This research study focuses on addressing the limitations of current neuropathic pain (NP) treatments by developing a novel dual-target modulator, E0199, targeting both Na_V1.7, Na_V1.8, and Na_V1.9 and K_V7 channels, a crucial regulator in controlling NP symptoms. The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP. Through an experimental design involving both in vitro and in vivo methods, E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury (CCI) mouse model. The results demonstrated that E0199 significantly inhibited Na_V1.7, Na_V1.8, and Na_V1.9 channels with a particularly low half maximal inhibitory concentration (IC₅₀) for Na_V1.9 by promoting sodium channel inactivation, and also effectively increased K_V7.2/7.3, K_V7.2, and K_V7.5 channels, excluding K_V7.1 by promoting potassium channel activation. This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses, indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically. The safety of E0199 was supported by neurobehavioral evaluations. Conclusively, E0199 represents a ground-breaking approach in NP treatment, showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP. This study introduces a promising direction for the future development of NP therapeutics.

Objective:To verify the predictive value of the Second Revision of the International Staging System (R2-ISS) in newly diagnosed patients with multiple myeloma (MM) who underwent first-line autologous hematopoietic stem cell transplantation (ASCT) in a new drug era in China.Methods:This multicenter retrospective cohort study enrolled patients with newly diagnosed MM from three centers in China (Beijing Chao-Yang Hospital, Capital Medical University; the First Affiliated Hospital, Sun Yat-Sen University, and the Second Affiliated Hospital of Naval Medical University) from June 2008 to June 2018. A total of 401 newly diagnosed patients with MM who were candidates for ASCT were enrolled in this cohort, all received proteasome inhibitor and/or immunomodulator-based induction chemotherapy followed by ASCT. Baseline and follow-up data were collected. The patients were regrouped using R2-ISS. Progression-free survival (PFS) and overall survival (OS) were analyzed. The Kaplan-Meier method was used to analyze the survival curve and two survival curves were compared using the log-rank test. Cox regression analysis were performed to analyze the relationship between risk factors and survival.Results:The median age of the patients was 53 years (range 25-69 years) and 59.5% (240 cases) were men. Newly diagnosed patients with renal impairment accounted for 11.5% (46 cases). According to Revised-International Staging System (R-ISS), 74 patients (18.5 %) were diagnosed with stage Ⅰ, 259 patients (64.6%) with stage Ⅱ, and 68 patients (17.0%) with stage Ⅲ. According to the R2-ISS, the distribution of patients in each group was as follows: 50 patients (12.5%) in stage Ⅰ, 95 patients (23.7%) in stage Ⅱ, 206 patients (51.4%) in stage Ⅲ, and 50 patients (12.5%) in stage Ⅳ. The median follow-up time was 35.9 months (range, 6-119 months). According to the R2-ISS stage, the median PFS in each group was: 75.3 months for stage Ⅰ; 62.0 months for stage Ⅱ, 39.2 months for stage Ⅲ, and 30.3 months for stage Ⅳ; and the median OS was not reached, 86.6 months, 71.6 months, and 38.5 months, respectively. There were statistically significant differences in PFS and OS between different groups (both P<0.001). Multivariate Cox regression analysis showed that stages Ⅲ and Ⅳ of the R2-ISS were independent prognostic factors for PFS ( HR=2.37, 95% CI 1.30-4.30; HR=4.50, 95% CI 2.35-9.01) and OS ( HR=4.20, 95% CI 1.50-11.80; HR=9.53, 95% CI 3.21-28.29). Conclusions:The R2-ISS has significant predictive value for PFS and OS for transplant-eligible patients with MM in the new drug era. However, the universality of the R2-ISS still needs to be further verified in different populations.

Objective:To identify the characteristics of the bone marrow immune microenvironment associated with long-term survival in multiple myeloma (MM) patients.Methods:In the follow-up cohort of patients with newly diagnosed MM and who received “novel agent induction therapy and subsequent autologous stem cell transplantation and immunomodulator maintenance therapy” in the First Affiliated Hospital of Sun Yat-sen University, a cross-sectional study was carried out between August 2019 and May 2020. Using NanoString technology, the RNA expression of 770 bone marrow immune-related markers was compared between 16 patients who had progression-free survival ≥5 years and 5 patients with progressive disease. Among the 16 patients who achieved long-term survival, 9 achieved persistent minimal residual disease (MRD) negative while the other 7 had persistent positive MRD. The functional scores of each kind of immune cells were calculated based on the expression level of characteristic genes, so as to indirectly obtained the proportion of each immune cell subset. The Mann-Whitney U test and the Kruskal Wallis test were used for statistical analysis. Results:The proportion of neutrophils was significantly higher in long-surviving MM patients than in patients with progressive disease [functional scores, 13.61 (13.33, 14.25) vs. 12.93 (12.58, 13.38); Z=2.31, P=0.021]. Among long-surviving patients, those who were MRD-positive had a significantly greater number of mast cells compared with those who were MRD-negative [functional scores, 7.09 (6.49, 8.57) vs. 6.03 (5.18, 6.69); H=2.18, P=0.029]. Compared with patients with progressive disease, four genes (CTSG, IFIT2, S100B, and CHIT1) were significantly downregulated and six (C4B, TNFRSF17, CD70, IRF4, C2, and GAGE1) were upregulated in long-surviving patients. Among long-surviving patients, only gene CMA1 was significantly upgraded, 10 genes (ISG15, OAS3, MX1, IFIT2, DDX58, SIGLEC1, CXCL10, IL1RN, SERPING and TNFSF10) were significantly downregulated in the MRD-positive group compared with that in the MRD-negative group, the first 5 of which are related to the interferon response pathway. Conclusions:The increased neutrophil and mast cell numbers may be related to long-term survival in MM. Interferon signaling activation may be a key bone marrow immune profiling feature for MRD-negative, long-surviving patients with MM.

Objective: To evaluate the effect of Tai Chi and Qigong on patients with lumbar disc herniation (LDH). Methods: Relevant data were retrieved from nine English and Chinese databases, including Cochrane Library, PubMed, and Wanfang Data, etc. from inception to June 2024. All published randomized controlled trials assessing the effect of Tai Chi and Qigong on visual analog scale (VAS), Japanese Orthopedic Association (JOA) score, and other health indicators in participants with LDH compared to usual medical care or other treatments were included. Grey literature, trials involving the pushing of hands (Tui Shou) or Tai Chi with weapons, and trials with co-interventions (Tai Chi/Qigong plus another treatment) were excluded. Methodological quality was analyzed using the Cochrane risk of bias tool, and evidence quality was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool. Results: Fourteen trials (954 patients) were included in this study. Tai Chi and Qigong were associated with lower VAS pain scores (standardized mean difference −0.55, 95% confidence interval [CI] −0.95 to −0.15, P = .01), higher JOA scores (mean difference [MD] 4.40, 95% CI 2.62 to 6.18, P < .001) and straight leg raise test results (MD 9.40°, 95% CI 7.64 to 11.15, P < .001) in patients with LDH. Furthermore, compared with usual care, Tai Chi and Qigong showed enhanced effects on pain and JOA scores. When compared to other exercises or massage, the effect on pain scores was similar but that on JOA scores was significant. Conclusions Tai Chi and Qigong may have favorable effects on VAS pain and JOA scores compared with usual care, and on JOA scores compared with other exercises or massage in patients with LDH. Given the overall poor quality of the evidence, the results of current study should be interpreted cautiously.

Objective:To explore the application status, research hotspots and frontiers of blended teaching mode in undergraduate nursing education at home and abroad, so as to provide reference for related research.Methods:In Chinese, CNKI, Wanfang Database and VIP, and in English, Web of Science database were used as search sources. CiteSpace was used to conduct a quantitative analysis of the retrieved literatures published from 2008 to 2022.Results:A total of 43 literatures in Chinese and 83 in English were retrieved, and the number of publications showed an overall increasing trend. The research hotspots in China focused on education reform, online learning and curriculum system evaluation, and the research frontiers were network teaching, moral education and humanistic care. Foreign research focused on the choice of education model and emphasizes interaction, and the research frontier were to carry out innovative blended teaching and pay attention to the learning experience and learning environment construction of nursing students.Conclusions:In the future, blended teaching should pay attention to carrying out innovative research and dynamic evaluation and feedback of students' satisfaction. In particular, it is necessary to strengthen the cultivation of blended learning competence among nursing teachers, aiming to promote the knowledge and skills of nursing students, and continuously optimize and innovate the application of blended learning in the field of undergraduate nursing education.

Objective To investigate the effect of early glucose metabolism abnormality on skeletal muscle content of young men.Methods 88 males who underwent physical examinations in our hospital from September 2020 to September 2021 were divided into normal blood glucose group(NGT,n=47)and IGR group(n=41),according to their FPG and 2 hPG levels.FPG,FIns and visceral fat area(VFA)were measured.HOMA-IR,HOMA-β,skeletal muscle index(SMI)and body fat ratio(BFR)were calculated.Results Compared with NGT group,the males in IGR group showed elevated BMI,WC,FPG,2 hPG,HOMA-IR and VFA(P＜0.05),but decreased HDL-C and SMI(P＜0.05).Pearson correlation analysis showed that SMI was negatively correlated with BMI,WC,FPG,2 hPG,HOMA-IR,VFA and BFR in young men(P＜0.05 or P＜0.01).Logistic regression analysis showed that BMI was the influencing factor of FPG,while SMI was the influencing factor of 2 hPG.Conclusions In young men with abnormal glucose metabolism,the postprandial blood glucose significantly increase with the decrease of skeletal muscle content,and fasting blood glucose is mainly affected by BMI.

Objective:To evaluate the effects of different exercises on executive function, moter skills and core symptoms in children with attention deficit hyperactivity disorder (ADHD) using network Meta-analysis, and to provide evidence-based basis for the treatment of children with ADHD.Methods:The randomized controlled trails(RCTs)of exercises on children with ADHD were searched in Web of Science, PubMed, Cochrane Library, Embase, PsycINFO, CNKI, Wanfang Data, VIP and CBM databases.The retrieval time limit was from the establishment of each database to May 2023.The Cochrane quality review manual was used to evaluate the quality of the included literatures.Stata 17.0 software was used to perform network Meta-analysis.Results:Finally, twenty-four studies were enrolled including five types of exercise intervention, such as aerobic exercise, multicomponent exercise, exergaming, high intensity interval training (HIIT) and traditional low-to-moderate intensity exercise therapy (TRAD).The results of network Meta-analysis showed that: in terms of improving executive function(working memory, inhibitory control, and cognitive flexibility), motor skills and core symptoms of children with ADHD, the optimal exercise intervention was aerobic exercises (surface under the cumulative ranking were 78.9%, 73.0%, 88.7%, 77.9% and 69.9% respectively).Conclusion:Exercises can improve executive function, improve motor skills, and alleviate ADHD core symptoms.Aerobic exercise has a better effect on improving executive function, motor skills and core symptoms of ADHD children.

Objective To investigate the pathomorphological features of mucosa-associated lymphoid tissue(MALT)lymphoma of the lacrimal gland and the expression and significance of BCL10 and MALT1 in tumor tissues.Methods Diseased lacrimal gland tissue specimens from 19 patients with lacrimal gland MALT lymphoma(19 eyes,including nine right eyes and ten left eyes)were selected as the experimental group,and normal lacrimal gland tissue specimens from eight patients with orbital content removal(eight eyes,including three right eyes and five left eyes)were selected as the control group.Hematoxylin-eosin(HE)staining was performed to observe the mor-phological characteristics of the lacrimal gland tissues,and immunohistochemical(IHC)staining was performed to observe the expression of BCL10 and MALT1 in the lacrimal gland tissues.Results In the experimental group,marginal B cells,monocyte-like tumor cells,small lymphocyte-like tumor cells,and plasma cell-like tumor cells appeared in the marginal zone.Large cells were occasionally distri-buted among these cells.The tumor cells invaded the lymphoid follicles and epithelium,destroyed normal tissue structure,and formed follicular colonization and lymphoepithelial lesions.The positive expression area of BCL10 and MALT1 in the experimental group was sig-nificantly larger than that in the control group(Z=-2.177,P=0.029;t=3.237,P=0.003).Conclusion Lacrimal gland MALT lymphoma shows pathological changes in diffusely distributed marginal B cells and tumor cells with diverse morphology,acquired lymphoid follicles,and scattered distribution of large cells.This may be related to apoptosis blockage caused by the upregulation of BCL10 and MALT1 expression.

Objective To investigate the effect of progesterone receptor membrane component 1(PGRMC1)mediated autophagy on the sensitivity of liver cancer cells to 125I particles irradiation.Methods Hepatoma cell lines Huh7 and LM3 were exposed to different doses(0,2,4,6 and 8 Gy)of 125I particles,and cell autophagy was observed by transmission electron microscopy(TEM).Then,autophagy inhibitor chloroquine(CQ),agonist rapamycin(Rapa),and PGRMC1 inhibitor AG-205 were used respectively to verify that PGRMC1-mediated autophagy plays a key role in the sensitivity of hepatocellular carcinoma cells to 125I particle irradiation.Cell proliferation,colony formation and apoptosis were detected by CCK-8 assay,clonal formation test and flow cytometry,respectively.The expression levels of PGRMC1,microtubule-associated protein light chain 3-Ⅰ(LC3-Ⅰ),LC3-Ⅱ and p62 were detected by Western blotting.Results Different doses of 125I particles irradiation significantly decreased the proliferation and clonogenesis of Huh7 and LM3 cells(P＜0.05),and increased the apoptotic cells(P＜0.01),in a dose-dependent manner.Compared with the 0 Gy group,the ratio of LC3-Ⅱ/LC3-Ⅰ in Huh7 and LM3 cells was obviously increased,and the expression of p62 was significantly down-regulated in the 6 Gy group.The proliferation capacity and clonal formation ability of Huh7 and LM3 cells were decreased significantly,and their apoptotic cells were increased notably in the 6 Gy+CQ group than the 6 Gy group,while the above results were on the contrary in the 6 Gy+Rapa group.The 6 Gy+AG205 group had notably decreased LC3-Ⅱ/LC3-Ⅰ ratio in the Huh7 and LM3 cells,up-regulated p62 expression,reduced cell proliferation capacity and clone formation ability,and enhanced cell apoptosis when compared with the 6 Gy group,and the above results of the 6 Gy+PGRMC1 group were opposite.Conclusion Increment of PGRMC1 induced by 125I irradiation can promote autophagy,increase the proliferation and clonogenesis,and reduce the apoptosis in hepatocellular carcinoma cells.

Objective:To investigate the prognosis of newly diagnosed multiple myeloma (MM) patients with t (14;16) abnormality.Methods:Clinical data from 564 patients diagnosed with initial MM from January 2018 to November 2020 at Beijing Chaoyang Hospital affiliated with Capital Medical University and the First Affiliated Hospital of Sun Yat-sen University were collected and retrospectively analyzed. The prognoses of patients with t (14;16) were analyzed and compared with the prognoses of patients with normal FISH, and those with t (4;14) and del (17p) .Results:Among 564 newly diagnosed MM patients, 19 (3.4%) exhibited t (14;16) abnormalities, with 14 cases diagnosed with 1q21+ and three cases with del (17p). Progression-free survival (PFS) and overall survival (OS) of patients with t (14;16) were significantly shorter compared with patients with normal FISH (the median PFS: 14 months vs not reached, P<0.001; the median OS: 42 months vs not reached, P=0.002). No statistically significant difference was detected in PFS and OS between the 15 patients with t (14;16) and the 15 with t (4;14) after propensity score matching (the median PFS: 13.0 months vs not reached, P=0.247; the median OS: 42 months vs not reached, P=0.609). Similarly, no statistically significant difference was observed in PFS and OS between 15 patients with t (14;16) and 15 with del (17p) (the median PFS: 13 months vs 31 months, P=0.939; the median OS: 42 months vs 37.3 months, P=0.557). Propensity score matching indicated that when combined with 1q21+, no statistically significant differences were present in PFS and OS between patients with t (14;16) and patients with t (4;14) or patients with del (17p) (all P>0.05). Whether or not the patients with t (14;16) had undergone auto-HSCT did not significantly impact the PFS and OS (all P>0.05) . Conclusion:t (14;16) is often associated with high-risk cytogenetic abnormalities in newly diagnosed MM patients, and its adverse prognostic value is similar to that of t (4;14) and del (17p) .