ObjectivePancreatic ductal adenocarcinoma (PDAC) exhibits a limited response to current treatments due to its dense fibrotic stroma and highly immunosuppressive tumor microenvironment. In recent years, advancements in cellular immunotherapy, particularly chimeric antigen receptor macrophage (CAR-M) therapy, have offered new hope for pancreatic cancer treatment. Although CAR-M therapy demonstrates dual potential in directly killing tumor cells and remodeling the immune microenvironment, it still faces challenges such as complex in vitro preparation processes and low in vivo targeting and delivery efficiency. Therefore, developing strategies for efficient and targeted in vivo delivery of CAR genes has become crucial for overcoming current therapeutic limitations. This study aims to develop an orally administrable nano-gene delivery system for the targeted delivery of CAR genes to pancreatic tumor sites. MethodsCore nano-gene particles (PNP/pCAR) were constructed by loading plasmid DNA encoding CAR (pCAR) with cationic polypeptides (PNP). Subsequently, PNP/pCAR was surface-modified with β-glucan to prepare the targeted nanoparticles (βGlus-PNP/pCAR). The loading efficiency of PNP for pCAR was quantitatively assessed by gel retardation assay. The particle size, Zeta potential, morphology, and storage stability of PNP/pCAR were characterized using a Malvern particle size analyzer and transmission electron microscopy. At the cellular level, RAW 264.7 macrophages were selected. The cytotoxicity of PNP/pCAR was evaluated using the CCK-8 assay. The cellular uptake efficiency and lysosomal escape ability of the nanoparticles were assessed via flow cytometry and confocal microscopy. Transfection efficiency was quantitatively evaluated by detecting the expression of the reporter gene GFP using flow cytometry. At the in vivo level, an orthotopic pancreatic cancer mouse model was established. Cy7-labeled βGlus-PNP/pCAR nanoparticles were administered orally, and the fluorescence distribution in mice was dynamically monitored at 1, 2, 4, 8, and 16 h post-administration using a small animal in vivo imaging system. Forty-eight hours after oral gavage, the mice were euthanized, and pancreatic tumor tissues were collected for further analysis of intratumoral fluorescence signals using the imaging system. Additionally, βGlus-PNP/pCAR-GFP nanoparticles loaded with the reporter gene (GFP) were administered orally. Forty-eight hours post-administration, pancreatic tumor tissues were harvested to prepare frozen sections, and GFP expression was observed and analyzed under a fluorescence microscope. ResultsThe PNP carrier exhibited a high loading capacity for pCAR. The successfully prepared PNP/pCAR nanoparticles were regular spheres with a hydrodynamic diameter of approximately (120±10) nm and a Zeta potential of about +(6±1) mV. They maintained good structural stability after incubation in PBS buffer for 7 d. Cell experiments demonstrated that PNP/pCAR exhibited no significant cytotoxicity in RAW 264.7 cells while being efficiently internalized and effectively escaping lysosomal degradation. The transfection positive rate of PNP/pCAR-GFP in RAW 264.7 cells reached (25±3)%, surpassing that of Lipofectamine 2000-loaded pCAR-GFP (Lipo/pCAR-GFP), which was (20±1)%.In vivo experiments revealed that, compared to unmodified PNP/pCAR, βGlus-PNP/pCAR exhibited strongerin situ pancreatic tumor targeting ability after oral administration. Furthermore, oral administration of βGlus-PNP/pCAR-GFP resulted in significant GFP protein expression detectable within pancreatic tumor tissues. ConclusionThis study successfully constructed and validated an orally administrable, pancreatic cancer-targeting polypeptide-based nano-gene delivery system. It provides an important technological foundation in delivery systems and experimental basis for the subsequent development of in situ CAR-M-based therapeutic strategies for pancreatic cancer.

ObjectivePancreatic ductal adenocarcinoma (PDAC) exhibits a limited response to current treatments due to its dense fibrotic stroma and highly immunosuppressive tumor microenvironment. In recent years, advancements in cellular immunotherapy, particularly chimeric antigen receptor macrophage (CAR-M) therapy, have offered new hope for pancreatic cancer treatment. Although CAR-M therapy demonstrates dual potential in directly killing tumor cells and remodeling the immune microenvironment, it still faces challenges such as complex in vitro preparation processes and low in vivo targeting and delivery efficiency. Therefore, developing strategies for efficient and targeted in vivo delivery of CAR genes has become crucial for overcoming current therapeutic limitations. This study aims to develop an orally administrable nano-gene delivery system for the targeted delivery of CAR genes to pancreatic tumor sites. MethodsCore nano-gene particles (PNP/pCAR) were constructed by loading plasmid DNA encoding CAR (pCAR) with cationic polypeptides (PNP). Subsequently, PNP/pCAR was surface-modified with β-glucan to prepare the targeted nanoparticles (βGlus-PNP/pCAR). The loading efficiency of PNP for pCAR was quantitatively assessed by gel retardation assay. The particle size, Zeta potential, morphology, and storage stability of PNP/pCAR were characterized using a Malvern particle size analyzer and transmission electron microscopy. At the cellular level, RAW 264.7 macrophages were selected. The cytotoxicity of PNP/pCAR was evaluated using the CCK-8 assay. The cellular uptake efficiency and lysosomal escape ability of the nanoparticles were assessed via flow cytometry and confocal microscopy. Transfection efficiency was quantitatively evaluated by detecting the expression of the reporter gene GFP using flow cytometry. At the in vivo level, an orthotopic pancreatic cancer mouse model was established. Cy7-labeled βGlus-PNP/pCAR nanoparticles were administered orally, and the fluorescence distribution in mice was dynamically monitored at 1, 2, 4, 8, and 16 h post-administration using a small animal in vivo imaging system. Forty-eight hours after oral gavage, the mice were euthanized, and pancreatic tumor tissues were collected for further analysis of intratumoral fluorescence signals using the imaging system. Additionally, βGlus-PNP/pCAR-GFP nanoparticles loaded with the reporter gene (GFP) were administered orally. Forty-eight hours post-administration, pancreatic tumor tissues were harvested to prepare frozen sections, and GFP expression was observed and analyzed under a fluorescence microscope. ResultsThe PNP carrier exhibited a high loading capacity for pCAR. The successfully prepared PNP/pCAR nanoparticles were regular spheres with a hydrodynamic diameter of approximately (120±10) nm and a Zeta potential of about +(6±1) mV. They maintained good structural stability after incubation in PBS buffer for 7 d. Cell experiments demonstrated that PNP/pCAR exhibited no significant cytotoxicity in RAW 264.7 cells while being efficiently internalized and effectively escaping lysosomal degradation. The transfection positive rate of PNP/pCAR-GFP in RAW 264.7 cells reached (25±3)%, surpassing that of Lipofectamine 2000-loaded pCAR-GFP (Lipo/pCAR-GFP), which was (20±1)%.In vivo experiments revealed that, compared to unmodified PNP/pCAR, βGlus-PNP/pCAR exhibited strongerin situ pancreatic tumor targeting ability after oral administration. Furthermore, oral administration of βGlus-PNP/pCAR-GFP resulted in significant GFP protein expression detectable within pancreatic tumor tissues. ConclusionThis study successfully constructed and validated an orally administrable, pancreatic cancer-targeting polypeptide-based nano-gene delivery system. It provides an important technological foundation in delivery systems and experimental basis for the subsequent development of in situ CAR-M-based therapeutic strategies for pancreatic cancer.

Objective To explore the effect of remote ischemic preconditioning (RIPC) on preoperative heart rate variability in patients with heart valves. Methods Patients scheduled to undergo on-pump cardiac valve surgery in the Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, between January and July 2022 were initially enrolled. Eligible patients were randomly assigned at a 1 : 1 ratio to either the RIPC group or the control group. Relevant indicators of heart rate variability [standard deviation of NN interval (SDNN), standard deviation of mean value of NN interval in every five minutes (SDANN), mean square root of difference between consecutive NN intervals (RMSSD), percentage of adjacent RR interval>50 ms (PNN50), low frequency (LF) component, high frequency (HF) component and LF/HF] at 8 hours in the morning on the surgical day between two groups were compared. Results A total of 118 patients were initially assessed. After screening, 58 patients were excluded, and 60 patients provided written informed consent and were enrolled in the trial, with 30 allocated to the RIPC group and 30 to the control group. Seven patients in the control group and 5 patients in the RIPC group were subsequently excluded due to missing heart rate variability data resulting from cancelled operations. Finally, 23 patients in the control group and 25 patients in the RIPC group were included in the analysis. There was no statistical difference in baseline characteristics between the two groups, and there was no significant difference in heart rate variability 24 hours before intervention (P>0.05). After the intervention measures were taken, the comparison of the results of heart rate variability at 8 hours on the day of operation showed that SDNN and SDANN of patients in the RIPC group were higher than those in the control group, with statistical differences (P<0.05). Conclusion RIPC can stabilize the preoperative heart rate variability of patients undergoing cardiac valve surgery.

AIM:To analyze the efficacy of modified Zhujing formula combined with intravitreal ranibizumab(IVR)injection in the treatment of wet age-related macular degeneration(wARMD).METHODS: A prospective study was conducted on wARMD patients at the Ophthalmology Department of Yulin Hospital of Traditional Chinese Medicine from September 2022 to October 2024. The study subjects were divided into the experimental group and the control group according to the random number table method. The control group received IVR treatment, while the experimental group was treated with modified Zhujing formula in addition to IVR injection. The clinical efficacy, TCM symptom scores, central retinal thickness(CRT), best corrected visual acuity(BCVA), macular hemorrhage area, choroidal neovascularization area(CNV), ocular hemodynamic parameters [resistance index(RI), maximum diastolic blood flow(EDV), maximum systolic blood flow(PSV)], and 1-year recurrence rate were compared between the two groups.RESULTS: This study included 60 eyes from 60 wARMD patients. Among them, the control group consisted of 30 patients and 30 eyes, while the experimental group consisted of 30 patients and 30 eyes. The age of the control group was 67.52±3.12 y, with 17 males and 13 females. The age of the experimental group was 67.62±3.04 y, with 18 males and 12 females.The clinical efficacy of the experimental group(97%)was higher than that of the control group(73%)(P<0.05). After treatment, the scores of blurred vision, soreness and weakness of the waist and knees, restlessness and insomnia, dizziness and tinnitus in the experimental group were all lower than those in the control group(all P<0.05); the EDV and PSV in the experimental group were both higher than those in the control group(both P<0.05); the BCVA, CRT, macular hemorrhage area, CNV and RI of the experimental group were all lower than those of the control group(all P<0.05), and the 1-year recurrence rate in the experimental group(3%)was lower than that in the control group(27%)(P<0.05). CONCLUSION:The combined use of modified Zhujing formula and IVR can effectively alleviate symptoms such as blurred vision and retinal hemorrhage in wARMD patients, improve vision and ocular hemodynamic conditions, and reduce the recurrence rate. This suggests that there may be a synergistic enhancing effect.

Residual inflammatory risk （RIR） is a key issue to be urgently addressed in the secondary prevention of atherosclerotic cardiovascular disease （ASCVD）. Targeted intervention of RIR has become a novel target for drug development and clinical management. A series of high-quality randomized controlled trials （RCTs）， including COLCOT， LoDoCo2 and CLEAR SYNERGY， provided high-level evidence and confirmed that low-dose colchicine （0.5 mg/d） significantly reduced the risk of cardiovascular events in ASCVD patients at stable stage or after the acute phase， while its efficacy varied in different clinical scenarios. International authoritative guidelines from the European Society of Cardiology and the American Heart Association/American College of Cardiology include low-dose colchicine in the recommendations for ASCVD secondary prevention. Two domestic guidelines released in 2024， namely the Guideline for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndrome （ 2024 ） and the Guideline for the Diagnosis and Management of Chronic Coronary Syndrome in China ， have also added relevant recommendations. Nevertheless， due to potential racial differences， safety concerns regarding drug-drug interactions， and the relative lack of clinical evidence in China， especially the absence of prospective RCTs using low-dose colchicine for secondary prevention of ASCVD patients， current clinical recommendations still mainly based on international evidence and guidelines， and should not be simply extrapolated.

Purpose: This study assessed the performance of the ultrasound-guided attenuation parameter (UGAP) in diagnosing and grading hepatic steatosis in patients with metabolic dysfunctionassociated steatotic liver disease (MASLD). Magnetic resonance imaging proton density fat fraction (MRI-PDFF) served as the reference standard. Methods: Patients with hepatic steatosis were enrolled in this prospective study and underwent UGAP measurements. MRI-PDFF values of ≥5%, ≥15%, and ≥25% were used as references for the diagnosis of steatosis grades ≥S1, ≥S2, and S3, respectively. Spearman correlation coefficients and area under the receiver operating characteristic curves (AUCs) were calculated. Results: Between July 2023 and June 2024, the study included 88 patients (median age, 40 years; interquartile range [IQR], 36 to 46 years), of whom 54.5% (48/88) were men and 45.5% (40/88) were women. Steatosis grades exhibited the following distribution: 22.7% (20/88) had S0, 50.0% (44/88) had S1, 21.6% (19/88) had S2, and 5.7% (5/88) had S3. The success rate for UGAP measurements was 100%. The median UGAP value was 0.74 dB/cm/MHz (IQR, 0.65 to 0.82 dB/ cm/MHz), and UGAP values were positively correlated with MRI-PDFF (r=0.77, P<0.001). The AUCs of UGAP for the diagnoses of ≥S1, ≥S2, and S3 steatosis were 0.91, 0.90, and 0.88, respectively. In the subgroup analysis, 98.4% (60/61) of patients had valid controlled attenuation parameter (CAP) values. UGAP measurements were positively correlated with CAP values (r=0.65, P<0.001). Conclusion Using MRI-PDFF as the reference standard, UGAP demonstrates good diagnostic performance in the detection and grading of hepatic steatosis in patients with MASLD.

Objective To compare the mid- and long-term clinical results of mitral valve plasty (MVP) and mitral valve replacement (MVR) in the treatment of functional mitral regurgitation (FMR). Methods Patients with FMR who underwent surgical treatment in the Department of Cardiovascular Surgery of the General Hospital of Northern Theater Command from 2012 to 2021 were collected. The patients who underwent MVP were divided into a MVP group, and those who underwent MVR into a MVR group. The clinical data and mid-term follow-up efficacy of two groups were compared. Results Finally 236 patients were included. There were 100 patients in the MVP group, including 53 males and 47 females, with an average age of (61.80±8.03) years. There were 136 patients in the MVR group, including 72 males and 64 females, with an average age of (61.29±8.97) years. There was no statistical difference in baseline data between the two groups (P＞0.05). There was no statistical difference between the two groups in the extracorporeal circulation time, aortic occlusion time, postoperative hospital and ICU stay, intraoperative blood loss, or hospitalization death (P＞0.05), but the time of mechanical ventilation in the MVP group was significantly shorter than that in the MVR group (P=0.022). The total follow-up rate was 100.0%, the longest follow-up was 10 years, and the average follow-up time was (3.60±2.55) years. There were statistical differences in the left atrial diameter, left ventricular end-diastolic diameter, left ventricular end-systolic diameter and cardiac function between the two groups compared with those before surgery (P<0.05). The postoperative left ventricular ejection fraction in the MVP group was statistically higher than that before surgery (P=0.002), but there was no statistical difference in the MVR group before and after surgery (P=0.658). The left atrial diameter in the MVP group was reduced compared with the MVR group (P=0.026). The recurrence rate of mitral regurgitation in the MVP group was higher than that in the MVR group, and the difference was statistically significant (10.0% vs. 1.5%, P=0.003). There were 14 deaths in the MVP group and 19 in the MVR group. The cumulative survival rate (P=0.605) and cardiovascular events-free survival rate (P=0.875) were not statistically significant between the two groups by Kaplan-Meier survival analysis. Conclusion The safety, and mid- and long-term clinical efficacy of MVP in the treatment of FMR patients are better than MVR, and the left atrial and left ventricular diameters are statistically reduced, and cardiac function is statistically improved. However, the surgeon needs to be well aware of the indications for the MVP procedure to reduce the rate of mitral regurgitation recurrence.

Peri-implant keratinized mucosa (PIKM) augmentation refers to surgical procedures aimed at increasing the width of PIKM. Consensus reports emphasize the necessity of maintaining a minimum width of PIKM to ensure long-term peri-implant health. Currently, several surgical techniques have been validated for their effectiveness in increasing PIKM. However, the selection and application of PIKM augmentation methods may present challenges for dental practitioners due to heterogeneity in surgical techniques, variations in clinical scenarios, and anatomical differences. Therefore, clear guidelines and considerations for PIKM augmentation are needed. This expert consensus focuses on the commonly employed surgical techniques for PIKM augmentation and the factors influencing their selection at second-stage surgery. It aims to establish a standardized framework for assessing, planning, and executing PIKM augmentation procedures, with the goal of offering evidence-based guidance to enhance the predictability and success of PIKM augmentation.
Humans ; Consensus ; Dental Implants ; Mouth Mucosa/surgery* ; Keratins

OBJECTIVE: Data on homocysteine (Hcy) status and its determinants are limited among women during pregnancy and postpartum. This cross-sectional study aimed to investigate Hcy levels during pregnancy and postpartum, and to explore the determinants like geographic factor. METHODS: This study was conducted in women at mid-pregnancy, late-pregnancy and postpartum from southern, central and northern China. Approximately 132 women were included in each stratum by the three phases and regions. Plasma Hcy concentrations were assessed using high-performance liquid chromatography (HPLC), with hyperhomocysteinemia defined as > 10.0 µmol/L. Quantile regression was to estimate medians and interquartile ranges ( IQRs), and logistic regression to examine the determinants of hyperhomocysteinemia. RESULTS: For 1,190 women included, the median (IQR) Hcy concentration was 5.66 (4.62, 7.37) μmol/L. The adjusted median in mid-pregnancy, late-pregnancy and postpartum women was 4.75 (4.13, 5.54), 5.72 (4.81, 6.85) and 7.09 (5.65, 8.75) μmol/L, respectively, showing an increasing trend ( P < 0.001). This increasing trend persisted across the three regions. Higher Hcy concentrations were observed in women residing in northern region and those with younger age or lower economic status. A total of 106 (8.9%) women had hyperhomocysteinemia, with a higher prevalence in those residing in northern region (16.0%), or in postpartum women (16.5%). CONCLUSION Hcy levels, varying with geographic region, maternal age and economic status, are increased from mid-pregnancy to late-pregnancy and postpartum, indicating a need to monitor Hcy levels in pregnant and postpartum women to control potential risks related to elevated Hcy levels.
Humans ; Female ; Pregnancy ; Homocysteine/blood* ; China/epidemiology* ; Adult ; Postpartum Period/blood* ; Cross-Sectional Studies ; Hyperhomocysteinemia/blood* ; Young Adult ; Pregnancy Trimester, Third/blood* ; Pregnancy Trimester, Second ; East Asian People