BACKGROUND:BCR/ABL gene is a specific gene of Ph chromosome-positive acute lymphoblastic leukemia,and its expression level has become a sensitive indicator for monitoring minimal residual disease before and after allogeneic hematopoietic stem cell transplantation.However,whether the expression level of BCR/ABL gene before transplantation affects the efficacy of transplantation and how to guide the early intervention of relapse with tyrosine kinase inhibitors after transplantation is still inconclusive.OBJECTIVE:To explore the relationship between BCR/ABL gene expression and recurrence in patients with Ph chromosome positive acute lymphoblastic leukemia before and after related and allogeneic hematopoietic stem cell transplantation.METHODS:Twenty-four patients with Ph chromosome positive acute lymphoblastic leukemia who achieved complete hematological remission and underwent allogeneic hematopoietic stem cell transplantation were selected at the Affiliated Hospital of North China University of Science and Technology between January 2015 and December 2022.Real time fluorescence quantitative polymerase chain reaction was used to dynamically detect the expression levels of BCR/ABL genes during treatment,representing minimal residual disease.Based on BCR/ABL gene expression,tyrosine kinase inhibitors combined with chemotherapy was administered before transplantation to select the timing of allogeneic hematopoietic stem cell transplantation.After transplantation,the disease status was evaluated to guide the use of tyrosine kinase inhibitors,and an early intervention plan for recurrence was developed.RESULTS AND CONCLUSION:Follow-up was until December 2023,with a median follow-up time of 49(12-82)months.There were 8 cases of hematological recurrence,with a median recurrence time of 14(8-39)months and a cumulative recurrence rate of 33％(8/24).Univariate analysis showed that recurrence after allogeneic hematopoietic stem cell transplantation was not significantly correlated with gender,age,extramedullary complications,time from diagnosis to transplantation,HLA typing,acute graft-versus-host disease,and chronic graft-versus-host disease(P＞0.05).There was a significant correlation between the relief treatment course and minimal residual disease levels before transplantation.The second hematology completely resolution and positive minimal residual disease before transplantation had a higher hematological recurrence rate(P＜0.05).The 3-year cumulative recurrence rate,disease-free survival rate,and overall survival rate were 27％,63％,and 74％;the 5-year cumulative recurrence rate,disease-free survival rate,and overall survival rate were 38％,57％,and 74％,respectively.It is concluded that Ph chromosome positive acute lymphoblastic leukemia patients with BCR/ABL gene positive before transplantation have a higher recurrence rate.BCR/ABL gene expression after transplantation can guide the application of tyrosine kinase inhibitors and serve as a basis for early intervention in recurrence.

BACKGROUND:BCR/ABL gene is a specific gene of Ph chromosome-positive acute lymphoblastic leukemia,and its expression level has become a sensitive indicator for monitoring minimal residual disease before and after allogeneic hematopoietic stem cell transplantation.However,whether the expression level of BCR/ABL gene before transplantation affects the efficacy of transplantation and how to guide the early intervention of relapse with tyrosine kinase inhibitors after transplantation is still inconclusive.OBJECTIVE:To explore the relationship between BCR/ABL gene expression and recurrence in patients with Ph chromosome positive acute lymphoblastic leukemia before and after related and allogeneic hematopoietic stem cell transplantation.METHODS:Twenty-four patients with Ph chromosome positive acute lymphoblastic leukemia who achieved complete hematological remission and underwent allogeneic hematopoietic stem cell transplantation were selected at the Affiliated Hospital of North China University of Science and Technology between January 2015 and December 2022.Real time fluorescence quantitative polymerase chain reaction was used to dynamically detect the expression levels of BCR/ABL genes during treatment,representing minimal residual disease.Based on BCR/ABL gene expression,tyrosine kinase inhibitors combined with chemotherapy was administered before transplantation to select the timing of allogeneic hematopoietic stem cell transplantation.After transplantation,the disease status was evaluated to guide the use of tyrosine kinase inhibitors,and an early intervention plan for recurrence was developed.RESULTS AND CONCLUSION:Follow-up was until December 2023,with a median follow-up time of 49(12-82)months.There were 8 cases of hematological recurrence,with a median recurrence time of 14(8-39)months and a cumulative recurrence rate of 33％(8/24).Univariate analysis showed that recurrence after allogeneic hematopoietic stem cell transplantation was not significantly correlated with gender,age,extramedullary complications,time from diagnosis to transplantation,HLA typing,acute graft-versus-host disease,and chronic graft-versus-host disease(P＞0.05).There was a significant correlation between the relief treatment course and minimal residual disease levels before transplantation.The second hematology completely resolution and positive minimal residual disease before transplantation had a higher hematological recurrence rate(P＜0.05).The 3-year cumulative recurrence rate,disease-free survival rate,and overall survival rate were 27％,63％,and 74％;the 5-year cumulative recurrence rate,disease-free survival rate,and overall survival rate were 38％,57％,and 74％,respectively.It is concluded that Ph chromosome positive acute lymphoblastic leukemia patients with BCR/ABL gene positive before transplantation have a higher recurrence rate.BCR/ABL gene expression after transplantation can guide the application of tyrosine kinase inhibitors and serve as a basis for early intervention in recurrence.

The field of post-marketing benefit-risk assessment for traditional Chinese medicine（TCM） is still in its nascent stage， lacking a universally accepted and cohesive evaluation framework and standards. This study presented a strategy developed for the benefit-risk assessment of post-marketing of TCM， and explored the critical techniques and specific implementation steps involved in the assessment process. Initially， appropriate qualitative assessment frameworks and quantitative analysis models were selected for the integrated qualitative and quantitative benefit-risk assessment. Subsequently， key technologies were outlined， including the establishment of a benefit-risk indicator system， the assignment of indicator weights， and the definition of criteria attributes. Furthermore， the implementation steps were elaborated， which involved defining decision-making issues， data collection， evaluation methodologies， variability factors， and sensitivity analysis. Finally， a case study of the benefit-risk assessment of a TCM injection for hepatitis B treatment was conducted to validate the feasibility of the proposed strategy. The objective of this research was to provide theoretical support and practical references for the development of a comprehensive post-marketing benefit-risk assessment system for TCM.

BACKGROUND: T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction. METHODS: A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models. RESULTS: In vitro , blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg -1 ·day -1 ) and Rapamycin (0.1 mg·kg -1 ·day -1 ) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression. CONCLUSIONS Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.
Animals ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Interferon Regulatory Factors/metabolism* ; Heart Transplantation/methods* ; T-Lymphocytes/immunology* ; Sirolimus/therapeutic use* ; Pyridones/therapeutic use* ; Graft Survival/drug effects* ; Pyrimidinones/therapeutic use* ; Cell Proliferation/drug effects* ; Apoptosis/drug effects* ; Male ; Signal Transduction/drug effects*

PURPOSE: The secondary damage of spinal cord injury (SCI) starts from the collapse of the blood spinal cord barrier (BSCB) to chronic and devastating neurological deficits. Thereby, the retention of the integrity and permeability of BSCB is well-recognized as one of the major therapies to promote functional recovery after SCI. Previous studies have demonstrated that activation of hypoxia inducible factor-1α (HIF-1α) provides anti-apoptosis and neuroprotection in SCI. Endogenous HIF-1α, rapidly degraded by prolylhydroxylase, is insufficient for promoting functional recovery. Dimethyloxalylglycine (DMOG), a highly selective inhibitor of prolylhydroxylase, has been reported to have a positive effect on axon regeneration. However, the roles and underlying mechanisms of DMOG in BSCB restoration remain unclear. Herein, we aim to investigate pathological changes of BSCB restoration in rats with SCI treated by DOMG and evaluate the therapeutic effects of DMOG. METHODS: The work was performed from 2022 to 2023. In this study, Allen's impact model and human umbilical vein endothelial cells were employed to explore the mechanism of DMOG. In the phenotypic validation experiment, the rats were randomly divided into 3 groups: sham group, SCI group, and SCI + DMOG group (10 rats for each). Histological analysis via Nissl staining, Basso-Beattie-Bresnahan scale, and footprint analysis was used to evaluate the functional recovery after SCI. Western blotting, TUNEL assay, and immunofluorescence staining were employed to exhibit levels of tight junction and adhesion junction of BSCB, HIF-1α, cell apoptosis, and endoplasmic reticulum (ER) stress. The one-way ANOVA test was used for statistical analysis. The difference was considered statistically significant at p < 0.05. RESULTS: In this study, we observed the expression of HIF-1α reduced in the SCI model. DMOG treatment remarkably augmented HIF-1α level, alleviated endothelial cells apoptosis and disruption of BSCB, and enhanced functional recovery post-SCI. Besides, the administration of DMOG offset the activation of ER stress induced by SCI, but this phenomenon was blocked by tunicamycin (an ER stress activator). Finally, we disclosed that DMOG maintained the integrity and permeability of BSCB by inhibiting ER stress, and inhibition of HIF-1α erased the protection from DMOG. CONCLUSIONS Our findings illustrate that the administration of DMOG alleviates the devastation of BSCB and HIF-1α-induced inhibition of ER stress.
Spinal Cord Injuries/pathology* ; Animals ; Apoptosis/drug effects* ; Amino Acids, Dicarboxylic/therapeutic use* ; Recovery of Function/drug effects* ; Rats ; Rats, Sprague-Dawley ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Male ; Spinal Cord/blood supply*

OBJECTIVE: To precise classify sacral meningeal cysts, effective guide minimally invasive neurosurgery and postoperative personalized rehabilitation by multiple dimensions radiographic reconstruction MRI. METHODS: From March to December 2021, based on the original 3D-fast imaging employing steadystate acquisition (FIESTA) scanning sequence, 92 patients with sacral meningeal cysts were pre-operatively evaluated by multiple dimensional reconstruction MRI. The shape of nerve root and the leakage of cyst were reconstructed according to the direction of nerve root or leakage track showed on original MRI scans. Sacral canal cysts were accurately classified as including nerve root and without nerve root, so as to accurately design the incision of skin and formulate corresponding open range of the posterior wall of the sacral canal. Under the microscope intraoperation, the shape of the nerve roots inside cysts or leakage track of the cysts without nerve roots were verified and explored. After the reinforcement and shaping operation, several reexaminations of multiple dimensional reconstruction MRI were performed to understand the deformation of the nerve root and hydrops in the operation cavity, so as to formulate a persona-lized rehabilitation plan for the patients. RESULTS: Among the 92 patients with sacral mengingeal cyst, 58 (63.0%) cysts with nerve root cyst, 29 (31.5%) cysts without nerve root cyst, and 5 (5.4%) cysts with mixed sacral canal cyst. In 58 patients with nerve root cysts, the accuracy of preoperative clinical classification on MRI image reached 96.6% (56/58) through confirmation by operating microscope. Only 2 cases of large single cyst with nerve root on the head of cyst were mistaken for without nerve root type. In 29 patients with sacral cyst without nerve root, the accuracy of preoperative image reached 100% through confirmation by operating microscope. The accuracy of judging the internal nerve root and leakage of 12 cases with recurrent sacral cyst was also 100%. Two cases of delayed postoperative hydrops were found one month after operation. After rehabilitation treatment by moxibustion and bathing, the hydrops disappeared 4-6 months after operation. CONCLUSION Multiple dimensional reconstruction MRI can precisely make clinical classification of sacral meningeal cysts before operation, guide minimally invasive neurosurgery effectively, and improve the rehabilitation effect.
Humans ; Magnetic Resonance Imaging/methods* ; Male ; Female ; Sacrum/surgery* ; Adult ; Middle Aged ; Imaging, Three-Dimensional/methods* ; Cysts/rehabilitation* ; Aged ; Adolescent ; Young Adult ; Spinal Nerve Roots/diagnostic imaging* ; Minimally Invasive Surgical Procedures ; Neurosurgical Procedures/methods*

The article introduces the formation process of bacterial infection and encrustation on the surface of ureteral stents, elaborates in detail on six surface modification methods for ureteral stents, namely impregnation, spraying, vapor deposition, chemical grafting, self-assembly, and electrospinning, then analyzes the advantages and limitations of each technique during application. Meanwhile, it introduces three commonly used materials for ureteral stents, namely polymers, metals, and biodegradable materials, and further explains the commonly used surface modification methods corresponding to different materials. Looking ahead, with the continuous strengthening of the multi-technology integration trend and the continuous advancement of new material research and development, it is expected that a more ideal ureteral stent can be developed.
Stents ; Ureter ; Surface Properties ; Humans

OBJECTIVE: To evaluate the clinical effect and safety of acupuncture manipulation on treatment of intractable facial paralysis (IFP), and verify the practicality and precision of the Anzhong Facial Paralysis Precision Scale (Eyelid Closure Grading Scale, AFPPS-ECGS). METHODS: A multicentre, single-blind, randomized controlled trial was conducted from October 2022 to June 2024. Eighty-nine IFP participants were randomly assigned to an ordinary acupuncture group (OAG, 45 cases) and a characteristic acupuncture group (CAG, 44 cases) using a random number table method. The main acupoints selected included Yangbai (GB 14), Quanliao (SI 18), Yingxiang (LI 20), Shuigou (GV 26), Dicang (ST 4), Chengjiang (CV 24), Taiyang (EX-HN 5), Jiache (ST 6), Fengchi (GB 20), and Hegu (LI 4). The OAG patients received ordinary acupuncture manipulation, while the CAG received characteristic acupuncture manipulation. Both groups received acupuncture treatment 3 times a week, with 10 times per course, lasting for 10 weeks. Facial recovery was assessed at baseline and after the 1st, 2nd and 3rd treatment course by AFPPS-ECGS and the House-Brackmann (H-B) Grading Scale. Infrared thermography technology was used to observe the temperature difference between healthy and affected sides in various facial regions. Adverse events and laboratory test abnormalities were recorded. The correlation between the scores of the two scales was analyzed using Pearson correlation coefficient. RESULTS: After the 2nd treatment course, the two groups showed statistically significant differences in AFPPS-ECGS scores (P<0.05), with even greater significance after the 3rd course (P<0.01). Similarly, H-B Grading Scale scores demonstrated significant differences between groups following the 3rd treatment course (P<0.05). Regarding temperature measurements, significant differences in temperatures of frontal and ocular areas were observed after the 2nd course (P<0.05), becoming more pronounced after the 3rd course (P<0.01). Additionally, mouth corner temperature differences reached statistical significance by the 3rd course (P<0.05). No safety-related incidents were observed during the study. Correlation analysis revealed that the AFPPS-ECGS and the H-B Grading Scale were strongly correlated (r=0.86, 0.91, 0.93, and 0.91 at baseline, and after 1st, 2nd, and 3rd treatment course, respectively, all P<0.01). CONCLUSIONS Acupuncture is an effective treatment for IFP, and the characteristic acupuncture manipulation enhances the therapeutic effect. The use of the AFPPS-ECGS can more accurately reflect the recovery status of patients with IFP. (Trial registration No. ChiCTR2200065442).
Humans ; Acupuncture Therapy/methods* ; Facial Paralysis/therapy* ; Female ; Male ; Middle Aged ; Adult ; Treatment Outcome ; Acupuncture Points ; Aged