Integrin α _v β ₃ is overexpressed in various tumor cells and angiogenesis. To date, no drug has been proven to target it for therapy. A first-in-human study was designed to investigate the safety, pharmacokinetics, and dosimetry of ¹⁷⁷Lu-AB-3PRGD2, a novel integrin α _v β ₃-targeting radionuclide drug with an albumin-binding motif to optimize the pharmacokinetics. Ten patients (3 men, 7 women; aged 45 ± 16 years) with integrin α _v β ₃-avid tumors were recruited to accept ¹⁷⁷Lu-AB-3PRGD2 injection in a dosage of 1.57 ± 0.08 GBq (42.32 ± 2.11 mCi), followed by serial scans to obtain its dynamic distribution in the body. Safety tests were performed before and every 2 weeks after the treatment for 6-8 weeks. No adverse event over grade 3 was observed. ¹⁷⁷Lu-AB-3PRGD2 was excreted mainly through the urinary system, with intense radioactivity in the kidneys and bladder. Moderate distribution was found in the liver, spleen, and intestines. The estimated blood half-life was 2.85 ± 2.17 h. The whole-body effective dose was 0.251 ± 0.047 mSv/MBq. The absorbed doses were 0.157 ± 0.032 mGy/MBq in red bone marrow and 0.684 ± 0.132 mGy/MBq in kidneys. This first-in-human study of ¹⁷⁷Lu-AB-3PRGD2 treatment indicates its promising potential for targeted radionuclide therapy of integrin α _v β ₃-avid tumors. It merits further studies in more patients with escalating doses and multiple treatment courses.

OBJECTIVES: To investigate the role of the BNIP3-PI3K/Akt signaling pathway in mediating the inhibitory effect of Buyang Huanwu Decoction (BYHWT) on mitochondrial autophagy in human synovial fibroblasts from rheumatoid arthritis patients (FLS-RA) cultured under a hypoxic condition. METHODS: Forty normal Wistar rats were randomized into two groups (n=20) for daily gavage of BYHWT or distilled water for 7 days to prepare BYHWT-medicated or control sera. FLS-RA were cultured in routine condition or exposed to hypoxia (10% O₂) for 24 h wigh subsequent treatment with IL-1β, followed by treatment with diluted BYHWT-medicated serum (5%, 10% and 20%) or control serum. AnnexinV-APC/7-AAD double staining and T-AOC kit were used for detecting apoptosis and total antioxidant capacity of the cells, and the changes in ROS, ATP level, mitochondrial membrane potential and Ca²⁺ homeostasis were analyzed. The changes in mRNA and protein expressions of BNIP3, PI3K and AKT and mRNA expressions of LC3, Beclin-1 and P62 were detected using RT-qPCR and Western blotting. RESULTS: Treatment with BYHWT-medicated serum dose-dependently lowered apoptosis rate of IL-1β-induced FLS-RA with hypoxic exposure. The treatment significantly decreased T-AOC concentration, increased ROS production, autophagosome formation and ATPase levels, and lowered mitochondrial membrane potential and Ca²⁺ level in the cells. In IL-1β-induced FLS-RA with hypoxic exposure, treatment with BYHWT-medicated serum significantly increased BNIP3 protein expression, decreased the protein expressions of PI3K and AKT, increased the mRNA expressions of BNIP3 and P62, and lowered the mRNA expressions of PI3K, AKT, LC3 and Beclin-1 without significantly affecting Beclin-1 protein expression. The cells treated with 5% and 10% BYHWT-medicated serum showed no significant changes in LC3 expression. CONCLUSIONS BYHWT inhibits mitochondrial autophagy in IL-1β-induced FLS-RA with hypoxic exposure possibly by inhibiting BNIP3-mediated PI3K/AKT signaling pathway.
Drugs, Chinese Herbal/pharmacology* ; Arthritis, Rheumatoid/pathology* ; Animals ; Signal Transduction/drug effects* ; Proto-Oncogene Proteins c-akt/metabolism* ; Autophagy/drug effects* ; Humans ; Fibroblasts/cytology* ; Rats, Wistar ; Membrane Proteins/metabolism* ; Rats ; Phosphatidylinositol 3-Kinases/metabolism* ; Mitochondria/metabolism* ; Cells, Cultured ; Proto-Oncogene Proteins/metabolism* ; Apoptosis/drug effects* ; Cell Hypoxia ; Synovial Membrane/cytology* ; Male ; Mitochondrial Proteins

Objective:To elucidate the genomic characteristics of the immunoglobulin (IG) heavy-chain variable region and light-chain variable region, the expression of subclones, and the prognostic significance in patients with CLL.Methods:Blood and/or bone marrow specimens were gathered from a cohort of 36 patients with CLL diagnosed at Jiangsu Province Hospital from December 2018 to May 2023, including 12 cases of B cell receptor (BCR) stereotyped patients. IG heavy-chain (IGH) and light-chain (IG Kappa [IGK] and IG lambda [IGL]) gene rearrangements were performed using next-generation sequencing (NGS) technology to analyze the characteristics and prognostic value in CLL.Results:NGS detection of IG variable region (IGHV) demonstrated a significant correlation and superior consistency with Sanger sequencing ( r=0.957, P < 0.001). Among the 36 patients, the IGH variant (IGHV) was observed in 9 (25.0%) but not in 27 (75.0%) participants. The incidence of the MYD88 mutation was higher among patients with mutated IGHV [1/27 (3.7%) vs 4/9 (44.4%), P=0.00]. A high incidence of trisomy 12 was observed in the IGHV #8/#8B subset [4/11 (36.4%) vs 1/25 (4.0%), P=0.023], which were more likely to develop Richter transformation [8/11 (72.7%) vs 4/25 (16.0%), P=0.002]. In the patient cohort, 36 individuals (36/36, 100.0%) used the IGK variable, whereas 15 individuals (15/36, 41.7%) employed the IGL variable (IGLV). IGLV3 - 21 reported the highest utilization rate in IGLV (5/15, 33.3%). Remarkably, patients with CLL with IGLV3-21 fragments were exclusively observed in the Binet C stage and Rai Phase Ⅲ-Ⅳ, with an incidence of del (13) (q14) at 60.0% (3/5). The median time to first treatment (TTFT) of patients with or without IGLV3 - 21 fragments was 5.2 (1.1 - 41.5) and 9.9 (0.1 - 94.4) months, respectively. Using the total reads threshold of 2.5%, 4 (4/36, 11.1%) samples were detected to have two IGHV productive clones. The median TTFT and overall survival (OS) time were 2.8 (0.9-72.7) and 12.8 months in patients with one mutated clone and 57.5 (32.0-120.7) and 51.8 months in those with two mutated clones, respectively. The median TTFT and OS time were 10.9 (0.3-94.4) and 6.3 (0.1 - 12.5) months in patients with one unmutated clone and 49.9 (22.2 - 211.1) and 30.0 (9.6 - 50.3) months in those with multiple unmutated clones, respectively ( P>0.05) . Conclusions:Detection of IG gene rearrangements using NGS technology not only facilitates the analysis of the IGHV mutation status, dominant clones, and prognostic value but also contributes to the exploration of IGK/IGL gene rearrangement fragments and the utilization of subclones. Further, it provides information about the poor prognosis of IGLV3 - 21 CLL. The shortened survival of the two unmutated clone groups in the IGHV unmutated group may indicate a poor prognosis.

Objective Based on multi-dimensional bioinformatics technology,the molecular pathological mechanism of acute hypotension is systematically analyzed.Methods Integrate the gene expression profile of the Gene Expression Omnibus database(GSE2401),use limma package(R software)to screen differential genes,and optimize targets through data dimensionality reduction(log2(FC)＞1,P＜0.05);Further combine Gene Ontology,Kyoto Encyclopedia of Genes and Genomes and gene set enrichment analysis pathway enrichment and STRING-Cytoscape(MCODE,CytoHubba plug-in)to build a protein-protein interaction(PPI)network to mine core genes;realize the full-chain analysis of"differential gene-functional pathway-PPI network".Results 676 differential genes(304 upregulated,372 downregulated),ribosome structural components(Rps8,Rps27,Rpl35,etc.)and multiple pathways such as forkhead box protein and cyclic adenosine monophosphate were found to coordinate the regulation of acute hypotension.Conclusion This study uses a low-cost and efficient bioinformatics analysis framework to reveal the association between ribosomal dysfunction,changes in insulin signal efficacy and blood pressure regulation,providing new ideas for targeted therapy.

Objective:To compare the efficacy of pars plana vitrectomy (PPV) combined with subretinal or intravitreal injection of Conbercept for the treatment of refractory diabetic macular edema (DME).Methods:A retrospective case control study. From June 2022 to March 2024, 32 eyes of 32 patients with refractory DME diagnosed at The Affiliated Eye Hospital of Nanchang University were included in the study. There were 17 male cases with 17 eyes and 15 female cases with 15 eyes. Age was (57.44±8.99) years old; The duration of diabetes was (12.72±6.11) years. All patients had received regular treatment with anti-vascular endothelial growth factor (VEGF) drugs or corticosteroid drugs for at least 5 times, and had undergone focal retinal laser photocoagulation or panretinal laser photocoagulation, the central macular thickness (CMT) persisted or decreased by less than 50 μm. All affected eyes underwent best-corrected visual acuity (BCVA), intraocular pressure, optical coherence tomography (OCT), microperimetry, and laboratory glycated hemoglobin (HbA1c) testing. BCVA was measured using a standard logarithmic visual acuity chart, and converted to the logarithm of the minimum angle of resolution (logMAR) for statistical analysis. CMT was measured using an OCT device. Microperimetry was performed using an MP-3 microperimeter, recording the mean sensitivity (MS) of the retina within a 12° range of the fovea. The affected eyes were treated with 23G PPV combined with internal limiting membrane peeling and either macular subretinal or intravitreal injection of Conbercept, and were divided into subretinal injection group and the intravitreal injection group, each consisting of 16 cases and 16 eyes. The same equipment and methods as before surgery were used for related examinations at 1, 3, and 6 months post-surgery. Changes in BCVA, CMT, and MS were observed and compared, as well as the number of additional anti-VEGF treatments required within 6 months after surgery. Intergroup comparisons were made using independent samples t tests, and repeated measures data were analyzed using repeated measures analysis of variance. Results:The age ( t=-0.271), gender composition ( χ2=0.001), duration of diabetes ( Z=-0.868), HbA1c ( t=-0.789), intraocular pressure ( t=1.689), logMAR BCVA ( t=1.393), CMT ( t=-0.613), MS ( Z=-0.132), and the number of anti-VEGF injections ( t=-0.752) between the subretinal injection group and the intravitreal injection group showed no statistically significant differences ( P>0.05). The within-subject effects comparison of BCVA, CMT, and MS at 1, 3, and 6 months post-surgery compared to pre-surgery for all affected eyes showed statistically significant differences ( F=8.060, 125.722, 39.054; P<0.05). The overall comparison of logMAR BCVA between the subretinal and intravitreal injection groups post-surgery showed no statistically significant difference ( F=0.662, P=0.422), however, comparisons of CMT ( F=4.540) and MS ( F=6.066) showed statistically significant differences ( P<0.05). At 1, 3, and 6 months post-surgery, comparisons of logMAR BCVA between the two groups showed no statistically significant differences ( t=-0.123, 0.239, 1.087; P>0.05), comparisons of CMT showed statistically significant differences ( t=-3.474, -4.832, -2.482; P<0.05), comparisons of MS showed statistically significant differences at 1 and 3 months ( t=-2.940, -2.545; P<0.05), but not at 6 months ( t=-1.527, P>0.05). At 6 months post-surgery, the number of additional intravitreal anti-VEGF injections required in the subretinal and intravitreal injection groups showed a statistically significant difference ( Z=-2.033, P=0.042). During the follow-up period and at the final follow-up, no complications such as injection site bleeding, retinal detachment, vitreous hemorrhage, macular hole, or retinal pigment epithelial tear or atrophy occurred in all affected eyes. Conclusion:Compared with intravitreal injection, subretinal injection of Conbercept for the treatment of refractory DME has more advantages in reducing macular edema and improving visual function in the macular area, and also reduces the number of postoperative anti-VEGF drug treatments.

Objective To investigate the role of the BNIP3-PI3K/Akt signaling pathway in mediating the inhibitory effect of Buyang Huanwu Decoction(BYHWT)on mitochondrial autophagy in human synovial fibroblasts from rheumatoid arthritis patients(FLS-RA)cultured under a hypoxic condition.Methods Forty normal Wistar rats were randomized into two groups(n=20)for daily gavage of BYHWT or distilled water for 7 days to prepare BYHWT-medicated or control sera.FLS-RA were cultured in routine condition or exposed to hypoxia(10％O2)for 24 h wigh subsequent treatment with IL-1β,followed by treatment with diluted BYHWT-medicated serum(5％,10％and 20％)or control serum.AnnexinV-APC/7-AAD double staining and T-AOC kit were used for detecting apoptosis and total antioxidant capacity of the cells,and the changes in ROS,ATP level,mitochondrial membrane potential and Ca2+homeostasis were analyzed.The changes in mRNA and protein expressions of BNIP3,PI3K and AKT and mRNA expressions of LC3,Beclin-1 and P62 were detected using RT-qPCR and Western blotting.Results Treatment with BYHWT-medicated serum dose-dependently lowered apoptosis rate of IL-1β-induced FLS-RA with hypoxic exposure.The treatment significantly decreased T-AOC concentration,increased ROS production,autophagosome formation and ATPase levels,and lowered mitochondrial membrane potential and Ca2+level in the cells.In IL-1β-induced FLS-RA with hypoxic exposure,treatment with BYHWT-medicated serum significantly increased BNIP3 protein expression,decreased the protein expressions of PI3K and AKT,increased the mRNA expressions of BNIP3 and P62,and lowered the mRNA expressions of PI3K,AKT,LC3 and Beclin-1 without significantly affecting Beclin-1 protein expression.The cells treated with 5％and 10％BYHWT-medicated serum showed no significant changes in LC3 expression.Conclusion BYHWT inhibits mitochondrial autophagy in IL-1β-induced FLS-RA with hypoxic exposure possibly by inhibiting BNIP3-mediated PI3K/AKT signaling pathway.

Objective:To explore latent categories of trajectories in intrinsic capacity in elderly hemodialysis patients and to analyze their influencing factors.Methods:Elderly hemodialysis patients in the Blood Purification Center of Beijing Tongren Hospital affiliated with Capital Medical University from September 2022 to January 2023, were selected for the study using a convenience sampling method. A baseline survey was conducted using the General Information Questionnaire, Hemodialysis Self-Management Instrument, Social Environmental Factor Scale, and Intrinsic Capacity Scale. The Intrinsic Capacity Scale was used to investigate the intrinsic capacity of patients at 6 and 12 months after baseline. The latent class growth model was used to identify latent categories of intrinsic capacity trajectories of elderly hemodialysis patients. Ordered multiclass Logistic regression was used to analyze the influencing factors of latent categories.Results:A total of 317 elderly hemodialysis patients were investigated at baseline, and finally, 309 completed follow-ups. Among the 309 elderly hemodialysis patients, the trajectory of intrinsic capacity was categorized into a low-level slow-decline group (26.2%, 81/309) , a medium-level smooth-decline group (39.8%, 123/309) , and a high-level slow-decline group (34.0%, 105/309) . Ordered multiclass Logistic regression analysis showed that gender, age, mode of residence, per capita monthly income, type of dialyzer, C-reactive protein, score of hemodialysis self-management scale, housing conditions score, transportation condition score, and environmental condition score were the influencing factors of the latent categories of the trajectory in intrinsic capacity of elderly hemodialysis patients, and the difference was statistically significant ( P<0.05) . Conclusions:There is population heterogeneity in the intrinsic capacity trajectory of elderly hemodialysis patients. Healthcare professionals can provide targeted interventions based on the factors influencing the trajectory.

Objective:To investigate the current status and trajectory of intrinsic capacity in community-dwelling older adults and to analyze its influencing factors.Methods:A longitudinal study was conducted from September 2022 to March 2024. A total of 360 older adults were selected by convenience sampling from the Desheng community, Xicheng District of Beijing City and Liucun Community of Xingtai City, Hebei Province. The Intrinsic Capacity Assessment Scale and the Influencing Factors Questionnaire were administered at three-time points: baseline (T1), 6 months (T2), and 12 months (T3). Binary Logistic regression analysis revealed that age, grip strength, the number of geriatric syndromes, and types of social activities were significant influencing factors of intrinsic capacity trajectories in community-dwelling older adults ( P<0.05) . Results:A total of 360 participants were assessed at T1, with 58 and 30 lost to follow-up at T2 and T3, development respectively. Ultimately, 272 older adults completed the follow-up. The growth mixture modeling identified two trajectory types: a high-score stable group (92.3%, 251/272) and a low-score declining group (7.7%, 21/272). Binary Logistic regression analysis showed that age, grip strength, number of geriatric syndromes, and types of social activities were influencing factors of intrinsic capacity trajectories in community-dwelling older adults ( P<0.05) . Conclusions:Intrinsic capacity development trajectories in community-dwelling older adults are heterogeneous. Healthcare professionals should focus on older adults with advanced age, lower grip strength, more geriatric syndromes, and fewer types of social activities to assess and manage their intrinsic capacity and formulate targeted interventions at an early stage.

Objective Based on multi-dimensional bioinformatics technology,the molecular pathological mechanism of acute hypotension is systematically analyzed.Methods Integrate the gene expression profile of the Gene Expression Omnibus database(GSE2401),use limma package(R software)to screen differential genes,and optimize targets through data dimensionality reduction(log2(FC)＞1,P＜0.05);Further combine Gene Ontology,Kyoto Encyclopedia of Genes and Genomes and gene set enrichment analysis pathway enrichment and STRING-Cytoscape(MCODE,CytoHubba plug-in)to build a protein-protein interaction(PPI)network to mine core genes;realize the full-chain analysis of"differential gene-functional pathway-PPI network".Results 676 differential genes(304 upregulated,372 downregulated),ribosome structural components(Rps8,Rps27,Rpl35,etc.)and multiple pathways such as forkhead box protein and cyclic adenosine monophosphate were found to coordinate the regulation of acute hypotension.Conclusion This study uses a low-cost and efficient bioinformatics analysis framework to reveal the association between ribosomal dysfunction,changes in insulin signal efficacy and blood pressure regulation,providing new ideas for targeted therapy.

Objective:To elucidate the genomic characteristics of the immunoglobulin (IG) heavy-chain variable region and light-chain variable region, the expression of subclones, and the prognostic significance in patients with CLL.Methods:Blood and/or bone marrow specimens were gathered from a cohort of 36 patients with CLL diagnosed at Jiangsu Province Hospital from December 2018 to May 2023, including 12 cases of B cell receptor (BCR) stereotyped patients. IG heavy-chain (IGH) and light-chain (IG Kappa [IGK] and IG lambda [IGL]) gene rearrangements were performed using next-generation sequencing (NGS) technology to analyze the characteristics and prognostic value in CLL.Results:NGS detection of IG variable region (IGHV) demonstrated a significant correlation and superior consistency with Sanger sequencing ( r=0.957, P < 0.001). Among the 36 patients, the IGH variant (IGHV) was observed in 9 (25.0%) but not in 27 (75.0%) participants. The incidence of the MYD88 mutation was higher among patients with mutated IGHV [1/27 (3.7%) vs 4/9 (44.4%), P=0.00]. A high incidence of trisomy 12 was observed in the IGHV #8/#8B subset [4/11 (36.4%) vs 1/25 (4.0%), P=0.023], which were more likely to develop Richter transformation [8/11 (72.7%) vs 4/25 (16.0%), P=0.002]. In the patient cohort, 36 individuals (36/36, 100.0%) used the IGK variable, whereas 15 individuals (15/36, 41.7%) employed the IGL variable (IGLV). IGLV3 - 21 reported the highest utilization rate in IGLV (5/15, 33.3%). Remarkably, patients with CLL with IGLV3-21 fragments were exclusively observed in the Binet C stage and Rai Phase Ⅲ-Ⅳ, with an incidence of del (13) (q14) at 60.0% (3/5). The median time to first treatment (TTFT) of patients with or without IGLV3 - 21 fragments was 5.2 (1.1 - 41.5) and 9.9 (0.1 - 94.4) months, respectively. Using the total reads threshold of 2.5%, 4 (4/36, 11.1%) samples were detected to have two IGHV productive clones. The median TTFT and overall survival (OS) time were 2.8 (0.9-72.7) and 12.8 months in patients with one mutated clone and 57.5 (32.0-120.7) and 51.8 months in those with two mutated clones, respectively. The median TTFT and OS time were 10.9 (0.3-94.4) and 6.3 (0.1 - 12.5) months in patients with one unmutated clone and 49.9 (22.2 - 211.1) and 30.0 (9.6 - 50.3) months in those with multiple unmutated clones, respectively ( P>0.05) . Conclusions:Detection of IG gene rearrangements using NGS technology not only facilitates the analysis of the IGHV mutation status, dominant clones, and prognostic value but also contributes to the exploration of IGK/IGL gene rearrangement fragments and the utilization of subclones. Further, it provides information about the poor prognosis of IGLV3 - 21 CLL. The shortened survival of the two unmutated clone groups in the IGHV unmutated group may indicate a poor prognosis.