This study aimed to design and synthesize a series of novel photocaged compounds based on the precise binding mode of cyclin-dependent kinase 2 (CDK2) inhibitor AT7519 with its target, to achieve precise optical control over molecular activity. Using AT7519 as the structural foundation, different types of photoremovable protecting groups were introduced at its key interaction sites (the NH of the pyrazole ring and the NH of the piperidine ring), resulting in the synthesis of eight dual-photocaged compounds. Their structures were confirmed by NMR and mass spectrometry, and their photochemical properties—including photolysis wavelength, photolysis time, and photolysis efficiency—were systematically evaluated. The optically controlled inhibitory effects of the compounds on HCT116 cell proliferation were assessed using MTT assay. The photoresponsive characteristics of the photocaged compounds were significantly influenced by the type of photoremovable protecting group and its introduction site. Among them, compounds 1a, 1b, and 2d exhibited excellent photolysis efficiency, each achieving a rate exceeding 90%. Particularly, compounds 1b and 2d demonstrated excellent optically controlled activity: under dark conditions, their half maximal inhibitory concentration (IC50) values were both greater than 150 µmol/L, indicating negligible cell proliferation inhibitory activity; however, upon irradiation, their cell proliferation inhibitory activity significantly increased, with IC50 values comparable to those of the positive control AT7519. The obtained compounds 1b and 2d possess excellent optically controlled properties, and can be further investigated as potential candidates for optically controlled CDK2 inhibitors.

Objective:To explore the diagnostic value of combining Ki67, molecular subtyping, and ultrasonographic parameters in predicting axillary lymph node metastasis in breast cancer.Methods:200 breast cancer patients who were admitted to Meizhou People’s Hospital from Jan. 2020 to Dec. 2022 were collected. Based on the presence or absence of axillary lymph node metastasis in breast cancer, the patients were divided into an axillary lymph node metastasis group and a non-axillary lymph node metastasis group. Age, clinical stage, tumor location, tumor size, degree of differentiation, boundary, blood flow, echo, calcification, morphology, vascular invasion, Ki67, molecular typing, resistance index (RI) , shear wave velocity were collected. Multivariate Logistic regression analysis was used to screen the risk factors for axillary lymph node metastasis of breast cancer, and receiver operating characteristic curve (ROC) was used to evaluate the clinical value of ki67, molecular typing combined with ultrasound parameters in the diagnosis of axillary lymph node metastasis of breast cancer.Results:There were no statistically significant differences in age, clinical stage, tumor location, tumor size, differentiation degree, boundary, blood flow, echo or calcification between the axillary lymph node metastasis group and the non-axillary lymph node metastasis group ( t=0.80, χ20.13, χ2=0.14, χ2=0.90, χ2=0.64, χ2=1.03, χ2=0.04, χ2=0.34, χ2=1.2, P>0.05) , while there were statistically significant differences in morphology, vascular invasion, Ki67, molecular classification, RI and shear wave velocity between the two groups ( χ2=12.01, χ2=8.75, χ2=11.36, χ2=11.43, t=6.34, t=7.25, P<0.05) . Multivariate Logistic regression analysis showed that vascular invasion, Ki67 high expression, triple negative breast cancer, RI and shear wave velocity were all risk factors for axillary lymph node metastasis ( OR=5.572,4.026,3.632,107.639,1.936, P<0.05) . ROC curve analysis results showed that the AUC of Ki67, molecular typing, RI and shear wave velocity in the diagnosis of axillary lymph node metastasis of breast cancer was 0.620, 0.594, 0.744 and 0.792, respectively, and the AUC of Ki67, molecular typing, RI and shear wave velocity in the diagnosis of axillary lymph node metastasis of breast cancer was 0.846. The AUC of the combination of Ki67, molecular typing, RI and shear wave velocity in the diagnosis of axillary lymph node metastasis of breast cancer was higher than that of Ki67, molecular typing, RI and shear wave velocity alone ( Z=5.55,7.10,3.44,2.45, P<0.05) . Conclusions:High Ki67 expression, triple-negative breast cancer, lymphovascular invasion,RI, and shear wave velocity are all risk factors for axillary lymph node metastasis in breast cancer. The combined use of Ki67, molecular subtype, RI, and shear wave velocity can improve the diagnostic accuracy for axillary lymph node metastasis in breast cancer.

Objective To evaluate the recognition capability of AI-enabled Cellsee CS-BM1 automatic cell morphology analyzer for pe-ripheral blood smears and its roles in assisting manual classification,and explore the application value of AI system in the diagnosis network of tiered primary medical units.Methods The blood samples which triggered the re-examination rules were collected from six primary medical units,including the Laboratory Department of Shanghai Jiahui International Hospital,and so on,from March to No-vember 2023.The smears of peripheral blood were prepared and AI analyzer was used for pre-classification to evaluate its recognition performance in identifying the samples with abnormal WBC and RBC.The sensitivity,specificity,and accuracy of WBC classification by six junior and intermediate technicians,both with and without AI assistance,were analyzed.Additionally,the roles of the AI system in tiered diagnosis of primary medical units were also evaluated.Results The sensitivity,specificity,and accuracy of AI system in recognizing malignant primitive cells were 92.86％,95.16％,and 95.10％,respectively.The sensitivities of AI system in recognizing immature granulocytes,reactive lymphocytes,and nucleated RBCs were all greater than 90％.The sensitivity of AI system in identif-ying abnormal morphology of RBCs reached 99.59％,along with rapid quantitative analysis for various anomalous types of RBCs.In AI-assisted mode,the sensitivity of recognition for all cell types was improved to varying degrees by junior and intermediate technicians,and the sensitivity for recognizing malignant primitive cells,reactive lymphocytes,and immature granulocytes increased to 58.24％,53.39％,and 62.37％for junior technicians,and to 92.06％,83.24％,and 83.12％for intermediate technicians,respectively.The improvements for junior technicians were particularly significant,with increases of 12.46％,10.61％,and 3.71％for each cell type,respectively.Both groups achieved higher specificity and accuracy.Through AI pre-classification and manual review,a variety of pe-ripheral blood cell-related diseases were accurately diagnosed in the tiered healthcare practice of primary medical units,including 339 cases(11.13％)of red blood cell diseases,5 cases(0.16％)of platelet diseases,2 343 cases(76.90％)of infection-related disea-ses,and 28 cases(0.92％)of malignant hematological diseases.In addition,332 cases(10.90％)which lacked an obvious related cause or required further examinations were identified as well.Conclusion AI pre-classification has demonstrated strong cell recogni-tion capabilities and may assist technicians in improving the sensitivity,specificity,and accuracy of blood cell classification.AI could en-hance the disease-screening capabilities in the tiered diagnosis network of primary medical units,presenting a broad application prospect.

Objective:To analyze the clinical efficacy and safety of carglumic acid in the treatment of neonatal hyperammonemia caused by organic acidemia.Methods:A case summary was made.Six cases of neonatal hyperammonemia caused by organic acidemia treated at the Neonatal Intensive Care Unit of Henan Children′s Hospital from March to September in 2024 were included.They received comprehensive ammonia-lowering treatment in combination with oral carglumic acid dispersible tablets.The clinical data of the children were collected and analyzed retrospectively.Changes in blood ammonia levels, blood gas parameters, and complete blood count before and after treatment with carglumic acid were analyzed using the Wilcoxon test.The incidence of adverse reactions and clinical regression during the treatment with carglumic acid was observed.Results:There were 2 females and 4 males in the 6 patients included.Four children suffered from isolated methylmalonic acidemia caused by MUT gene mutations, and the other 2 had propionic acidemia.The clinical manifestations were poor breastfeeding in 6 cases, vomiting in 2 cases, poor response in 6 cases, weight loss in 6 cases, and convulsions in 3 cases.Acute metabolic decompensation abnormalities were presented in all children, such as metabolic acidosis, hyperammonemia, leukopenia and thrombocytopenia.The first dose of carglumic acid was 62-255 mg/kg, the second dose was 75-172 mg/kg.The blood ammonia level decreased from 411.7 (339.7, 623.8) μmol/L before treatment to 108.1 (35.5, 229.1) μmol/L after 48 hours of treatment, showing a statistically significant reduction ( Z=2.20, P<0.05).Three cases with a blood ammonia level higher than 400 μmol/L, it was effectively reduced after treatment with carglumic acid.Two cases did not undergo hemodialysis or peritoneal dialysis.One case underwent hemodialysis but died after withdrawing the treatment.After administration of carglumic acid, metabolic acidosis was corrected in all children, and 2 patients ultimately died after discontinuing the treatment.No causal relationship was identified between adverse events and carglumic acid treatment.The examinations at discharge and during the follow-up period (2-7 months) showed that most laboratory abnormalities (including leukopenia, anemia, thrombocytopenia, hyperlactatemia, hyponatremia, hyperkalemia, elevated myocardial enzymes, and hyperbilirubinemia) returned to normal. Conclusions:Carglumic acid can effectively reduce neonatal hyperammonemia caused by organic academia, improve metabolic disorders, and reduce the need for blood purification or peritoneal dialysis, with good safety.

Objective:To investigate clinical characteristics of immunocompromised individuals with herpes zoster.Methods:A retrospective study was conducted on 78 immunocompromised patients with herpes zoster hospitalized at Zhongda Hospital affiliated to Southeast University from January 2016 to December 2023, and these patients were assigned to the observation group. During the same period, 78 immunocompetent inpatients with herpes zoster matched (1∶1 ratio) by age and admission time served as a control group. General data, clinical manifestations, and laboratory findings (including blood routine test, liver and kidney function, and inflammatory markers) were compared between the two groups.Results:In the observation group, there were 27 males and 51 females, with the age being 65.76 ± 14.47 years; the main causes of immunocompromise in this group were solid tumors (47 cases, 60.26%) and hematologic tumors (7 cases, 8.97%) ; 26 (33.33%) patients with autoimmune diseases were treated with prednisone at a dose of ≥ 10 mg/d for more than 2 weeks. In the control group, there were 35 males and 43 females, with the age being 67.73 ± 13.89 years. No significant differences were found between the two groups in terms of gender, age, time from the onset of rashes or pain to hospitalization, time to lesion healing, the order of appearance of pain and rashes, the affected side of the body, or the proportion of patients with disseminated herpes zoster (all P > 0.05). However, there was a significant difference in the distribution of affected nerve segments between the two groups ( P = 0.013) ; the main affected nerves were the thoracic and brachial nerves (34 cases, 43.59%) and the lumbosacral nerves (29 cases, 37.18%) in the observation group, while the lumbosacral nerves (31 cases, 39.74%) and cranial-cervical nerves (25 cases, 32.05%) were more commonly affected in the control group. The skin lesions in both groups mainly manifested as blisters, pustules and/or hemorrhagic blisters, and the proportion of patients with pustules and/or hemorrhagic blisters was significantly higher in the observation group (25 cases, 32.05%) than in the control group (11 cases, 14.10%; χ2 = 7.08, P = 0.008). The observation group showed a significantly higher proportion of patients with fever (24 cases, 30.77%), frequency of oral analgesic use during hospital stay [2.00 (1.26, 2.33) times/day], and recurrence rate (6 cases, 7.69%) compared with those in the control group (13 cases, 16.67%; 1.43 [1.00, 2.00] times/day; 0, respectively). Additionally, the observation group exhibited significant increases in several parameters compared with the control group, including the proportions of patients with anemia (27 cases [34.62%] vs. 6 cases [7.69%]), kidney function abnormalities (9 cases [11.54%] vs. 2 cases [2.56%]), elevated alanine aminotransferase/aspartate aminotransferase ratios, increased erythrocyte sedimentation rates, and with elevated C-reactive protein levels, as well as those with decreased white blood cell counts, albumin levels, prealbumin levels, and with CD8 + T cell counts (all P < 0.05). In terms of novel inflammatory markers, the observation group showed significantly increased neutrophil/lymphocyte ratios, red blood cell distribution width/hemoglobin ratios, and C-reactive protein/albumin ratios, but significantly decreased albumin/fibrinogen ratios and platelet/neutrophil ratios compared with the control group (all P < 0.05) . Conclusion:Compared with the immunocompetent patients with herpes zoster, the immunocompromised patients with herpes zoster showed poorer cell-mediated immunity, more complex clinical manifestations, more severe systemic inflammatory responses, more pronounced pain, and higher likelihood of recurrent herpes zoster.

Objective:To compare the clinical outcomes of reconstruction of oral and maxillofacial soft tissue defects using superficial circumflex iliac artery perforator flap （SCIA PF） and radial forearm free flap （RFF）. Methods:A retrospective analysis was conducted on 90 patients with head, neck, and maxillofacial tumors who were treated in our department from June 2019 to January 2024. Patients were divided into two groups based on the surgical method used: the SCIA group（n=45）, who underwent reconstruction with SCIA PF, and the RFF group（n=45）, who received RFF reconstruction. Six months postoperatively, clinical efficacy was evaluated by comparing flap swelling, flap survival rate, and patient satisfaction. Oral function was assessed using standardized scoring systems before surgery, at 1 week, 3 months, and 6 months post-surgery. Hemorheological parameters, including high-shear viscosity（shear rate 200/s）, low-shear viscosity（shear rate 30/s）, plasma viscosity, erythrocyte aggregation index, and erythrocyte sedimentation rate（ESR）, were also measured at each time point. Results:Compared with the RFF group, the SCIA group showed significantly larger flap size, longer flap harvesting and reconstruction times, earlier nasogastric tube removal and oral intake initiation, higher scores in all aspects of oral function, reduced flap edema and faster resolution, higher flap survival rates, and greater overall satisfaction （all P<0.05）. During the follow-up period （preoperative, 1 week, 3 months, and 6 months post-surgery）, hemorheological indices including high-and low-shear viscosity, plasma viscosity, erythrocyte aggregation index, and ESR progressively decreased in the SCIA group （P<0.05）. In the RFF group, these parameters improved significantly by 6 months postoperatively compared with preoperatively and 1-week postoperatively, with a notable decrease in erythrocyte aggregation index at 6 months （P<0.05）. Conclusion:Compared with RFF, SCIA PF provides larger flaps, better functional recovery, higher patient satisfaction, improved flap survival, fewer complications, and more favorable hemorheological profiles following reconstructive surgery for oral and maxillofacial defects.
Humans ; Perforator Flap/blood supply* ; Plastic Surgery Procedures/methods* ; Retrospective Studies ; Free Tissue Flaps ; Iliac Artery/transplantation* ; Forearm/surgery* ; Male ; Female ; Soft Tissue Injuries/surgery* ; Head and Neck Neoplasms/surgery* ; Middle Aged ; Treatment Outcome ; Adult

Peptide receptor radionuclide therapy (PRRT) with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors (NETs). Previous studies have shown that an SSTR2 agonist combined with albumin binding moiety Evans blue (denoted as ¹⁷⁷Lu-EB-TATE) is characterized by a higher tumor uptake and residence time in preclinical models and in patients with metastatic NETs. This study aimed to enhance the in vivo stability, pharmacokinetics, and pharmacodynamics of ¹⁷⁷Lu-EB-TATE by replacing the maleimide-thiol group with a polyethylene glycol chain, resulting in a novel EB conjugated SSTR2-targeting radiopharmaceutical, ¹⁷⁷Lu-LNC1010, for PRRT. In preclinical studies, ¹⁷⁷Lu-LNC1010 exhibited good stability and SSTR2-binding affinity in AR42J tumor cells and enhanced uptake and prolonged retention in AR42J tumor xenografts. Thereafter, we presented the first-in-human dose escalation study of ¹⁷⁷Lu-LNC1010 in patients with advanced/metastatic NETs. ¹⁷⁷Lu-LNC1010 was well-tolerated by all patients, with minor adverse effects, and exhibited significant uptake and prolonged retention in tumor lesions, with higher tumor radiation doses than those of ¹⁷⁷Lu-EB-TATE. Preliminary PRRT efficacy results showed an 83% disease control rate and a 42% overall response rate after two ¹⁷⁷Lu-LNC1010 treatment cycles. These encouraging findings warrant further investigations through multicenter, prospective, and randomized controlled trials.

Cells and exosomes derived from them are extensively used as biological carrier systems. Cells demonstrate superior targeting specificity and prolonged circulation facilitated by their rich array of surface proteins, while exosomes, due to their small size, cross barriers and penetrate tumors efficiently. However, challenges remain, cells' large size restricts tissue penetration, and exosomes have limited targeting accuracy and short circulation times. To address these challenges, we developed a novel concept termed exosomal spheres. This approach involved incorporating platelet-derived exosomes shielded with phosphatidylserine (PS) and linked via pH-sensitive bonds for drug delivery applications. The study demonstrated that, compared with exosomes, the exosomal spheres improved blood circulation through the upregulation of CD47 expression and shielding of phosphatidylserine, thereby minimizing immune clearance. Moreover, the increased expression of P-selectin promoted adhesion to circulating tumor cells, thereby enhancing targeting efficiency. Upon reaching the tumor site, the hydrazone bonds of exosome spheres were protonated in the acidic tumor microenvironment, leading to disintegration into uniform-sized exosomes capable of deeper tumor penetration compared to platelets. These findings suggested that exosome spheres addressed the challenges and offered significant potential for efficient and precise drug delivery.

With the rapid advancement of vaccines, the research and application of vaccine adjuvants have garnered significant attention. Despite the development of numerous vaccine adjuvants, their applications in human vaccines remain limited due to either insufficient efficacy or severe side effects. Consequently, there is growing interest in developing bioactive compounds derived from traditional Chinese medicines (TCMs) as vaccine adjuvants, owing to their natural biocompatibility, diversity, and safety. Here, we systematically review the current application status and potential value of TCM-based bioactive compounds in vaccine adjuvants. Firstly, we elaborate on the types and characteristics of active ingredients, such as polysaccharides, saponins, flavonoids, acids, and alkaloids. The mechanisms by which these compounds function as vaccine adjuvants are then discussed, including their roles in enhancing humoral immunity, cellular immunity, and relieving the immune suppression in the microenvironment. Additionally, we summarize the current strategies for structural modification and platform optimization to adapt to different application scenarios. Finally, we offer insights into the future development directions for these potential adjuvants, highlighting research priorities, technical approaches, and application prospects. In conclusion, natural vaccine adjuvants derived from TCMs present broad application prospects and hold promise for future vaccine development.

OBJECTIVES: To investigate the associations between Tau protein deposition and brain biochemical metabolites detected by proton magnetic resonance spectroscopy (¹H-MRS) in patients with advanced Alzheimer's disease (AD). METHODS: From April, 2022 to December, 2024, 64 Tau-positive AD patients and 29 healthy individuals underwent ¹⁸F-APN-1607 PET/MR and simultaneously acquired multi-voxel ¹H-MRS in the Department of Nuclear Medicine, Nanjing First Hospital. Visual analysis and voxel-based analysis of PET/MR data were performed to investigate the Tau protein deposition patterns in AD patients. Valid voxels within the ¹H-MRS field of view were selected, and their standardized uptake value ratio (SUVr) in PET and metabolite levels of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), NAA/Cr, and Cho/Cr were recorded. The Tau-positive (Tau⁺) voxels and Tau-negative (Tau^-) voxels of the AD patients were compared for PET and ¹H-MRS parameters, and the correlations between the metabolites and Tau PET SUVr within Tau⁺ voxels were analyzed. RESULTS: Significant Tau protein deposition were observed in the AD patients, involving mainly the bilateral frontal lobes (30.07%), parietal lobes (29.96%), temporal lobes (21.07%), and occipital lobes (15.89%). A total of 1422 valid voxels in AD group (including 994 Tau⁺ and 428 Tau^- voxels) and 814 voxels in the control group were selected. The AD patients showed significantly decreased NAA level and increased SUVr compared with the control group (P<0.05). Subgroup analyses revealed that Tau⁺ voxels had higher SUVr and lower Cr and Cho/Cr than Tau^- voxels (P<0.05). Compared with the control group, Tau⁺ voxels exhibited higher SUVr and lower Cr (P<0.05), while Tau^- voxels showed lower NAA (P=0.004). No significant differences were found in Cho or NAA/Cr among the subgroups (P>0.05). Within Tau⁺ voxels, NAA, Cho, and Cr were negatively correlated with SUVr (P<0.001). CONCLUSIONS The patients with progressive AD have significant Tau protein deposition in the brain, which is correlated with alterations in metabolite levels. Decreased NAA is more prominent in early or pre-tau deposition stages, while Cr changes is more significant in the regions with Tau protein deposition, suggesting the potential of NAA and Cr as biomarkers for Tau protein deposition in AD for disease monitoring and treatment evaluation.
Humans ; Alzheimer Disease/diagnostic imaging* ; Aspartic Acid/metabolism* ; tau Proteins/metabolism* ; Creatine/metabolism* ; Brain/metabolism* ; Biomarkers/metabolism* ; Positron-Emission Tomography ; Male ; Female ; Proton Magnetic Resonance Spectroscopy ; Choline/metabolism* ; Aged ; Middle Aged