Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits. The dorsal hippocampus (dHPC), a well-defined region responsible for learning and memory, displays maladaptive plasticity upon injury, which is assumed to underlie pain hypersensitivity and cognitive deficits. However, much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes. Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix (ECM) and decreases ECM rigidity in the dHPC. Despite this, it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits. Laminin, a key element of the ECM, consists of α-, β-, and γ-chains and has been implicated in several pathophysiological processes. Here, we showed that peripheral nerve injury downregulates laminin β1 (LAMB1) in the dHPC. Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction. Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrin β1, leading to decreased Ca²⁺ levels in pyramidal neurons, which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits. In this study, we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits, and reveal a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified hippocampal LAMB1/integrin β1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
Animals ; Laminin/genetics* ; Hippocampus/metabolism* ; Neuralgia/metabolism* ; Cognitive Dysfunction/etiology* ; Male ; Peripheral Nerve Injuries/metabolism* ; Extracellular Matrix/metabolism* ; Integrin beta1/metabolism* ; Pyramidal Cells/metabolism* ; Signal Transduction

Objective To investigate the value of prone-position MRI of lumbar spine for diagnosing pediatric occult tethered cord syndrome(OTCS).Methods A total of 67 children with suspected tethered cord syndrome(TCS)and confirmed OTCS by surgery were prospectively enrolled as OTCS group,while 73 healthy subjects were recruited as control group.Supine-and prone-position lumbar MR examinations were performed in both groups.The position of filum terminale on prone axial T2WI and the presence or absence of"sunset sign"(i.e.filum terminale located within the dorsal 1/2 of spinal canal on prone axial T2WI)were observed,spinal cord conus mobility was calculated.The efficacy of"sunset sign"for diagnosing OTCS in children was calculated through comparison between groups.Receiver operating characteristic curve was drawn,the area under the curve(AUC)was calculated to evaluate the diagnostic efficacy of spinal cord conus mobility.Results On prone-position axial T2WI,"sunset sign"was found in 58 cases(58/67,86.57％)but not in 9 cases(9/67,13.43％)in OTCS group,which was not even observed in control group.The sensitivity of"sunset sign"for diagnosing pediatric OTCS was 86.57％(58/67),with specificity of 100％(73/73),positive predictive value of 100％(58/58)and negative predictive value of 89.02％(73/82).The spinal cord conus mobility was(19.30±5.89)％in OTCS group and(31.71±6.58)％in control group,being statistically different between groups(t=-11.722,P＜0.001).The sensitivity,specificity and AUC of spinal cord conus mobility for diagnosing pediatric OTCS was 80.60％,90.41％and 0.920,respectively.Conclusion Prone-position MRI of lumbar spine could be used in diagnosing pediatric OTCS.

BACKGROUND:Many recent studies have shown a close relationship between inflammatory cytokines and osteoporosis and bone mineral density(BMD).However,the causal relationship between inflammatory cytokines and BMD has not been fully revealed. OBJECTIVE:To explore the potential causal relationship between inflammatory cytokines and BMD using a two-sample Mendelian randomization analysis. METHODS:The single nucleotide polymorphisms associated with 41 circulating inflammatory cytokines were selected from the open database of genome-wide association studies(GWAS)as instrumental variables.The GWAS data about BMD were from the Genetic Factors for Osteoporosis Consortium,involving a total of 32 735 individuals of European ancestry.Inverse variance weighting was used as the primary analysis to evaluate the causal effect.Weighted median,MR Egger regression,simple mode,and weighted mode methods were used to supplement the explanation.We used the MR-Egger intercept and MR-PRESSO method to conduct a pleiotropy test,the Cochran's Q test was used to determine whether there was heterogeneity in the results,and the leave-one-out method was used to evaluate the stability of the results.In addition,to more accurately assess the causality,the Bonferroni-corrected test was used to identify inflammatory cytokines that have a strong causal relationship with BMD. RESULTS AND CONCLUSION:(1)According to the results of the inverse variance weighting method,we found a positive causal relationship between interleukin-8 and lumbar spine BMD[β=0.075,95%confidence interval(CI):0.033-0.117,P=0.000 5),while a negative causal relationship between interleukin-17 and lumbar spine BMD(β=-0.083,95%CI:-0.152 to-0.014,P=0.018).There might be a negative causal relationship between tumor necrosis factor b and femoral neck BMD(β=-0.053,95%CI:-0.088 to-0.018,P=0.003),while a positive causal relationship between basic fibroblast growth factor and femoral neck BMD(β=0.085,95%CI:0.016-0.154,P=0.015).There might be a negative causal relationship between macrophage inflammatory protein-1a and total body BMD(β=-0.056,95%CI:-0.105 to-0.007,P=0.025).There was a negative causal relationship between interleukin-5(β=-0.019,95%CI:-0.031 to-0.006,P=0.004),stromal cell-derived factor-1a(β=-0.022,95%CI:-0.038 to-0.005,P=0.010),hepatocyte growth factor(β=-0.021,95%CI:-0.041 to-0.002,P=0.030),interleukin-4(β=-0.016,95%CI:-0.032 to-0.001,P=0.034)and heel BMD,while a positive causal relationship between nerve growth factor(β=0.019,95%CI:0.002-0.036,P=0.033),granulocyte colony-stimulating factor(β=0.011,95%CI:0.000-0.022,P=0.050),and heel BMD.Meanwhile,after the Bonferroni-corrected test,there was a strong positive causal effect between interleukin-8 and lumbar spine BMD(P=0.000 5).And consistent directional effects for all analyses were observed in MR Egger,weighted median,simple mode,and weighted mode methods.(2)Sensitivity analyses revealed no heterogeneity,pleiotropy,or outliers for the causal effect of circulating inflammatory cytokines on BMD.

Objective To investigate the value of prone-position MRI of lumbar spine for diagnosing pediatric occult tethered cord syndrome(OTCS).Methods A total of 67 children with suspected tethered cord syndrome(TCS)and confirmed OTCS by surgery were prospectively enrolled as OTCS group,while 73 healthy subjects were recruited as control group.Supine-and prone-position lumbar MR examinations were performed in both groups.The position of filum terminale on prone axial T2WI and the presence or absence of"sunset sign"(i.e.filum terminale located within the dorsal 1/2 of spinal canal on prone axial T2WI)were observed,spinal cord conus mobility was calculated.The efficacy of"sunset sign"for diagnosing OTCS in children was calculated through comparison between groups.Receiver operating characteristic curve was drawn,the area under the curve(AUC)was calculated to evaluate the diagnostic efficacy of spinal cord conus mobility.Results On prone-position axial T2WI,"sunset sign"was found in 58 cases(58/67,86.57％)but not in 9 cases(9/67,13.43％)in OTCS group,which was not even observed in control group.The sensitivity of"sunset sign"for diagnosing pediatric OTCS was 86.57％(58/67),with specificity of 100％(73/73),positive predictive value of 100％(58/58)and negative predictive value of 89.02％(73/82).The spinal cord conus mobility was(19.30±5.89)％in OTCS group and(31.71±6.58)％in control group,being statistically different between groups(t=-11.722,P＜0.001).The sensitivity,specificity and AUC of spinal cord conus mobility for diagnosing pediatric OTCS was 80.60％,90.41％and 0.920,respectively.Conclusion Prone-position MRI of lumbar spine could be used in diagnosing pediatric OTCS.

Background and purpose:Pancreatic cancer is a highly aggressive solid tumor of the digestive system,with radical resection being unfeasible in approximately 80%of patients due to the absence of specific clinical manifestations in the early stages.The use of gemcitabine as a first-line chemotherapeutic agent has not significantly improved patient prognosis,primarily due to the development of chemoresistance.The precise mechanisms underlying gemcitabine resistance in pancreatic cancer remain unclear.This study aimed to explore potential biomarkers associated with gemcitabine chemoresistance in pancreatic cancer by utilizing gemcitabine-resistant cell lines and pathological pancreatic cancer tissues,in conjunction with data from online databases.Additionally,we analyzed follow-up data from pancreatic cancer patients to assess the impact of relevant targets on patient prognosis.Methods:In this study,gemcitabine-resistant cell lines were developed through stepwise induction using a gemcitabine concentration gradient.Second-generation high-throughput RNA-seq sequencing was conducted on these resistant cells,and bioinformatics analysis was employed to identify four pancreatic cancer genes from the Gene Expression Omnibus(GEO)datasets(GSE106336,GSE110580,GSE35141,and GSE140077).Co-expressed genes were screened using real-time fluorescence quantitative polymerase chain reaction(RTFQ-PCR),Western blot and immunohistochemistry to verify the expression levels of target molecules.Surgical specimens from 70 patients diagnosed with pancreatic adenocarcinoma at the First Affiliated Hospital of Xi'an Jiao Tong University between June 2018 and June 2021 were analyzed.These included 30 specimens resistant to gemcitabine,16 non-resistant specimens,and 24 normal pancreatic tissues as controls.Ethical approval was obtained(Ethical approval:2021 LunxuanKeZi No.457,No.XJTU1AF2021LSK-457).Clinical and prognostic information was collected,and the log-rank test was used to evaluate the relationship between target molecule expression and patient prognosis.Results:The half maximal inhibitory concentration(IC50)for gemcitabine was significantly higher in the gemcitabine-resistant cell strain(Mia GR)than in the wild-type cell line(Mia WT)(258.10 μmol/L vs 0.18 μmol/L),with a resistance index(RI)of 1 443.9.Transcriptome sequencing identified 3 985 differentially expressed genes,of which 25 were shared with the GEO datasets.Further analysis highlighted INPP4B as a key gene.RTFQ-PCR and Western blot confirmed that INPP4B mRNA and protein levels were significantly elevated in drug resistant cells compared to wild-type cells(P＜0.05).Immunohistochemical analysis revealed that INPP4B expression was significantly higher in drug resistant pancreatic cancer tissues compared to non-drug resistant tissues,and lower in normal tissues than in both cancerous tissue types.Kaplan-Meier curves demonstrated that patients with low INPP4B expression had significantly better progression-free survival(PFS)than those with high expression(HR=2.874,95%CI:1.262-6.544,P=0.013).Although patients with low INPP4B expression also showed better overall survival(OS),the difference was not statistically significant(HR=1.484,95%CI:0.518-4.250,P=0.465).Conclusion:INPP4B may serve as a potential biomarker for gemcitabine chemoresistance in pancreatic cancer and is associated with poor prognosis in drug resistant patients.Developing targeted assays and treatments for INPP4B could facilitate early identification of patients likely to exhibit resistance to gemcitabine therapy,thereby improving their prognosis.

Neck dissection(ND)is one of the main treatment methods for oral and maxillofacial malignancies.Although ND type is in con-stant improvement,but intraoperative peal-pull-push injury of the accessory nerve,muscle,muscle membrane,fascia and ligament induced shoulder syndrome(SS)is still a common postoperative complication,combined with the influence of radiochemotherapy,not only can cause pain,stiffness,numbness,limited dysfunction of shoulder neck and arm,but also may have serious impact on patient's life quality and phys-ical and mental health.At present,there is still a lack of a systematic evaluation and rehabilitation management program for postoperative SS of oral and maxillofacial malignant tumors.Based on the previous clinical practice and the current available evidence,refer to the relevant lit-erature at home and abroad,the experts in the field of maxillofacial tumor surgery and rehabilitation were invited to discuss,modify and reach a consenusus on the etiology,assessment diagnosis,differential diagnosis,rehabilitation strategy and prevention of SS,in order to provide clinical reference.

Background and purpose:Pancreatic cancer is a highly aggressive solid tumor of the digestive system,with radical resection being unfeasible in approximately 80%of patients due to the absence of specific clinical manifestations in the early stages.The use of gemcitabine as a first-line chemotherapeutic agent has not significantly improved patient prognosis,primarily due to the development of chemoresistance.The precise mechanisms underlying gemcitabine resistance in pancreatic cancer remain unclear.This study aimed to explore potential biomarkers associated with gemcitabine chemoresistance in pancreatic cancer by utilizing gemcitabine-resistant cell lines and pathological pancreatic cancer tissues,in conjunction with data from online databases.Additionally,we analyzed follow-up data from pancreatic cancer patients to assess the impact of relevant targets on patient prognosis.Methods:In this study,gemcitabine-resistant cell lines were developed through stepwise induction using a gemcitabine concentration gradient.Second-generation high-throughput RNA-seq sequencing was conducted on these resistant cells,and bioinformatics analysis was employed to identify four pancreatic cancer genes from the Gene Expression Omnibus(GEO)datasets(GSE106336,GSE110580,GSE35141,and GSE140077).Co-expressed genes were screened using real-time fluorescence quantitative polymerase chain reaction(RTFQ-PCR),Western blot and immunohistochemistry to verify the expression levels of target molecules.Surgical specimens from 70 patients diagnosed with pancreatic adenocarcinoma at the First Affiliated Hospital of Xi'an Jiao Tong University between June 2018 and June 2021 were analyzed.These included 30 specimens resistant to gemcitabine,16 non-resistant specimens,and 24 normal pancreatic tissues as controls.Ethical approval was obtained(Ethical approval:2021 LunxuanKeZi No.457,No.XJTU1AF2021LSK-457).Clinical and prognostic information was collected,and the log-rank test was used to evaluate the relationship between target molecule expression and patient prognosis.Results:The half maximal inhibitory concentration(IC50)for gemcitabine was significantly higher in the gemcitabine-resistant cell strain(Mia GR)than in the wild-type cell line(Mia WT)(258.10 μmol/L vs 0.18 μmol/L),with a resistance index(RI)of 1 443.9.Transcriptome sequencing identified 3 985 differentially expressed genes,of which 25 were shared with the GEO datasets.Further analysis highlighted INPP4B as a key gene.RTFQ-PCR and Western blot confirmed that INPP4B mRNA and protein levels were significantly elevated in drug resistant cells compared to wild-type cells(P＜0.05).Immunohistochemical analysis revealed that INPP4B expression was significantly higher in drug resistant pancreatic cancer tissues compared to non-drug resistant tissues,and lower in normal tissues than in both cancerous tissue types.Kaplan-Meier curves demonstrated that patients with low INPP4B expression had significantly better progression-free survival(PFS)than those with high expression(HR=2.874,95%CI:1.262-6.544,P=0.013).Although patients with low INPP4B expression also showed better overall survival(OS),the difference was not statistically significant(HR=1.484,95%CI:0.518-4.250,P=0.465).Conclusion:INPP4B may serve as a potential biomarker for gemcitabine chemoresistance in pancreatic cancer and is associated with poor prognosis in drug resistant patients.Developing targeted assays and treatments for INPP4B could facilitate early identification of patients likely to exhibit resistance to gemcitabine therapy,thereby improving their prognosis.

Objective: To analyze and compare therapy responses, outcomes, and incidence of severe hematologic adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia (CML) . Methods: Data of patients with chronic phase CML diagnosed between January 2006 and November 2022 from 76 centers, aged ≥18 years, and received initial flumatinib or imatinib therapy within 6 months after diagnosis in China were retrospectively interrogated. Propensity score matching (PSM) analysis was performed to reduce the bias of the initial TKI selection, and the therapy responses and outcomes of patients receiving initial flumatinib or imatinib therapy were compared. Results: A total of 4 833 adult patients with CML receiving initial imatinib (n=4 380) or flumatinib (n=453) therapy were included in the study. In the imatinib cohort, the median follow-up time was 54 [interquartile range (IQR), 31-85] months, and the 7-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.2%, 88.4%, 78.3%, and 63.0%, respectively. The 7-year FFS, PFS, and OS rates were 71.8%, 93.0%, and 96.9%, respectively. With the median follow-up of 18 (IQR, 13-25) months in the flumatinib cohort, the 2-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.4%, 86.5%, 58.4%, and 46.6%, respectively. The 2-year FFS, PFS, and OS rates were 80.1%, 95.0%, and 99.5%, respectively. The PSM analysis indicated that patients receiving initial flumatinib therapy had significantly higher cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) and higher probabilities of FFS than those receiving the initial imatinib therapy (all P<0.001), whereas the PFS (P=0.230) and OS (P=0.268) were comparable between the two cohorts. The incidence of severe hematologic adverse events (grade≥Ⅲ) was comparable in the two cohorts. Conclusion: Patients receiving initial flumatinib therapy had higher cumulative incidences of therapy responses and higher probability of FFS than those receiving initial imatinib therapy, whereas the incidence of severe hematologic adverse events was comparable between the two cohorts.
Adult ; Humans ; Adolescent ; Imatinib Mesylate/adverse effects* ; Incidence ; Antineoplastic Agents/adverse effects* ; Retrospective Studies ; Pyrimidines/adverse effects* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Treatment Outcome ; Benzamides/adverse effects* ; Leukemia, Myeloid, Chronic-Phase/drug therapy* ; Aminopyridines/therapeutic use* ; Protein Kinase Inhibitors/therapeutic use*

Post-amputation pain causes great suffering to amputees, but still no effective drugs are available due to its elusive mechanisms. Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump effectively relieves the phantom pain afflicting patients after amputation. This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain (CPAP). However, the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery. In this study, we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infiltrated into the dorsal root ganglion (DRG) neurons worked synergistically to promote CPAP. Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG, and the expression of TMEM63A increased significantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer (TNT). Behavioral tests showed that the mechanical, heat, and cold sensitivity were not affected in the Tmem63a^-/- mice in the naïve state, suggesting the basal pain was not affected. In the inflammatory and post-amputation state, the mechanical allodynia but not the heat hyperalgesia or cold allodynia was significantly decreased in Tmem63a^-/- mice. Further study showed that there was severe neuronal injury and macrophage infiltration in the DRG, tibial nerve, residual stump, and the neuroma-like structure of the TNT mouse model, Consistent with this, expression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β all increased dramatically in the DRG. Interestingly, the deletion of Tmem63a significantly reduced the macrophage infiltration in the DRG but not in the tibial nerve stump. Furthermore, the ablation of macrophages significantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model, indicating an interaction between nociceptors and macrophages, and that these two factors gang up together to regulate the formation of CPAP. This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.
Animals ; Mice ; Amputation, Surgical ; Chronic Pain/pathology* ; Disease Models, Animal ; Ganglia, Spinal/pathology* ; Hyperalgesia/etiology* ; Ion Channels/metabolism* ; Macrophages ; Neuroma/pathology*

Objective To investigate the effectiveness of a new health education pathway for echinococcosis control among primary school students in regions highly prevalent for echinococcosis in China. Methods Six primary schools were randomly selected from echinococcosis hyper-endemic regions, with 13 classes assigned to the intervention group and 9 to the control group, and all students in these 21 classes were recruited as the study subjects. Echinococcosis health education was performed through the pathway of assessing the current status-strengthening the building of teaching resources-focusing on practices in the intervention group, while routine health education was given in the control group. A questionnaire survey was performed to assess the score of echinococcosis control knowledge (including theoretical knowledge score and mean daily practical capability score) before and after the health education interventions to evaluate the effectiveness of this new health education pathway for echinococcosis control. Results The mean score of echinococcosis control knowledge was 68.86 ± 18.70 points at baseline, with the mean theoretical knowledge score of 40.97 ± 10.75 points, and the mean daily practical capability score of 27.89 ± 12.50 points. Clustering analysis showed three types of populations, including “unsatisfactory”, “learn and apply creatively”, and “rote learning”, which accounted for 24.62% (240/975), 45.74% (446/975) and 29.64% (289/975), respectively. The mean score of echinococcosis control knowledge was 81.08 ± 18.15 points in the intervention group during the final assessment, with the mean theoretical knowledge score of 43.65 ± 9.40 points, and the mean daily practical capability score of 37.43 ± 12.22 points, and both were significantly higher relative to baseline (t = −4.201 and −15.202, both P values < 0.01). The mean score of echinococcosis control knowledge was comparable between at baseline (70.55 ± 19.46 points) and final assessment (71.74 ± 19.37 points) in the control group (t = −0.87, P > 0.05). Conclusions The awareness of echinococcosis control knowledge is fair among primary school students in echinococcosis hyper-endemic regions; however, the capability of combining theoretical learning and practices requires to be improved. The health education mode based on the pathway of assessing the current status-strengthening the building of teaching resources-focusing on practices seems to remarkably improve the understanding of echinococcosis control knowledge among primary school students in echinococcosis hyper-endemic regions.