BACKGROUND:Yougui Pill is a famous formula of the Chinese traditional medicine,which has good efficacy for lumbar disc herniation due to kidney yang insufficiency. OBJECTIVE:To investigate the potential targets and mechanism of action of Yougui Pill in the treatment of lumbar disc herniation by using network pharmacology and molecular docking technology,and verified by animal experiments. METHODS:(1)Network pharmacological analysis:We obtained the active ingredients and targets of Yougui Pill from TCMSP and other databases,collected genes related to lumbar disc herniation from GeneCards database,and took the intersection of the two for the topological analysis to derive the main active ingredients and core therapeutic targets.Gene ontology function analysis and Kyoto encyclopedia of genes and genomes pathway enrichment analysis were performed using R software.(2)Molecular docking:Autodock and Pymol software were utilized for the prediction of molecular binding energy of TCM active ingredients to core therapeutic targets.(3)Animal experiments:Eighteen Sprague-Dawley rats were randomly divided into a control group,a degeneration group and a Yougui Pill group,with 6 rats in each group.A rat model of intervertebral disc degeneration was prepared by fiber puncture method in the degeneration and Yougui Pill groups.At 2 weeks after modeling,Yougui Pill was given by gavage in the Yougui Pill group,once a day for 2 consecutive weeks.The level of tumor necrosis factor-α in serum was detected by the ELISA method,and morphological changes of the annulus fibrosus and nucleus pulposus cells were observed using hematoxylin-eosin staining. RESULTS AND CONCLUSION:There were 90 active ingredients and 64 targets,and the main active ingredients were found to be quercetin,kaempferol,β-carotene,soybean flavonoid,and 4'-O-methylnyasol.The core targets of Yougui Pill for the treatment of lumbar disc herniation were interleukin 6,tumor necrosis factor-α,AKT1,interleukin 1B,and vascular endothelial growth factor A.Enrichment analysis revealed that the intersecting genes might be expressed through the interleukin-17 signaling pathway,tumor necrosis factor signaling pathway,MAPK signaling pathway,PI3K-AKT signaling pathway,and other signaling pathways to improve intervertebral disc degeneration.The molecular docking test verified that quercetin,kaempferol,and β-carotene had strong binding ability to the core targets.Animal experiments showed that the level of serum tumor necrosis factor α in the degeneration group was higher than that in the control group(P<0.05),and the level of serum tumor necrosis factor α in the Yougui Pill group was lower than that in the degeneration group(P<0.05).Hematoxylin-eosin staining showed that the fibrous annulus of the intervertebral discs and the structure of the nucleus pulposus in the degeneration group were destroyed,and the number of nucleus pulposus cells was reduced;there was a tendency to reconstructing the fibrous annulus of the intervertebral discs in the Yougui Pill group,and the number of nucleus pulposus cells increased compared with the degeneration group.To conclude,Yougui Pill may treat lumbar disc herniation by improving disc degeneration through the effects of quercetin,kaempferol,beta-carotene and other key active ingredients on core targets such as tumor necrosis factor.

Objective To design a multisensory supported device and evaluate its effectiveness on preterm infants(born before 34 weeks)during NICU hospitalization.Methods The multisensory supported device is composed of a basement,several soft cushions and an adjustable eye mask.The inner layer of the device comprises of the head and tail boundaries,serves as uterine wall-like circular boundaries.The outer skeleton is equipped with multisensory stimulation modules to provide visual,hearing,and tactile sensory stimulations for premature infants.The study was conducted in a NICU of a tertiary A children specialist hospital in Shanghai,China.The convenience sampling method was used and based on the ratio of 1∶2 between the experimental and the control group in this study.The control group was treated by standard nursing care,while the experiment group was treated with the multisensory supported device in addition to NICU conventional care.All infants were assessed during the week of admission and again at corrected gestational age of 36 weeks.The actigraphy watch which was used for 72 hours continuous record of the activities of study infants,allows the researcher to compare the activity scores,wakefulness and sleep indicators of 2 groups of infants.Results 71 preterm infants were enrolled in the study,and 60 preterm infants completed data collection for study data analysis,including 20 in the experimental group and 40 in the control group.There were no statistical differences in demographic characteristics and clinical status regarding wakefulness,sleep and physical development between the 2 groups in baseline(P＞0.05).At 36 weeks of corrected gestational age,the activity score of the experimental group was(46.61±12.14)points,and that of the control group was(57.33±18.36)points,with statistically significant differences in 2 groups(P=0.024).The total waking time of the experimental group was(384.85±169.42)min,and that of the control group was(492.08±220.45)min,with statistically significant differences in 2 groups(P=0.049).There was no statistical difference in other indicators between 2 groups(P＞0.05).Conclusion The multisensory supported device can reduce high-frequency unpleasant activity as well as frequent wakefulness status,which could promote the sleeping quality of preterm infants.Further studies are needed to verify further effects of the device on premature infants'physical development.

Objective:To investigate the clinical application of 68Ga-cyclo( L-arginylglycyl- L-α-aspartyl- D-tyrosyl-N6-(((4, 7-bis(carboxymethyl)-1, 4, 7-triazonan-1-yl)acetyl))- L-lysyl) (NODAGA-RGD) PET/CT to evaluate short-term efficacy of tyrosine kinase inhibitor (TKI) in distant metastatic differentiated thyroid cancer (dmDTC). Methods:From October 2019 to March 2023, 13 dmDTC patients (5 males, 8 females; age: 68(65, 69) years) from Nanjing First Hospital were retrospectively enrolled, of which 9 were clinically confirmed as radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) and 4 were dmDTC without radioactive iodine treatment. All patients underwent 68Ga-NODAGA-RGD PET/CT to assess neovascularization of the target lesions (TL), and the SUV max and target background ratio (T/B) were recorded. After 3 months of TKI treatment (anrotinib ( n=9) or apatinib ( n=4)), change rates of the maximum diameter of TL and thyroglobulin (Tg) were measured. The correlation of SUV max, T/B and the change rate of the maximum diameter of TL were analyzed by Spearman rank correlation analysis. ROC curve analysis was performed for the effectiveness of the T/B and TKI therapy, and the difference of the remission rate of lesions was analyzed by Fisher exact test. Results:In 13 patients, 36 TL were measured by 68Ga-NODAGA-RGD PET/CT with SUV max of 5.44(3.43, 7.56) and T/B of 5.25(4.50, 7.23). The change rate of the maximum diameter of TL was -30%(-39%, -21%) and the change rate of Tg was -68%(-96%, -52%). T/B was negatively correlated with the change rate of the maximum diameter of TL after TKI therapy ( rs=-0.46, P=0.005), while SUV max was not correlated with the change rate of the maximum diameter of TL ( rs=0.03, P=0.883). ROC curve analysis showed that the optimal cut-off value for T/B was 4.95, with the AUC of 0.698, the sensitivity of 87.5%, and the specificity of 60.0%. Compared to lesions with T/B<4.95, those with T/B≥4.95 showed higher remission rate (2/14 vs 63.6%(14/22); P=0.006). After 3 months of TKI treatment, the disease control rate was 12/13. Conclusion:68Ga-NODAGA-RGD PET/CT can effectively reflect tumor neovascularization, predict efficacy of TKI therapy, and provide powerful imaging evidence for TKI therapy in dmDTC.

Objective:This study aimed to evaluate the effect of early tocilizumab intervention to relieve cytokine release syndrome (CRS) following chimeric antigen receptor T cell (CAR-T) therapy.Methods:Twenty-two patients with acute lymphoblastic leukemia who received tocilizumab to relieve CRS response after CAR-T cell infusion in our research center from October 2015 to July 2021 were retrospectively analyzed. According to the timing of tocilizumab intervention, patients were divided into the conventional and early intervention groups. Patients who received tocilizumab treatment after sustained high fever for 4 h were included in the early intervention group. The clinical data, CRS grade, and event-free survival (EFS) between the two groups were evaluated.Results:Compared with patients who used tocilizumab after severe CRS, no patients in the early intervention group died from CRS, and there was no increased risk of neurotoxicity. Eleven patients (84.62%) achieved complete remission with minimal residual lesions. The median EFS of patients in the early intervention and conventional groups was 2 (95% CI 0-5) and 7 (95% CI 3-11) months, respectively. Conclusion:Early tocilizumab intervention in patients with CRS reduces severe CRS and provides a more optimized therapeutic strategy for CRS caused by CAR-T cell therapy.

Objective:To observe any relationship between corticospinal tract integrity and the upper limb motor function of stroke survivors treated with repetitive transcranial magnetic stimulation (rTMS).Methods:Bilateral corticospinal tracts (CSTs) were reconstructed in ischemic or hemorrhagic stroke survivors with upper limb motor dysfunction using diffusion tensor imaging (DTI). Thirty patients with good CST integrity (rFA>0.5) and 30 with rFA≤0.5 were further divided into a high frequency rTMS group (HF, n=10), a low frequency group (LF, n=10), and a control group ( n=10). All groups were given routine rehabilitation, while the high and low frequency groups were additionally provided with 5Hz and 1Hz rTMS respectively applied over the M1 area of the contralesional hemisphere. Before and after 3 weeks of treatment, all of the subjects were evaluated using the Fugl-Meyer upper extremity scale (F-M UE), the Wolf Motor Function Test (WMFT) and the Modified Barthel Index (MBI). Results:For the high CST integrity group, significant improvement was observed in the average scores of all measurements, with the average FMA-UE, WMFT and MBI scores of the LF group [(38.10±5.71), (43.20±5.32) and (78.00±11.35)] significantly better than those of the other 2 groups. Among the low CST integrity group, the HF subgroup showed greater improvement than the other 2 on average.Conclusions:For patients with good CST integrity, LF-rTMS over the contralesional cortex is superior to HF-rTMS in promoting upper limb motor function, while for patients with low CST integrity HF-rTMS over the contralesional cortex has a better effect than LF-rTMS or sham stimulation in terms of improving upper limb motor function after a stroke.

Objective:To study the effect of eye-open/closed state on 40 Hz auditory steady state response (ASSR) in first-degree relatives of schizophrenia.Methods:Thirty-eight first-degree relatives of schizophrenic patients treated in Shanghai Mental Health Center from March 2010 to October 2011 were selected, and 31 healthy controls were recruited in the same period. All subjects were assessed with schizotypal personality questionnaire (SPQ). The 40 Hz EEG ASSR signals lasting for 3 min under open and closed eyes of all subjects were sequentially collected.Event-related spectrum perturbation (ERSP) and intertribal phase coherence (ITC) were used to evaluate ASSR. SPSS 22.0 software was used for statistical analysis. Two-way analysis of variance was used to compare ITC and ERSP between the two groups under open and closed eyes. Spearman correlation analysis was used to analyze the correlation between each measurement.Results:ITC in group main effect and group×the eye open/closed interaction effect were not significant (both P>0.05), but the main effect of eye-open and eye-closed was significant ( F(1, 67)=10.61, P=0.002). In the healthy control group, the ITC in eye-open state was significantly higher than that in eye-closed state ( P=0.014), and in the first-degree relatives group, the ITC in eye-open state was higher than that in eyes closed state ( P=0.039). ERSP in the main effect of eye-open and eye-closed ( F(1, 67)=0.195, P=0.660), group main effect ( F(1, 67) =0.627, P=0.431), group × the eye-open/closed interaction effect ( F(1, 67)= 1.034, P=0.313) was not significant. Spearman correlation analysis showed that there was no correlation between ERSP (eye open: r=-0.260, P=0.210; eye closed: r=-0.318, P=0.122), ITC (eye open: r=-0.248, P=0.232; eye closed: r=-0.260, P=0.209) and SPQ score in the healthy control group. There was also no correlation between ERSP (eye open: r=-0.387, P=0.226; eye closed: r=-0.363, P=0.238) or ITC (eye open: r=0.126, P=0.485; eye closed: r=0.096, P=0.595) and SPQ score in the first-degree relatives group of schizophrenia. Conclusion:The regulation pattern of 40 Hz ASSR in schizophrenic first-degree relatives is not significantly impaired in the eye-open/closed state, suggesting that the open/closed regulation pattern of 40 Hz ASSR may not be a potential marker for predicting the genetic high-risk prognosis of schizophrenia.

Mantle cell lymphoma (MCL) is a distinct histological type of B-cell lymphoma with a poor prognosis. Several agents, such as proteasome inhibitors, immunomodulatory drugs, and inhibitors of B cell lymphoma-2 and Bruton's tyrosine kinase have shown efficacy for relapsed or refractory (r/r) MCL but often have short-term responses. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a novel treatment modality for r/r non-Hodgkin's lymphoma. However, long-term safety and tolerability associated with CAR T-cell therapy are not defined well, especially in MCL. In this report, we described a 70-year-old patient with r/r MCL with 48-month duration of follow-up who achieved long-term remission after CAR T-cell therapy. CAR T-cell-related toxicities were also mild and tolerated well even in this elderly patient. This report suggested that CAR T-cell therapy is a promising treatment modality for patients with MCL, who are generally elderly and have comorbid conditions.
Adult ; Aged ; Cell- and Tissue-Based Therapy ; Humans ; Immunotherapy, Adoptive ; Lymphoma, Mantle-Cell/therapy* ; Neoplasm Recurrence, Local ; Receptors, Chimeric Antigen

Factors associated with complete and durable remissions after anti-CD19 chimeric antigen receptor T (CAR-T) cell immunotherapy for relapsed or refractory non-Hodgkin lymphoma (r/r NHL) have not been well characterized. In this study, we found that the different sites of extranodal involvement may affect response, overall survival (OS), and progression-free survival (PFS) in patients with r/r NHL treated with anti-CD19 CAR-T cells. In a cohort of 32 treated patients, 12 (37.5%) and 8 (25%) patients exhibited soft tissue lymphoma and bone marrow (BM) infiltrations, respectively, and 13 (41%) patients exhibited infiltration at other sites. The factors that may affect prognosis were identified through multivariable analysis. As an independent risk factor, soft tissue infiltration was the only factor significantly correlated with adverse prognosis (P < 0.05), whereas other factors did not reach statistical significance. Furthermore, the site of extranodal tumor infiltration significantly and negatively affected OS and PFS in patients with r/r NHL treated with anti-CD19 CAR-T cell therapy. PFS and OS in patients with BM involvement were not significantly different from those of patients with lymph node involvement alone. Thus, anti-CD19 CAR-T cell therapy may improve the prognosis of patients with BM infiltration.
Cell- and Tissue-Based Therapy ; Humans ; Immunotherapy, Adoptive ; Lymphoma, Non-Hodgkin/therapy* ; Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen

Most patients with schizophrenia have experienced a period called clinical high risk (CHR) preceding the first episode of psychosis.Early identification of CHR and timely medication or psychological intervention may reduce conversion to psychosis.By exploring biomarkers that predict the onset of psychosis and improving the accuracy of predicting the prognosis of CHR state, it is possible to take a more active intervention measure.As a fast and economical neurophysiological test, event-related potential (ERP) may reflect the perception process, pre-attention process, and attention distribution of the cognitive processes.And it holds promise for becoming objective indices in predicting the clinical outcomes of the CHR patients.This paper reviews the current studies on different ERP components in the CHR population and their performance as predictors of clinical outcomes.The results show that among ERP abnormalities, P300 and MMN amplitude reductions appear to be more reliable than others, which may indicate that distinct components reflect different stages of the disease.However, as a physiological index in the CHR group, aberrant ERP lacks certain specificity.The algorithm analysis combining different ERP components or combining components with symptoms may make the test more specific in the future.

[Abstract] Objective: To develop a new type of CD7 chimeric antigen receptor modified T cell (CD7-CAR-T) for the treatment of CD7 positive acute myeloid leukemia (AML), and to observe its killing effect on CD7 positive AML cells. Methods: The CD7-CAR lentiviral vector was constructed based on the CD7 Nanobody sequence and costimulatory domain sequence of CD28 and 4-1BB. The lentiviral particles were packaged and used to co-transfect human T cells with protein expression blocker (PEBL), so as to prepare CD7- CAR-T cells. Real time cellular analysis (RTCA) was used to monitor the cytotoxicity of CD7-CAR-T cells on CD7 overexpressed 293T cells. Flow cytometry assay was used to detect the effect of CD7-CAR-T cells on proliferation and cytokine secretion of AML cells with high, medium and low CD7 expressions (KG-1, HEL and Kasumi-1 cells, respectively). Results: CD7-CAR-T cell was successfully constructed and its surface expression of CD7 was successfully blocked. Compared with T cells, CD7-CAR-T cells could significantly inhibit the proliferation of CD7-293T cells and promote the release of TNF, Granzyme B and INF-γ; in addition, CD7-CAR-T cells also significantly promoted the apoptosis (t=147.1, P<0.01; t=23.57, P<0.01) and cytokine release (P<0.05 or P<0.01) in CD7 positive KG-1 and HEL cells, but had little effect on Kasumi-1 cells that only expressed minimal CD7 antigen (t=0.7058, P>0.05). Conclusion: CD7-CAR-T cells can specifically kill CD7-positive AML cells in vitro.