking out Stat3 in graft T cells reduces T cell damage to intestinal stem cells, thereby ultimately alleviating GI-aGVHD while maintaining a stable GVL effect.

Objective:To investigate the anti-tumor effect of the Histone Deacetylase 6 (HDAC6) inhibitor ACY-738 and its underlying mechanisms in Diffuse Large B-cell Lymphoma (DLBCL) .Methods:The expression of HDAC6 in various tumors and DLBCL was analyzed using bioinformatics. DLBCL cells were treated with different concentrations of ACY-738. Cell viability, DNA synthesis, and clone formation were assessed by CCK-8 assay, EdU assay, and soft agar assay, respectively. Intracellular reactive oxygen species (ROS) levels were detected by fluorescence microscopy. Morphological changes in cells were observed using transmission electron microscopy (TEM). Mitochondrial ROS levels and apoptosis were measured by flow cytometry. The expression levels of apoptosis-related and autophagy-related proteins were detected by Western blotting.Results:HDAC6 was highly expressed in DLBCL ( P<0.05). ACY-738 inhibited the proliferation, DNA synthesis, and colony formation of DLBCL cells in a dose-dependent manner ( P<0.05). Treatment with ACY-738 increased intracellular and mitochondrial ROS levels in DLBCL cells in a dose-dependent manner ( P<0.05). TEM revealed that after ACY-738 treatment, mitochondria in cells were swollen and ruptured, mitochondrial cristae were reduced or absent, autolysosomes appeared, and features characteristic of apoptosis were observed. Western blotting showed that after ACY-738 treatment, the expression of the anti-apoptotic protein BCL-2 was downregulated, while the expression of Cleaved-PARP, Cleaved caspase-3, and BAX was upregulated ( P<0.05). The expression of autophagy-related proteins Atg7, Atg3, LC3B, and P62 was downregulated, and the expression of acetylated P53 protein was upregulated ( P<0.05) . Conclusion:The HDAC6 inhibitor ACY-738 induces mitochondria-dependent apoptosis and autophagy in DLBCL cells by acetylating P53, thereby inhibiting DLBCL cell proliferation.

Objective:The clinical symptoms of children with global developmental delay (GDD) were analyzed to provide the scientific basis for the intervention of children with GDD.Methods:The results of the neuro-psychobehavioral scale were collected from 32 511 children with GDD from June 2020 to November 2023. Inclusion criteria: Children diagnosed with GDD according to the Diagnostic and Statistical Manual of Mental Disorders-V, ages 0.0 to 4.9 years. Exclusion criteria: children with common hearing impairment and visual impairment. The Chi-square tests were used for statistical analysis.Results:There were more boys than girls with GDD in outpatient clinics (68.2% vs. 31.8%). Among the children, the proportion of developmental delay in 5, 4, 3, and 2 domains was 31.1%, 23.4%, 22.9% and 22.6% respectively. The rate of delay in 2-3 domains was lower in boys (41.9%) than in girls (53.1%). The rate of delay in 4-5 domains was higher in boys (58.1%) than in girls (46.9%) ( χ2=352.11, P<0.001). Overall, outpatient GDD decreased with age. From 1.0-1.9 to 4.0-4.9 years of age, the proportion of children with developmental delay in 5 domains increased with age (18.2%, 36.4%, 43.9%, 52.4%). Among children aged 0.0-0.9 years, the proportion of 2 domains of developmental delay was higher (33.4%).Among children aged 1.0-1.9 years, the proportion of 2-3 domains of developmental delay was higher (30.7%). Among children aged 2.0-, 3.0-, 4.0-4.9 years, the proportion of developmental delay in 5 domains was higher (36.4%, 43.9%, 52.4%). In children with GDD, the fine motor delay occurred most frequently (85.1%), followed by social self-care (83.9%), language (79.0%), adaptation (62.3%), and gross motor (52.8%). The frequency of developmental delays in fine motor, adaptability, language, and social self-care in boys was higher than that in girls ( χ2=161.37, χ2=41.10, χ2=320.90, χ2=238.54, all P<0.001). The age groups with the highest delay incidence of gross motor, fine motor, adaptability, language, and social self-care were: 4.0-4.9 years (70.6%), 3.0-3.9 years (97.4%), 4.0-4.9 years (81.2%), 2.0-2.9 years (90.9%),2.0-2.9 years (95.4%). The proportions of fine motor delay in GDD children aged 0.0-0.9, 3.0-3.9 and 4.0-4.9 years were (74.5%, 97.4%, 96.8%) and the proportions of social self-care delay in GDD children aged 1.0- and 2.0-2.9 years were (92.1%, 95.4%). Peripheral and mild developmental delays were predominant in children with GDD. The proportion of severe language delay (6.4%) was higher than that in other fields. Conclusions:The proportion of GDD children with developmental delay in 4-5 domains was 54.5%. The most frequent domain of delay was fine motor. The frequencies of developmental delays in fine motor skills, adaptability, language, and social self-care in boys were higher than in girls. Most of the developmental delays in GDD children were marginal and mild. The rate of severe developmental delay in language was higher than in other domains.

Objective:To investigate the therapeutic effectiveness of double-anatomical plate-assisted reconstruction of a stable triangle in the treatment of chronic distal humerus fractures.Methods:A retrospective analysis was performed on the medical records of 10 patients with distal humerus fracture treated with double plate assisted reconstruction of a stable triangle from August 2021 to December 2024. All patients were followed up for more than 6 months. The cohort included 9 males and 1 female, with a mean age of 54.75±15.15 years (range, 31-73 years). Causes of injury: 4 cases of slip, 2 cases of high-energy fall, 3 cases of traffic accident, and 1 case of crush injury. According to the AO/OTA classification, all fractures were type C3, including 4 cases of C3.3 and 6 cases of C3.2. The operation duration, intraoperative blood loss, and length of hospital stay were recorded. Follow-up evaluations were conducted at 1, 3, and 6 months postoperatively and at the final follow-up. Radiographs were obtained to assess fracture reduction, healing, and implant positioning. Functional outcomes of the elbow were assessed using carrying angle, humeral condyle anteversion angle, modified trochleocapitellar index (mTCI), range of motion (ROM), visual analogue scale (VAS) for pain, Mayo elbow performance score (MEPS), and complication rates.Results:All 10 patients successfully completed the operation, with an average operation time of 221.75±48.73 min (range, 165-310 min), an average intraoperative blood loss of 462.50±215.05 ml (range 150-800 ml). 4 patients received blood transfusion. The average hospital stay was 10.75±2.55 d (range 6-14 d). The average carrying angle of 171.50°±5.37° (range 165°-179°) and the anterior angle of humeral condyle 39.75°±3.96° (range 34°-45°) were all within the standard range. At least one index in the mTCI was within the optimal range at the last follow-up. All patients were followed up with an average follow-up of 10.75±5.73 months (range 6-22 months). All 10 patients were healed after surgery with an average healing time of 4.75±2.05 months (range 3-9 months). At the final follow-up, the average elbow ROM was 93.75°±25.88° (range, 50°-115°), internal rotation was 83.13°±9.61° (range, 60°-90°), and external rotation was 88.13°±3.72° (range, 80°-90°). The mean VAS score was 0.63±0.92 (range, 0-2), and the average MEPS was 88.75±11.57 (range, 70-100), with 4 excellent, 4 good, and 2 fair outcomes, an excellent and good rate of 80%. Complications included one case of periarticular osteophyte formation, one case of transient ulnar nerve numbness that improved with conservative treatment, and three cases of occasional mild pain following increased activity. Conclusion Double-anatomical plate-assisted reconstruction of a stable triangle provides effective and stable fixation for chronic AO/OTA C3 distal humerus fractures. The short-term postoperative outcomes are satisfactory, with good functional recovery and a low complication rate.Conclusions:Double-anatomical plate-assisted reconstruction of a stable triangle provides effective and stable fixation for chronic AO/OTA C3 distal humerus fractures. The short-term postoperative outcomes are satisfactory, with good functional recovery and a low complication rate.