BACKGROUND:Previous studies have successfully constructed erythropoietin-overexpressed umbilical cord mesenchymal stem cells.It was found that the apoptosis of ischemic and hypoxic human neuroblastoma cell line(SH-SY5Y)was significantly reduced by erythropoietin-overexpressed umbilical cord mesenchymal stem cells. OBJECTIVE:To explore the possible neuroprotective mechanisms of erythropoietin-overexpressed umbilical cord mesenchymal stem cells against ischemic-hypoxic SH-SY5Y and their associated epigenetic mechanisms. METHODS:Oxygen-glucose deprivation was applied to ischemia-hypoxia-induced SH-SY5Y cell injury,and multifactorial assays were applied to detect the expression levels of inflammatory factors in the cells before and after hypoxia and co-culture,respectively,with mesenchymal stem cells,as well as lentiviral-transfected null-loaded plasmids of the negative control mesenchymal stem cells and erythropoietin-overexpressed umbilical cord mesenchymal stem cells.The expression levels of supernatant inflammatory factors were detected by multifactor assay after co-culture.Proteomics was used to detect the differentially expressed proteins of negative control mesenchymal stem cells and erythropoietin-overexpressed umbilical cord mesenchymal stem cells.Cleavage under targets and tagmentation sequencing was applied to detect genomic H3K4me2 modification,and joint analysis was conducted with RNA-sequencing.Lentiviral vector infection was applied to construct the stable knockdown of REST in SH-SY5Y cells.qRT-PCR and western blot assay were performed to detect the expression level of REST.The apoptosis was detected by flow cytometry after co-culture of oxygen-glucose deprivation treatment with erythropoietin-overexpressed umbilical cord mesenchymal stem cells.The expression difference of H3K36me3 group proteins was detected by western blot assay,and transcriptome sequencing was performed to analyze the differentially expressed genes. RESULTS AND CONCLUSION:(1)Compared with the control group,monocyte chemotactic protein 1,interleukin-6,interleukin-18,and interleukin-1 beta,interferon α2,and interleukin-23 levels significantly increased in the cerebrospinal fluid supernatant of patients with ischemic-hypoxic encephalopathy(P<0.01).(2)After co-culturing SH-SY5Y cells with erythropoietin-overexpressed umbilical cord mesenchymal stem cells under ischemia and hypoxia,the expression levels of monocyte chemotactic protein 1 and interleukin-6 were significantly reduced.(3)Analysis of protein network interactions revealed significant downregulation of monocyte chemotactic protein 1,interleukin-6 related regulatory proteins CXCL1 and BGN.(4)Transcriptome sequencing analysis found that pro-inflammatory genes were down-regulated,and functional enrichment of histone modifications,and the expression of transcription factors REST and TET3 significantly up-regulated in the erythropoietin-overexpressed umbilical cord mesenchymal stem cell group compared with the negative control mesenchymal stem cell group.(5)Combined analysis of transcriptome sequencing and cleavage under targets and tagmentation revealed changes in epigenetic levels as well as significant activation of the promoter regions of transcription factors REST and TET3.(6)Stable knockdown REST in SH-SY5Y cells was successfully constructed;the transcript levels of REST mRNA and protein expression were both decreased.(7)After the REST knockdown SH-SY5Y cells were co-cultured with erythropoietin-overexpressed umbilical cord mesenchymal stem cells,apoptosis was significantly increased and H3K36me3 expression was significantly decreased.Transcriptome sequencing results showed that the expression of inflammation-related genes Aldh1l2 and Cth,as well as apoptosis-suppressor genes Mapk8ip1 and Sod2 was reduced at mRNA transcription level(P<0.01).(8)It is concluded that erythropoietin-overexpressed umbilical cord mesenchymal stem cells activated the expression of REST and TET3 by altering the kurtosis of H3K4me2 and upregulated the modification level of H3K36me3,which in turn regulated the expression of inflammation-related genes Aldh1l2 and Cth,as well as apoptosis-suppressor genes Mapk8ip1 and Sod2,and facilitated neuronal survival.

Objective:To evaluate the efficacy of allogeneic hematopoietic stem cell transplantation for the treatment of combined immunodeficiency (CID) and explore prognostic risk factors.Methods:In this retrospective cohort study, clinical characteristics, laboratory tests and prognosis of 73 CID children who underwent allogeneic hematopoietic stem cell transplantation from February 2014 to April 2022 in the Children′s Hospital of Fudan University were analyzed. Based on the subtypes of diseases, all patients were divided into severe combined immunodeficiency disease (SCID) group and other CID group. Based on the types of donors, all patients were divided into matched sibling donor group, matched unrelated donor group, unrelated cord blood group, and haploidentical donor group. Kaplan-Meier method and Log-Rank test were used to analyze the survival data. Cox regression was used to analyze prognostic factors.Results:Among the 73 patients, there were 61 (84%) males and 12 (16%) females. Fifty-five (75%) patients were SCID, and 18 (25%) patients were other CID. Donor source included 2 (3%) matched sibling donors (MSD), 3 (4%) matched unrelated donors (MUD), 64 (88%) unrelated cord blood (UCB), and 4 (5%) haploidentical donors. The age at transplant was 10.7 (5.9, 27.5) months, and the follow-up time was 36.2 (2.5, 62.9) months. The 3-year overall survival rate of 73 patients with CID was (67±6) %. No significant difference was found in the 3-year overall survival rates between patients with SCID (55 cases) and other CID (18 cases) ((64±7) % vs. (78±10) %, χ2=1.31, P=0.252). And no significant difference was found in the 3-year overall survival rates among patients who received MSD or MUD (5 cases), UCB (64 cases), and haploidentical donor (4 cases) transplant (100% vs. (66±6)% vs. (50±25) %, χ2=2.30, P=0.317). Cox regression analysis showed that the medical history of sepsis ( HR=2.55, 95% CI 1.05-6.20, P=0.039) and hypoalbuminemia at transplant ( HR=2.96, 95% CI 1.14-7.68, P=0.026) were independent risk factors for the prognosis of allogeneic hematopoietic stem cell transplantation in pediatric patients with CID. Conclusions:Allogeneic hematopoietic stem cell transplantation is an effective treatment for CID. The medical history of sepsis and hypoalbuminemia at transplant were risk factors for prognosis. Enhancing infection prevention and nutritional intervention before transplant can improve patient prognosis.

Objective To develop an expert consensus on subcutaneous injection for allergen-specific immunotherapy.Methods Relevant domestic and intemational literature was reviewed,and nursing experts who had experiences in subcutaneous injection of allergen-specific immunotherapy were interviewed to form the initial draft of the consensus.A total of 85 experts from 42 hospitals nationwide were invited to participate in discussions.2 rounds of expert consultations,adjustments,revisions,and improvements were made to the initial draft,and an online meeting was held to form the final version of the consensus.The content approved by more than 75％of the expert group is adopted,or it will be discussed or deleted.Results The expert consensus includes operational standards for subcutaneous injection of allergen-specific immunotherapy,identification and management of adverse reactions,and health education.Conclusion The consensus demonstrates strong scientific rigor and practicality,providing guidance for nursing practices in the field of clinical allergology.

Pleomorphic adenoma (PA) is the most common benign tumour in the salivary gland and has high morphological complexity. However, the origin and intratumoral heterogeneity of PA are largely unknown. Here, we constructed a comprehensive atlas of PA at single-cell resolution and showed that PA exhibited five tumour subpopulations, three recapitulating the epithelial states of the normal parotid gland, and two PA-specific epithelial cell (PASE) populations unique to tumours. Then, six subgroups of PASE cells were identified, which varied in epithelium, bone, immune, metabolism, stemness and cell cycle signatures. Moreover, we revealed that CD36⁺ myoepithelial cells were the tumour-initiating cells (TICs) in PA, and were dominated by the PI3K-AKT pathway. Targeting the PI3K-AKT pathway significantly inhibited CD36⁺ myoepithelial cell-derived tumour spheres and the growth of PA organoids. Our results provide new insights into the diversity and origin of PA, offering an important clinical implication for targeting the PI3K-AKT signalling pathway in PA treatment.
Humans ; Adenoma, Pleomorphic/genetics* ; Phosphatidylinositol 3-Kinases ; Proto-Oncogene Proteins c-akt ; Transcriptome ; Myoepithelioma

Objective:To evaluate the value of curative effect in neuromyelitis spectrum disease (NMOSD) based on circulatory function evaluation of intracerebral glymphatic system by using diffusion tensor imaging analysis along the perivascular space.Methods:The clinical and imaging data of 23 patients diagnosed with NMOSD at Tianjin Medical University General Hospital from March 2018 to December 2019 were retrospectively analyzed in this study. The clinical data included expanded disability status scale (EDSS), average relapse rate (ARR) and retinal nerve fiber layer (RNFL) thickness at baseline and 1 year follow-up after treatment. Among the 23 NMOSD patients, there were 22 females and 1 male, aged from 21 to 71 (45±13) years old. All the patients underwent MR scans at both baseline and 1 year after treatment, and the scanning sequences included cerebral 3D-T 1WI, T 2WI, diffusion tensor imaging and cervical spinal sagittal 3D-T 2WI, and the cervical spinal cord volume and bilateral diffusion tensor imaging analysis along the perivascular space index (ALPS index) were calculated. The partial correlation test was used to analyze the correlations between ALPS index and the clinical indicators such as EDSS, ARR, and bilateral RNFL, with the control variables as gender, age, years of education and course of disease. The multiple linear regression model was used to analyze the independent predictors for ALPS index and EDSS after treatment. Receiver operating characteristic curve (ROC) and area under the curve (AUC) were used to evaluate the diagnostic value of NMOSD treatment outcome by using ALPS index. Results:When controlling for gender, age, years of education and course of disease, there were significant negative correlations between right ALPS index and EDSS ( r=-0.50, P=0.048), bilateral average ALPS index and EDSS ( r=-0.53, P=0.034), left ALPS index and ARR ( r=-0.58, P=0.018), while there was significant positive correlations between right ALPS index and RNFL ( r=0.88, P=0.008) at 1 year follow-up after treatment. Multiple linear regression analysis showed that cervical spinal cord volume was an independent impact factor of bilateral average ALPS indexes (β=0.24, 95%CI 0.10-0.38, P=0.002), and bilateral average ALPS indexes (β=-3.22, 95%CI -5.97--0.48, P=0.024) and right RNFL (β=-0.05, 95%CI -0.08--0.02, P=0.002) at baseline were the independent impact factors of EDSS after treatment. ROC curve analysis showed that the bilateral average ALPS index at baseline had the best efficacy in predicting the curative effect of NMOSD patients with AUC=0.92. Conclusions:After treatment, NMOSD patients with severe clinical disability, high frequency of disease attack, poor visual performance, and severe cervical spinal cord atrophy have more serious impairment of intracerebral glymphatic system circulatory function. The ALPS index could help in predicting the clinical curative effect of NMOSD patients.

Traumatic cerebrospinal fluid leakage commonly presents in traumatic brain injury patients, and it may lead to complications such as meningitis, ventriculitis, brain abscess, subdural hematoma or tension pneumocephalus. When misdiagnosed or inappropriately treated, traumatic cerebrospinal fluid leakage may result in severe complications and may be life-threatening. Some traumatic cerebrospinal fluid leakage has concealed manifestations and is prone to misdiagnosis. Due to different sites and mechanisms of trauma and degree of cerebrospinal fluid leak, treatments for traumatic cerebrospinal fluid leakage varies greatly. Hence, the Craniocerebral Trauma Professional Group of Neurosurgery Branch of Chinese Medical Association and the Neurological Injury Professional Group of Trauma Branch of Chinese Medical Association organized relevant experts to formulate the " Chinese expert consensus on the diagnosis and treatment of traumatic cerebrospinal fluid leakage in adults ( version 2023)" based on existing clinical evidence and experience. The consensus consisted of 16 recommendations, covering the leakage diagnosis, localization, treatments, and intracranial infection prevention, so as to standardize the diagnosis and treatment of traumatic cerebrospinal fluid leakage and improve the overall prognosis of the patients.

Objective:To investigate the effects of pre-pregnancy health examination combined with standardized health care during pregnancy on the pregnancy outcome at advanced maternal age.Methods:A total of 300 pregnant women who visited the Perinatal Clinic of the First Affiliated Hospital, School of Medicine, Shihezi University, China who received treatment between September 2018 and September 2019 were included in this study. They were divided into three groups according to pre-pregnancy health examination and heath care during pregnancy. In the observation group ( n = 78), pregnant women received pre-pregnancy health examination and health care during pregnancy on time and regularly. In the control group 1 ( n = 110): pregnant women did not receive pre-pregnancy health examination or regular health care during pregnancy. In the control group 2 ( n = 112), pregnant women received pre-pregnancy health examination or regular heath care during pregnancy. The pregnancy outcome was compared among three groups. The pre-pregnancy health examination and regular health care during pregnancy in women at advanced maternal age were correlated with gestational hypertension, gestational diabetes mellitus, premature delivery and other pregnancy risks. Results:There were significant differences in premature delivery (20.5%, 9.8%, 2.7%), gestational hypertension (23.1%, 12.5%, 3.6%), gestational diabetes mellitus (19.2%, 8.9%, 2.7%), premature rupture of membrane (17.9%, 10.7%, 3.6%), postpartum hemorrhage (12.8%, 8.0%, 1.8%), gestational anemia (19.2%, 8.0%, 2.7%) and placental abruption (7.7%, 8.0%, 0.9%) among control group 1, control group 2, and observation group ( χ2 = 16.047, 16.376, 14.724, 10.489, 8.781, 15.380, 6.744, all P < 0.05). The rate of cesarean section rate in the control group 1, control group 2, and observation group was statistically significant (70.5%, 44.6% and 27.3%, χ2 = 34.468, P < 0.05). There were significant differences in the incidence rates of macrosomia (15.4%, 8.9%, 2.7%), low birth weight infants (11.5%, 5.4%, 0.0%), stillbirth or late-term abortion (10.3%, 4.7%, 0.9%), neonatal asphyxia (16.7%, 7.1%, 1.8%) among the control group 1, control group 2 and observation group ( χ2 = 9.654, 12.840, 8.979, 14.284, all P < 0.05). Conclusion:The risk of adverse pregnancy outcomes is increased at advanced maternal age. Pre-pregnancy health examination combined with standardized health care during pregnancy can improve the pregnancy outcomes at advanced maternal age.

Objective:To evaluate the efficacy and safety of unrelated umbilical cord blood stem cell transplantation (UCBT) with reduced-intensity conditioning regimens in the treatment of hyper-IgM syndrome (HIGM) caused by CD40 ligand gene (CD40LG) mutation.Methods:Clinical features, laboratory data and treatment prognosis of 3 patients with HIGM caused by CD40LG mutation treated with UCBT in Children′s Hospital of Fudan University from May 2018 to August 2019 were analyzed retrospectively. The literature search was conducted with "CD40 ligand deficiency" and "hematopoietic stem cell transplantation" as keywords at China National Knowledge Infrastructure, Wanfang, Weipu and Pubmed databases (up to February 2021) to summarize donor selection, stem cell source, conditioning regimen and prognostic factors of this disease.Results:Three boys with recurrent respiratory tract infection were diagnosed as HIGM with CD40LG mutation. The age of UCBT was 1.0, 1.4 and 0.5 years respectively. Reduced-intensity conditioning regimen including busulifan, fludarabine and cyclophosphamide were used in all patients. Human leucocyte antigen matching of patients and umbilical cord blood was 8/10, 10/10 and 9/10 respectively. All patients achieved complete donor chimerism 14 days after UCBT. All patient suffered grade Ⅰ acute skin graft-versus-host disease without other severe complications. Up to the last follow-up, their disease-free survival time were 33, 18, 18 months after transplantation respectively. No reports were found in Chinese journals, while 24 publications were found in English journals. According to the literature, 258 HIGM patients with CD40LG mutation were treated with hematopoietic stem cell transplantation (HSCT). Matched sibling donors (30.6%(79/258)) and unrelated donors (40.3% (104/258)) were main donor types. Bone marrow (50.8%(131/258)) was the main source of grafts, myeloablative conditioning (66.7% (172/258)) was the main conditioning regimen, and the overall survival rate after transplantation was 70.9% (183/258). Lung injury and liver complications before transplantation were adverse factors affecting prognosis. Among the 14 patients who received UCBT, 2 patients suffered from engraftment failure, 2 patients had mixed chimerism and 3 patients died after transplantation.Conclusions:UCBT is safe and effective in the treatment of HIGM caused by CD40LG mutation. Reduced-intensity conditioning regimen is worthy of further study.

Purpose: Gamma-glutamyl transferase (GGT) has been reported as being involved in tumor progression. Previous studies documented a potential relationship between serum GGT level and survival outcome in several types of human malignancies. However, the association between serum GGT levels and response to neoadjuvant chemotherapy (NAC) has not yet been reported. The present study aimed to evaluate the association between pre-therapeutic serum GGT level and the efficacy, long-term survival, and adverse reactions of NAC and to investigate its role in predicting NAC sensitivity in patients with breast cancer. Methods: A total of 129 patients were recruited and stratified into 2 groups according to serum GGT level (< 29 U/L and ≥ 29 U/L). The association between pre-therapeutic serum GGT levels and clinicopathological parameters was examined. The correlation between pre-therapeutic serum GGT levels and pathological complete response (pCR) was analyzed using univariate and multivariate logistic regression. Survival analyses of relapse-free survival (RFS) and disease-free survival (DFS) were performed. Pearson's χ 2 test and multivariate logistic regression model were used to analyze the correlation between pre-therapeutic serum GGT levels and adverse reactions. Results: Pre-therapeutic serum GGT levels were associated with pCR among breast cancer patients treated with NAC. Multivariate analysis showed that low-level GGT significantly increased pCR rate. Patients in the high-level GGT group had poorer survival than those in the low-level GGT group. Subgroup analysis demonstrated that serum GGT level was potentially related to RFS and DFS in the hormone receptor-positive group. Low levels of GGT are significantly associated with a higher incidence of neutropenia. Conclusion Pre-therapeutic serum GGT level is an independent and novel biomarker for predicting the efficiency, prognosis, and adverse reactions to NAC in breast cancer patients.Patients with low pre-therapeutic serum GGT levels are more likely to have higher pCR rates, better RFS and DFS, and higher hematologic toxicity.

Objective:To summarize the surgical methods and experiences of intra-auditory meningioma, and discuss the techniques achieving complete resection of intra-auditory meningioma by retrosigmoid transmeatal approach on the basis of function reservation of the facial nerve and auditory nerve.Methods:The clinical data of 4 patients with intra-auditory meningioma confirmed by surgery and pathology in Xuanwu Hospital of Capital Medical University and Army General Hospital of People's Liberation Army from January 1998 to December 2018 were retrospectively analyzed. All these 4 patients accepted enlargment of the posterior wall of the internal auditory channel via retrosigmoid transmeatal approach to remove the tumors. The electro-audiogram, surgical records, discharge records and follow-up records were noted.Results:Total resection was achieved in all 4 patients; one was derived from the cerebral dura mater of the outside wall of the internal auditory canal, obtaining radical excision (Simpson grading I resection); the other three were derived from the cerebral dura mater of the internal auditory canal, and the epidural adhesion extended to the ventral internal auditory canal, only receiving Simpson grading II resection. The facial nerve and cochlear nerve in three patients were separated and protected by dissection; while the vestibular nerve and cochlear nerve in the left one patient were not found, and only the facial nerve was dissected and preserved. Two patients with preoperative hearing grading H2 and H3 were able to retain effective hearing after surgery, with postoperative hearing grading H3 and H4, respectively; and the other two patients had postoperative hearing grading H5. Postoperative Karnofsky Performance Scale (KPS) scores were 90 in 3 patients and 70 in one patient. There was no perioperative death.Conclusions:Retrosigmoid transmeatal approach is ideal approach for resection of the intra-auditory meningioma. Surgical excision of intra-auditory meningioma should accept the premise of protecting the facial auditory nerve and aim at extensive resection of tumors, including the dura and bone involved by tumors, so as to reduce the chance of recurrence; and it is necessary to open the width of intra-auditory.