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Type 2 Diabetes (T2D) is a chronic inflammatory disease characterized by inflamed adipose tissue. Patients with triple negative breast cancer (TNBC) and comorbid T2D have higher risk of metastasis and shorter survival. However, mechanisms that couple T2D to TNBC outcomes are unknown. Here we hypothesize that exosomes, small vesicles secreted by tumor microenvironment breast adipocytes, drive epithelial-to-mesenchymal transition (EMT) in TNBC, immune exhaustion and metastasis via Ampk-Akt signaling.Methods: Exosomes were purified from conditioned media of 3T3-L1 mature adipocytes that were insulin-sensitive (IS) or insulin-resistant (IR), then characterized and quantified by NanoSight and surface markers, CD63. Murine 4T1 cells, a TNBC model, were treated with exosomes in vitro (3 days). To establish 3D organoids, 4T1 spheroids were treated with exosomes and embedded in Matrigel. For in vivo models, mammary fat pads of BALB/c mice were injected with 4T1 cells treated with IS vs IR exosomes. 4T1 tumors were harvested and mRNA extracted for qPCR, RNAseq, and Ingenuity Pathway Analysis. Metastatic sites in lung and liver were visualized by H&E staining and clonogenic assay. Immune exhaustion markers of tumor infiltrated lymphocytes (TILs) were measured by flow cytometry. Results: In 4T1 cells treated with IR exosomes, EMT was upregulated and PD-L1 expression increased. Tumor-bearing mice exhibited metastasis in exosome-treated groups, visualized by microscopy and clonogenic assay. Immune exhaustion markers showed modified expression in TILs from exosome-treated groups. RNA-seq analysis revealed differences among exosome-treated groups that suggest dysregulated Ampk-Akt pathways.Conclusion: Exosomes from IR adipocytes modify the tumor microenvironment, increase EMT and immune exhaustion markers on tumor cells and TILs, and promote metastasis to distant organs through Ampk-Akt. Metabolic diseases such as T2D reshape the TNBC tumor microenvironment, promoting metastasis and decreasing survival. Clearly, TNBC patients with T2D should be more closely monitored for metastasis than metabolically normal patients, with metabolic medications considered. Citation Format: Yuhan Qiu, Conor Ross, Naser Jafari, Manohar Kolla, Pablo Llevenes, Christina Ennis, Carla S Mazzeo, Kiana Mahdaviani, Naomi Y Ko, Gerald V Denis. Exosomes produced by adipocytes induce EMT, immune exhaustion and tumor metastasis, in both in vivo and in vitro models of TNBC [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-06-02.

Objective Neuromyelitis optica spectrum disorder (NMOSD) is a rapidly disabling disease. Epidemiologic studies have suggested varying NMOSD mortality across ethnic groups. However, NMOSD mortality data in China are scarce. This study’s objectives were to explore mortality and causes of death among Chinese NMOSD patients and to identify independent predictors of death. Methods We performed a retrospective study with a 10‐year follow‐up of Chinese NMOSD patients. A Cox proportional hazards model was used to identify independent predictors of death. Results Five hundred and sixty‐nine patients were included; 24 patients died during follow‐up, for overall mortality of 4.2%. In these patients, the median disease duration at the time of death was 3.4 years. The most common cause of death was secondary infection (62.5%), especially respiratory infection (45.8%). The second most common cause of death was extensive cervical myelitis with respiratory failure (16.7%). Other causes included suicide (8.3%), cancer (4.2%), cerebral embolism (4.2%), and unknown causes (4.2%). The multivariate Cox analyses indicated that a short first interattack interval (HR = 0.93, 95% CI 0.89–0.98, p = 0.003), lack of regular immunotherapy (HR = 10.34, 95% CI 4.05–26.37, p

Mitophagy is a selective form of macroautophagy in which dysfunctional and damaged mitochondria can be efficiently degraded, removed and recycled through autophagy. Selective removal of damaged or fragmented mitochondria is critical to the functional integrity of the entire mitochondrial network and cells. In past decades, numerous studies have shown that mitophagy is involved in various diseases; however, since the dual role of mitophagy in tumour development, mitophagy role in tumour is controversial, and further elucidation is needed. That is, although mitophagy has been demonstrated to contribute to carcinogenesis, cell migration, ferroptosis inhibition, cancer stemness maintenance, tumour immune escape, drug resistance, etc. during cancer progression, many research also shows that to promote cancer cell death, mitophagy can be induced physiologically or pharmacologically to maintain normal cellular metabolism and prevent cell stress responses and genome damage by diminishing mitochondrial damage, thus suppressing tumour development accompanying these changes. Signalling pathway-specific molecular mechanisms are currently of great biological significance in the identification of potential therapeutic targets. Here, we review recent progress of molecular pathways mediating mitophagy including both canonical pathways (Parkin/PINK1- and FUNDC1-mediated mitophagy) and noncanonical pathways (FKBP8-, Nrf2-, and DRP1-mediated mitophagy); and the regulation of these pathways, and abovementioned pro-cancer and pro-death roles of mitophagy. Finally, we summarise the role of mitophagy in cancer therapy. Mitophagy can potentially be acted as the target for cancer therapy by promotion or inhibition.

Objective Our study aimed to investigate circulating CD8+ T cell subpopulations and pro-inflammatory cytokines in the neuromyelitis optica spectrum disorder (NMOSD). Methods A total of 121 peripheral blood samples were obtained from 57 patients with NMOSD, 34 patients with multiple sclerosis (MS), and 30 sex- and age-matched healthy controls (HCs) for detection of CD8+ T cell subpopulations, including phenotypes of naive (TN , CD62Lhi CD45RO- ), effector/memory (TE/M , CD62Llo CD45RO+ ), memory precursor (TMP , CD127hi KLRG1lo ), and short lived effector (TSLEC , CD127lo KLRG1hi ). In addition, 36 samples from 18 NMOSD, 12 MS, and 6 sex- and age-matched HCs for detecting pro-inflammatory cytokines (IFNγ and TNFα) using flow cytometry. Results Compared with HCs, we found significantly reduced CD8+ TN and increased CD8+ TE/M in both NMOSD and MS，while decreased CD8+ TMP was only observed in NMOSD. Patients treated with immunotherapy were associated with increased CD8+ TN and decreased CD8+ TE/M in NMOSD. Moreover NMOSD cohort showed significant higher proportions of IFNγ+ CD8+ T cells and proportions of TNFα+ CD8+ T cells than HC and MS cohorts. On the contrary, obviously decreased IFNγ and TNFα were found in NMOSD patients treated with immunotherapy. Furthermore, Multivariate linear regression analyses revealed that age was negatively correlated with CD8+ TN and TMP , and positively associated with TSLEC ; however, sex, EDSS scores and disease phase were not significantly associated with CD8+ T subpopulations. Interpretation This current study provides an evidence that circulating CD8+ T cell with abnormal subpopulations and increased pro-inflammatory were associated with pathogenesis of autoimmune demyelinating disease of CNS, especially in NMOSD.

Nanomedicines (NMs) have played an increasing role in cancer therapy as carriers to efficiently deliver therapeutics into tumor cells. For this application, the uptake of NMs by tumor cells is usually a prerequisite to deliver the cargo to intracellular locations, which mainly relies on endocytosis. NMs can enter cells through a variety of endocytosis pathways. Different endocytosis pathways exhibit different intracellular trafficking routes and diverse subcellular localizations. Therefore, a comprehensive understanding of endocytosis mechanisms is necessary for increasing cellular entry efficiency and to trace the fate of NMs after internalization. This review focuses on endocytosis pathways of NMs in tumor cells, mainly including clathrin- and caveolae-mediated endocytosis pathways, involving effector molecules, expression difference of those molecules between normal and tumor cells, as well as the intracellular trafficking route of corresponding endocytosis vesicles. Then, the latest strategies for NMs to actively employ endocytosis are described, including improving tumor cellular uptake of NMs by receptor-mediated endocytosis, transporter-mediated endocytosis and enabling drug activity by changing intracellular routes. Finally, active targeting strategies towards intracellular organelles are also mentioned. This review will be helpful not only in explicating endocytosis and the trafficking process of NMs and elucidating anti-tumor mechanisms inside the cell but also in rendering new ideas for the design of highly efficacious and cancer-targeted NMs.

Sophoridine is a quinolizidine natural product and the exploration of its derivatives has been carried out, and the potent anticancer compound IMB-HDC was acquired. Although previous studies have revealed that some sophoridine derivatives could induce DNA breakage, the underlying mechanisms of inhibition of DNA damage repair (ATR inactivation) and the apoptosis independent of p53, have not been elucidated. Our research reveals a novel DNA response mechanism different from general DNA-damaging agents, and that sophoridine derivate inhibits the phosphorylation of Tyr694 and Ser780 of STAT5a to induce the lessened shuttle from the cytoplasm to the nucleus, and leads to the decreased nuclear STAT5a and subsequently inhibits the expression of STAT5a target gene RAD51 that contributes to the checkpoint activation, thus inhibiting ATR activation. Meanwhile, IMB-HDC that induced the diminished expression of STAT5a target gene contributes to proliferation and leads to apoptosis. More importantly, we give the first evidence that promoting the effect of Tyr694 phosphorylation on nuclear location and subsequent STAT5a target gene transcription depends on Ser780 increased or unchanged phosphorylation and was not correlated with Ser726 phosphorylation.

Background. Preeclampsia (PE) is associated with insufficient placental perfusion attributed to maldevelopment of the placental vasculature. Reactive oxygen species (ROS) are implicated in angiogenesis, but their regulatory effects and mechanisms in placental vascular development remain unclear. Methods. Placental oxidative stress was determined throughout gestation by measuring 4-hydroxynonenal (4HNE) and malondialdehyde (MDA). The antioxidant MitoQ was administered to pregnant mice from GDs 7.5 to 11.5; placental morphology and angiogenesis pathways were examined on GDs 11.5 and 18.5. Moreover, we established a mouse mFlt-1-induced PE model and assessed blood pressure, urine protein levels, and placental vascular development on GDs 11.5 and 18.5. Human umbilical vein endothelial cells (HUVECs) were treated with various H2O2 concentrations to evaluate cell viability, intracellular ROS levels, and tube formation capability. MitoQ, an AKT inhibitor and an ERK1/2 inhibitor were applied to validate the ROS-mediated mechanism regulating placental angiogenesis. Results. First-trimester placentas presented significantly higher MDA and 4HNE levels. MitoQ significantly reduced the blood vessel density and angiogenesis pathway activity in the placenta on GDs 11.5 and 18.5. Serum sFlt-1 levels were elevated, and we observed poor placental angiogenesis and PE-like symptoms in cases with mFlt-1 overexpression. Moderate H2O2 treatment promoted HUVEC proliferation and angiogenesis, whereas these improvements were abolished by MitoQ, AKT inhibitor, or ERK1/2 inhibitor treatment. Conclusions. Moderate ROS levels are essential for placental angiogenesis; diminishing ROS with potent antioxidants during placentation decreases placental angiogenesis and increases PE risk. Therefore, antioxidant therapy should be considered carefully for normal pregnant women during early gestation.

Obesity and metabolic diseases, such as insulin resistance and type 2 diabetes (T2D), are associated with metastatic breast cancer in post-menopausal women. Here, we investigated the critical cellular and molecular factors behind this link. We found that primary human adipocytes shed extracellular vesicles—specifically exosomes—that induced the expression of genes associated with epithelial-to-mesenchymal transition (EMT) and cancer stem-like cell (CSC) traits in cocultured breast cancer cell lines. Transcription of these genes was further increased in cells exposed to exosomes shed from T2D patient-derived adipocytes or insulin-resistant adipocytes and required the epigenetic reader proteins BRD2 and BRD4 in recipient cells. The thrombospondin family protein TSP5, which is associated with cancer, was more abundant in exosomes from T2D or insulin-resistant adipocytes and partially contributed to EMT in recipient cells. Bioinformatic analysis of breast cancer patient tissue showed that greater co-expression of COMP (which encodes TSP5) and BRD2 or BRD3 correlated with poorer prognosis, specifically decreased distant metastasis-free survival. Our findings reveal a mechanism of exosome-mediated crosstalk between metabolically abnormal adipocytes and breast cancer cells that may promote tumor aggressiveness in T2D patients.

Neuromyelitis optica spectrum disorder (NMOSD), a relapsing autoimmune demyelinating disease of the CNS, often leads to severe visual and/or motor disability. This study aimed to evaluate the long-term effects of the first-line immunotherapies on relapse and disability, and identify the prognostic predictors in NMOSD. In this prospective cohort study, we enrolled patients with NMOSD from Southwest China and performed a long-term follow-up. We compared no immunotherapies (NIT) versus treatment of mycophenolate mofetil (MMF), azathioprine (AZA), or only corticosteroid (CS). Cox proportional-hazards model was used to explore the prognostic predictors in NMOSD. Ultimately, 281 patients were enrolled during 2009 to 2017. The proportions of relapse, motor disability, and mortality were significantly lower in treatments of MMF and AZA than in NIT (all P

In recent years, the rate of colorectal cancer has sharply increased, especially in China, where it ranks second for the number of cancer fatalities. Currently, the treatment of colorectal cancer patients involves the combination of resection surgery and treatment with postoperative anticancer drugs such as 5-FU and oxaliplatin. However, recurrence and metastasis after treatment are still the dominant reasons for the low survival rate. Colorectal cancer stem cells (CSCs) are regarded as the key contributors to tumour recurrence and metastasis due to their resistance to chemotherapy drugs and their extremely high tumourigenicity. Once CSCs overcome chemotherapy treatment, they continue to survive and reinitiate proliferation to form tumours, leading to recurrence. The dominant reason for CSC resistance is that most anticancer drugs are aimed at inhibiting proliferative pathways in cancer cells that differ from those in CSCs. Therefore, studies on the characteristics of CSCs and their intracellular molecular pathways are essential for the exploration of CSC-targeted drugs. In this report, we review recent advances in the research of CSCs and, in particular, review the important intracellular molecular pathways, such as HOXA5-catenin, STRAP-NOTCH and YAP/TAZ, related to the maintenance and differentiation of stem cells to generate a theoretical basis for the exploration of CSC-targeted drugs.

Pancreatic adenocarcinoma (PAAD) is one of the most lethal malignancies. Although gemcitabine (GEM) is a standard treatment for PAAD, resistance limits its application and therapy. Secoemestrin C (Sec C) is a natural compound from the endophytic fungus Emericella, and its anticancer activity has not been investigated since it was isolated. Our research is the first to indicate that Sec C is a broad-spectrum anticancer agent and could exhibit potently similar anticancer activity both in GEM-resistant and GEM-sensitive PAAD cells. Interestingly, Sec C exerted a rapid growth-inhibiting effect (80% death at 6 h), which might be beneficial for patients who need rapid tumor shrinkage before surgery. Liquid chromatography/mass spectrometry and N-acetyl-l-cysteine (NAC) reverse assays show that Sec C sulfates cysteines to disrupt disulfide-bonds formation in endoplasmic reticulum (ER) proteins to cause protein misfolding, leading to ER stress and disorder of lipid biosynthesis. Microarray data and subsequent assays show that ER stress-mediated ER-associated degradation (ERAD) ubiquitinates and downregulates YAP to enhance ER stress via destruction complex (YAP–Axin–GSK–βTrCP), which also elucidates a unique degrading style for YAP. Potent anticancer activity in GEM-resistant cells and low toxicity make Sec C a promising anti-PAAD candidate., Graphical abstract Secoemestrin C sulfates endoplasmic reticulum (ER) cysteines to disrupt disulfide-bonds formation in ER proteins, causing ER stress. Meanwhile, ER stress is cooperatively enhanced by ERAD-induced YAP degradation via YAP–Axin–GSK–βTrCP complex formation.Image 1

Breast cancer is the most commonly diagnosed cancer among women. Although routine and targeted therapies have improved the survival rate, there are still considerable challenges in the treatment of breast cancer. Metastasis is the leading cause of death in patients diagnosed with breast cancer. Yes-associated protein (YAP) and/or PDZ binding motif (TAZ) are usually abnormally activated in breast cancer leading to a variety of effects on tumour promotion, such as epithelial-mesenchymal transition, cancer stem cell production and drug-resistance. The abnormal activation of YAP/TAZ can affect metastasis-related processes and promote cancer progression and metastasis by interacting with some metastasis-related factors and pathways. In this article, we summarise the evidence that YAP/TAZ regulates breast cancer metastasis, its post-translational modification mechanisms, and the latest advances in the treatment of YAP/TAZ-related breast cancer metastasis, besides providing a new strategy of YAP/TAZ-based treatment of human breast cancer.

Background At present, patients positive for aquaporin-4 antibody (AQP4-Ab) or myelin oligodendrocyte glycoprotein antibody (MOG-Ab) are diagnosed as neuromyelitis optica spectrum disorder (NMOSD) and MOG-Ab-associated diseases, respectively. However, some patients who meet the diagnostic criteria for NMOSD and show demyelination of the central nervous system cannot be clearly classified. Methods We performed a prospective cohort study to evaluate the clinical characteristics and prognoses of double-seronegative patients with NMOSD. Results A total of 594 patients were included in the cohort, including 26 patients with MOG-Ab, 517 with AQP4-Ab, and 51 with double seronegativity. Compared to AQP4-Ab-positive patients, double-seronegative patients experienced less severe clinical attacks (51.0% vs. 78.1%; Pcorr Conclusions In patients who met the diagnostic criteria for NMOSD, compared with AQP4-Ab-seropositive patients, double-seronegative and MOG-Ab-seropositive patients had less severe clinical attacks and better prognoses, including lower EDSS scores and a lower proportion of disability.

Nanomedicines (NMs) have played an increasing role in cancer therapy as carriers to efficiently deliver therapeutics into tumor cells. For this application, the uptake of NMs by tumor cells is usually a prerequisite to deliver the cargo to intracellular locations, which mainly relies on endocytosis. NMs can enter cells through a variety of endocytosis pathways. Different endocytosis pathways exhibit different intracellular trafficking routes and diverse subcellular localizations. Therefore, a comprehensive understanding of endocytosis mechanisms is necessary for increasing cellular entry efficiency and to trace the fate of NMs after internalization. This review focuses on endocytosis pathways of NMs in tumor cells, mainly including clathrin- and caveolae-mediated endocytosis pathways, involving effector molecules, expression difference of those molecules between normal and tumor cells, as well as the intracellular trafficking route of corresponding endocytosis vesicles. Then, the latest strategies for NMs to actively employ endocytosis are described, including improving tumor cellular uptake of NMs by receptor-mediated endocytosis, transporter-mediated endocytosis and enabling drug activity by changing intracellular routes. Finally, active targeting strategies towards intracellular organelles are also mentioned. This review will be helpful not only in explicating endocytosis and the trafficking process of NMs and elucidating anti-tumor mechanisms inside the cell but also in rendering new ideas for the design of highly efficacious and cancer-targeted NMs.

Background Sex-specific differences in multiple sclerosis (MS) have been recognized, but few were known about how sex influences the characteristics of MS in Asian and the social burden of MS. This study aimed to investigate the symptoms, mental health, and social functions of Chinese MS patients and find differences between sexes. Methods MS patients were enrolled from January 2004 to September 2018. A questionnaire was distributed by 47 medical centers. Patients' physical symptoms, negative emotions, interpersonal communication, social intercourse, employment condition, and suicidal thoughts and behavior were collected. Patients were asked to fill in the questionnaire independently and undergo Expanded Disability Status Scale (EDSS) measurement. Unpaired t-tests between sexes were conducted for normally distributed continuous variables. Mann-Whitney u-tests were conducted for non-normally distributed data. Chi-square tests, Fisher exact tests and rank sum tests were performed for categorical variables. Results 931 patients were enrolled and 631 were female. Frequency of fatigue and pain were higher in female MS patients (P

OBJECTIVES: A single nucleotide polymorphism (SNP) in the transcription factor 7 like 2 (TCF7L2) gene is strongly associated with Type 2 Diabetes (T2D), and deletion of this SNP has been shown to reduce long chain acyl-CoA synthetase 5 (ACSL5) mRNA level. Previous research in our lab has shown chronic exposure to excess nutrients (glucose and fatty acid (FA)) increases lipid droplets in beta-cells and causes basal insulin hypersecretion, left-shifted glucose-stimulated insulin secretion (GSIS), blunted maximal GSIS and reduced insulin content. We tested the efficacy of a known phenylpyrazole-carboxamide compound (herein named ADIPO C) to reduce accumulation of intracellular lipid droplets and reverse the left-shift of GSIS in beta-cells. METHODS: INS-1832/13 cells were cultured in RPMI media containing 10% FBS (source of FA) and either 4 or 11 mM glucose. Insulin was measured by HTRF assay (CisBio). Intracellular lipid was detected by fluorescence microscopy using Nile red. Fluorescent Bodipy-FA was used as a surrogate FA in both ACS activity assays and lipid incorporation into cells. Oxygen consumption rate was measured using the Seahorse ion flux analyzer and intracellular calcium was measured in fura 2 loaded cells mounted on an Olympus confocal microscope. RESULTS: Adipo C (10–25 µM) acutely inhibited acyl-CoA synthetase activity by up to 40% in cell homogenates and similarly reduced FA incorporation into neutral lipids in INS-1 (832/13) cells measured using thin layer chromatography. Longer exposure (72 hrs) to ADIPO C significantly decreased intracellular lipid droplets, right-shifted GSIS and increased insulin content in cells cultured in excess nutrients. Cells cultured in excess nutrients exhibited both increased basal oxygen consumption rate and intracellular calcium oscillations, which were both reduced with 72 hrs ADIPO C incubation. CONCLUSIONS: Based on these results, we conclude that Adipo C has a protective effect on beta-cells exposed to a glucolipotoxic environment and thus may prove to have therapeutic potential in the prevention/treatment of T2D. FUNDING SOURCES: No funding sources to report.

Muscle damage has been found in patients with neuromyelitis optica spectrum disorder (NMOSD), but whether this damage is related to aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) is uncertain. The aim of this study was to investigate the relationship between AQP4-IgG and muscle damage.From January 2009 to May 2019, we prospectively screened 1209 Chinese Han patients with acute transverse myelitis (ATM). Ultimately, we included 203 ATM patients in the cohort study and compared log serum creatine kinase (sCK) levels between positive and negative AQP4-IgG statuses.Among all ATM patients, the mean log sCK levels of AQP4-IgG-positive patients were higher than those of AQP4-IgG-negative patients (4.46 ± 0.10 vs. 4.16 ± 0.06, p 0.001). In addition, among ATM patients diagnosed with NMOSD, the mean log sCK levels of AQP4-IgG-positive patients were higher than those of AQP4-IgG-negative patients (4.46 ± 0.10 vs. 4.05 ± 0.13, p = 0.025). The number of extremely high sCK values (sCK values 300 IU/L) was significantly higher in ATM patients positive for AQP4-IgG than in those negative for AQP4-IgG (p = 0.020). Furthermore, multivariable linear regression model analysis showed that male sex (coefficient [95% CI] = 0.548 [0.286, 0.809], p 0.001), serum AQP4-IgG (coefficient [95% CI] = 0.462 [0.237, 0.687], p 0.001), and combined connective tissue disease (CTD) (coefficient [95% CI] = -0.686 [-1.145, -0.226], p = 0.004) were independent predictors of log sCK levels.Our study suggests that muscle damage in NMOSD patients may be associated with AQP4-IgG.

Myasthenia gravis (MG) is an autoimmune disease that causes fatigueable muscle weakness. Sexual dysfunction (SD) is a common condition, but the association between SD and MG remains poorly understood.An observational study was conducted to explore SD incidence and risk factors in MG patients. The study enrolled 158 MG patients and 161 age- and sex-matched healthy individuals. SD was investigated using the Female Sexual Function Inventory (FSFI), the abridged International Index of Erectile Function-5 (IIEF-5), and the Chinese Index of Premature Ejaculation-5 (CIPE-5). The mental health was evaluated using Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA).A total of 52 male patients and 106 female patients were finally included. The average age of these patients was 41.82 ± 10.44 years. The incidence of female SD was significantly higher in MG patients (48.11%) than in healthy people (22.64%) (P 0.001). The incidence of SD in male MG patients was also higher. Age and depression were significantly correlated with decreased libido, wakefulness, lubrication, orgasm, and satisfaction scores, indicating that these are risk factors for SD. Age (OR:1.13, CI%:1.06-1.21, P 0.001) and HAMD scores (OR:1.53, CI%:1.0-2.13, P = 0.011) are independent risk factors for SD of MG patients.SD is a common problem in MG, and its severity does not change with the severity of the disease. Age and depression are risk factors for sexual dysfunction.

Objective Our study aimed to investigate circulating CD8+ T cell subpopulations and pro‐inflammatory cytokines in the neuromyelitis optica spectrum disorder (NMOSD). Methods A total of 121 peripheral blood samples were obtained from 57 patients with NMOSD, 34 patients with multiple sclerosis (MS), and 30 sex‐ and age‐matched healthy controls (HCs) for detection of CD8+ T cell subpopulations, including phenotypes of naïve (TN, CD62LhiCD45RO‐), effector/memory (TE/M, CD62LloCD45RO+), memory precursor (TMP, CD127hiKLRG1lo), and short lived effector (TSLEC, CD127loKLRG1hi). In addition, 36 samples from 18 NMOSD, 12 MS, and 6 sex‐ and age‐matched HCs for detecting pro‐inflammatory cytokines (IFNγ and TNFα) using flow cytometry. Results Compared with HCs, we found significantly reduced CD8+ TN and increased CD8+ TE/M in both NMOSD and MS，while decreased CD8+ TMP was only observed in NMOSD. Patients treated with immunotherapy were associated with increased CD8+ TN and decreased CD8+ TE/M in NMOSD. Moreover NMOSD cohort showed significant higher proportions of IFNγ+CD8+ T cells and proportions of TNFα+CD8+ T cells than HC and MS cohorts. On the contrary, obviously decreased IFNγ and TNFα were found in NMOSD patients treated with immunotherapy. Furthermore, Multivariate linear regression analyses revealed that age was negatively correlated with CD8+ TN and TMP, and positively associated with TSLEC; however, sex, EDSS scores and disease phase were not significantly associated with CD8+ T subpopulations. Interpretation This current study provides an evidence that circulating CD8+ T cell with abnormal subpopulations and increased pro‐inflammatory were associated with pathogenesis of autoimmune demyelinating disease of CNS, especially in NMOSD.

Sexual dysfunction (SD) is a common but poorly understood symptom in patients with neuromyelitis optica spectrum disorder (NMOSD). The study was designed to compare SD between NMOSD patients and healthy controls (HCs), and to investigate factors that influenced SD in NMOSD patients.The study enrolled 102 sexually active NMOSD patients and 110 HCs. SD was investigated with the Female Sexual Function Inventory (FSFI), the abridged International Index of Erectile Function-5 (IIEF-5) and the Chinese Index of Premature Ejaculation-5 (CIPE-5). Disability, lower urinary tract dysfunction (LUTD), fatigue, depression and anxiety were also evaluated.The prevalence of SD, including female sexual dysfunction (FSD), erectile dysfunction (ED), and premature ejaculation (PE), was significantly higher in NMOSD patients than in HCs (P .01). The FSFI, IIEF-5 and CIPE-5 scores were all significantly lower in NMOSD patients than in HCs (P .01). Correlation analysis showed that SD was strongly correlated with age, age at onset, disability, LUTD, fatigue, depression and anxiety (P .05). Regression analysis further revealed that age at onset (OR = 1.057, P = .036), disability (OR = 1.591, P = .011), and depression (OR = 1.111, P = .041) were independent predictors of FSD in NMOSD patients.This study provided evidence that SD is a common problem in NMOSD patients and that age at onset, disability, and depression are independent predictors of FSD. More attention should be paid to SD in patients with NMOSD.

Accumulating evidence points to an association of alternations in the gut microbiota with health and disease, including the development of neurological diseases. However, there are relatively scarce studies of the role of the gut microbiota in neuromyelitis optica spectrum disorders (NMOSD). Therefore, the aim of the present study was to evaluate the differences in the intestinal microbiota composition between patients with NMOSD and healthy control subjects.This was a cross-sectional study. Stool samples were obtained from 20 patients with NMOSD and 20 healthy family members of the patients as controls (HC). The bacterial 16S rRNA gene amplification sequencing (V3-V4 region) was used to detect the composition and structure of the intestinal microbiota community in the two groups.The gut microbiota compositions clearly differed between the NMOSD and HC groups, although there was no significant difference in the overall microbial community structure. In detail, patients with NMOSD had an increased abundance of the pathogenic genera Flavonifractor (P = .004) and Streptococcus (P = .007) compared with the HC. In addition, several intestinal commensal bacteria were detected at significantly lower abundance in the NMOSD patients compared to the controls, including Faecalibacterium, Lachnospiracea_incertae_sedis, Prevotella, Blautia, Roseburia, Romboutsia, Coprococcus, and Fusicatenibacter (all P .05). ROC curve analysis suggested that gut microbiota genera had potential to distinguish NMOSD from controls. Functional analysis further indicated that the gut microbiome of NMOSD patients was associated with three significantly downregulated metabolic pathways: "Photosynthesis" (P .001), "Photosynthesis proteins" (P .001), and "Thiamine metabolism" (P = .007). These differences remained significant even after correction for multiple comparisons (all POur results reveal the dysbiosis of intestinal bacteria and regarding metabolic abnormalities in patients with NMOSD. Further studies are warranted to elucidate the potential mechanism by which dysbiosis of microbiota contributes to the onset and progression of NMOSD.

Background X chromosome-linked interleukin-1 receptor-associated kinase (IRAK1) polymorphisms have been demonstrated to be associated with the risks of several autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, and autoimmune thyroid diseases. However, no studies have investigated the association of IRAK1 polymorphisms with neuromyelitis optica spectrum disorder (NMOSD). This case-control study was performed to determine the correlation between IRAK1 polymorphisms and the risk of NMOSD. Methods Two single nucleotide polymorphisms (SNPs) rs1059703G>A and rs3027898C>A of IRAK1 were selected and genotyped using SNPscan in a Chinese cohort, including 332 patients with NMOSD and 520 healthy controls. Chi-square tests and logistic regression analyses were used to determine the associations between IRAK1 polymorphisms and the risk of NMOSD. Results Patients with NMOSD showed a lower frequency of the minor allele A of rs1059703 than did controls (Odds ratio [OR] = 0.68; 95% confidence intervals [CI], 0.52–0.88; Pcorr = 0.007). Compared with wild genotype GG of rs1059703, homozygous mutation AA and heterozygous mutation GA were significantly associated with the decreased risk of NMOSD after adjusting for sex and age (adjusted OR = 0.64; 95%CI, 0.49–0.84; Pcorr = 0.002). Similar associations were also observed for IRAK1 rs3027898C>A. Stratification analysis according to sex revealed that the significantly different allele distributions of the two SNPs were mainly found in females. However, IRAK1 polymorphisms were not correlated with aquaporin-4-IgG, onset symptoms, or age at onset. Conclusions This study is first to demonstrate that X-chromosome-linked IRAK1 polymorphisms are associated with the risk of NMOSD and provide novel insights into the underlying mechanisms of this disease. Further studies are needed to elucidate the function of IRAK1 variants in the pathogenesis of NMOSD and the underlying molecular mechanisms.

The grounding grid is an important measure to maintain the safe operation of power system and to ensure the safety of staff and electrical equipments. The size of the grounding resistance can indirectly reflect if the grounding grid is intact. First, the principle, the key technology and the present research situation of a variety of grounding resistance detection methods are introduced and analyzed. Second, the principle of a variety of grounding grid fault diagnosis methods is introduced and analyzed.