Novel selective agents for the degradation of AR/AR-V7 to treat advanced prostate cancer.

The androgen receptor AR antagonists, such as enzalutamide and apalutamide, are efficient therapeutics for the treatment of prostate cancer (PCa). Even though they are effective at first, resistance to both drugs occurs frequently. Resistance is mainly driven by aberrations of the AR signaling pathway including AR gene amplification and the expression of AR splice variants (e.g. AR-V7). This highlights the urgent need for alternative therapeutic strategies. Here, a total of 24 compounds were synthesized and biologically evaluated to disclose compound 20i, exhibiting potent AR antagonistic activities (IC50 = 172.85 ± 21.33 nM), promising AR/AR-V7 protein degradation potency, and dual targeting site of probably AR (ligand-binding domain, LBD and N-terminal domain, NTD). It potently inhibits cell growth with IC50 values of 4.87 ± 0.52 and 2.07 ± 0.34 µM in the LNCaP and 22RV1 cell lines, respectively, and exhibited effective tumor growth inhibition (TGI = 50.9 %) in the 22RV1 xenograft study. These data suggest that 20i has the potential for development as an AR/AR-V7 inhibitor with degradation ability to treat advanced prostate cancer.

The effectiveness of vortioxetine on neurobiochemical metabolites and cognitive of major depressive disorders patients: A 8-week follow-up study.

OBJECTIVE: Vortioxetine has been shown to improve cognitive performance in people with depression. This study will look at the changes in neurobiochemical metabolites that occur when vortioxetine improves cognitive performance in MDD patients, with the goal of determining the neuroimaging mechanism through which vortioxetine improves cognitive function. METHODS: 30 depressed patients and 30 demographically matched healthy controls (HC) underwent MCCB cognitive assessment and 1H-MRS. After 8 weeks of vortioxetine medication, MCCB and 1H-MRS tests were retested in the MDD group. Before and after therapy, changes in cognitive performance, NAA/Cr, and Cho/Cr were examined in the MDD group. RESULTS: Compared with the HC group, the MDD group had significant reduced in verbal learning, social cognition, and total cognition (all p < 0.05). And the MDD group had lower NAA/Cr in Right thalamus and Left PFC; the Cho/Cr in Right thalamus was lower than HC; the Cho/Cr in Left ACC had significantly increase (all p < 0.05). The MDD group showed significant improvements in the areas of verbal learning, attention/alertness, and total cognitive function before and after Vortioxetine treatment (all p < 0.05). The NAA/Cr ratio of the right PFC before and after treatment (t = 2.338, p = 0.026) showed significant changes. CONCLUSIONS: Vortioxetine can enhance not just the depression symptoms of MDD patients in the initial period, but also their verbal learning, social cognition, and general cognitive capacities after 8 weeks of treatment. Furthermore, vortioxetine has been shown to enhance cognitive function in MDD patients by altering NAA/Cr and Cho/Cr levels in the frontal-thalamic-ACC.

Discovery of Novel Antitumor Small-Molecule Agent with Dual Action of CDK2/p-RB and MDM2/p53.

Cell cycle-dependent kinase 2 (CDK2) is located downstream of CDK4/6 in the cell cycle and regulates cell entry into S-phase by binding to Cyclin E and hyper-phosphorylating Rb. Proto-oncogene murine double minute 2 (MDM2) is a key negative regulator of p53, which is highly expressed in tumors and plays an important role in tumorigenesis and progression. In this study, we identified a dual inhibitor of CDK2 and MDM2, III-13, which had good selectivity for inhibiting CDK2 activity and significantly reduced MDM2 expression. In vitro results showed that III-13 inhibited proliferation of a wide range of tumor cells, regardless of whether Cyclin E1 (CCNE1) was overexpressed or not. The results of in vivo experiments showed that III-13 significantly inhibited proliferation of tumor cells and did not affect body weight of mice. The results of the druggability evaluation showed that III-13 was characterized by low bioavailability and poor membrane permeability when orally administered, suggesting the necessity of further structural modifications. Therefore, this study provided a lead compound for antitumor drugs, especially those against CCNE1-amplified tumor proliferation.

Personality traits as predictors for treatment response to sertraline among unmedicated obsessive-compulsive Disorder: A 12-weeks retrospective longitudinal study.

The effectiveness of selective serotonin reuptake inhibitors (SSRIs) as a primary treatment for obsessive-compulsive disorder (OCD) remains uncertain. Even after undergoing standard SSRIs treatment, 40%-60% of individuals with OCD persistently endure symptoms. Recent studies proposed that personality traits may influence the diversity of OCD treatment results. Thus, in this retrospective study, we evaluated the Eysenck Personality Questionnaire (EPQ) scores of 51 untreated patients with OCD and 35 healthy controls. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was employed to assess OCD symptom severity at weeks 0, 2, 4, 8, and 12 of sertraline treatment. The primary outcome focused on the reduction rate of Y-BOCS scores (response: ≥25%; marked response: ≥50%). Our findings revealed that individuals with OCD demonstrated a significantly higher neuroticism score compared to healthy controls. Correlation analyses exposed a positive link between psychoticism and the duration of the disease. Moreover, family history strongly correlated with both obsessive thoughts and the total Y-BOCS score. Subsequent univariate Cox proportional analyses indicated that both low neuroticism and high extraversion traits could forecast the response to sertraline. Furthermore, only a high extraversion trait was linked to a marked response. Our results support the idea that personality traits may contribute to OCD vulnerability and predict sertraline treatment outcomes.

A Method for Image Anomaly Detection Based on Distillation and Reconstruction.

Image anomaly detection is a trending research topic in computer vision. The objective is to build models using available normal samples to detect various abnormal images without depending on real abnormal samples. It has high research significance and value for applications in the detection of defects in product appearance, medical image analysis, hyperspectral image processing, and other fields. This paper proposes an image anomaly detection algorithm based on feature distillation and an autoencoder structure, which uses the feature distillation structure of a dual-teacher network to train the encoder, thus suppressing the reconstruction of abnormal regions. This system also introduces an attention mechanism to highlight the detection objects, achieving effective detection of different defects in product appearance. In addition, this paper proposes a method for anomaly evaluation based on patch similarity that calculates the difference between the reconstructed image and the input image according to different regions of the image, thus improving the sensitivity and accuracy of the anomaly score. This paper conducts experiments on several datasets, and the results show that the proposed algorithm has superior performance in image anomaly detection. It achieves 98.8% average AUC on the SMDC-DET dataset and 98.9% average AUC on the MVTec-AD dataset.

Design, synthesis, and biological evaluation of novel molecules as potent inhibitors of PLK1.

Polo-like kinase 1 (PLK1) is an attractive therapeutic target for the treatment of tumors, as it is an essential cell-cycle regulator frequently overexpressed in tumor tissues. PLK1 can promote tumor invasion and metastasis, and is often associated with poor prognosis in cancer patients. However, no PLK1 inhibitor has been granted marketing approval until now. Therefore, more potentially promising PLK1 inhibitors need to be investigated. In this study, a series of novel inhibitors targeting PLK1 was designed and optimized derived from a new scaffold. After synthesis and characterization, we obtained the structure-activity relationship and led to the discovery of the most promising compound 30e for PLK1. The antiproliferative activity against HCT116 cells (IC50 = 5 nM versus 45 nM for onvansertib) and the cellular permeability and efflux ratio were significantly improved (PappA→B = 2.03 versus 0.345 and efflux ratio = 1.65 versus 94.7 for 30e and onvansertib, respectively). Further in vivo studies indicated that 30e had favorable antitumor activity with 116.2% tumor growth inhibition (TGI) in comparison with TGI of 43.0% for onvansertib. Furthermore, 30e improved volume of tumor tissue distribution in mice as compared to onvansertib. This initial study on 30e holds promise for further development of an antitumor agent.

[Clinical features of children with febrile seizures caused by Omicron variant infection]. / Omicronå˜å¼‚æ ªæ„ŸæŸ“å¯¼è‡´å„¿ç«¥çƒ­æ€§æƒŠåŽ¥çš„ä¸´åºŠç‰¹å¾åˆ†æž.

OBJECTIVES: To study the clinical features of children with febrile seizures after Omicron variant infection. METHODS: A retrospective analysis was performed on the clinical data of children with febrile seizures after Omicron variant infection who were admitted to the Department of Neurology, Children's Hospital Affiliated to the Capital Institute of Pediatrics, from December 1 to 31, 2022 (during the epidemic of Omicron variant; Omicron group), and the children with febrile seizures (without Omicron variant infection) who were admitted from December 1 to 31, in 2021 were included as the non-Omicron group. Clinical features were compared between the two groups. RESULTS: There were 381 children in the Omicron group (250 boys and 131 girls), with a mean age of (3.2±2.4) years. There were 112 children in the non-Omicron group (72 boys and 40 girls), with a mean age of (3.5±1.8) years. The number of children in the Omicron group was 3.4 times that in the non-Omicron group. The proportion of children in two age groups, aged 1 to <2 years and 6-10.83 years, in the Omicron group was higher than that in the non-Omicron group, while the proportion of children in two age groups, aged 4 to <5 years and 5 to <6 years, was lower in the Omicron group than that in the non-Omicron group (P<0.05).The Omicron group had a significantly higher proportion of children with cluster seizures and status convulsion than the non-Omicron group (P<0.05). Among the children with recurrence of febrile seizures, the proportion of children aged 6-10.83 years in the Omicron group was higher than that in the non-Omicron group, while the proportion of children aged 3 years, 4 years, and 5 years in the Omicron group was lower than that in the non-Omicron group (P<0.05). CONCLUSIONS: Children with febrile seizures after Omicron variant infection tend to have a wider age range, with an increase in the proportion of children with cluster seizures and status convulsion during the course of fever.

Biological evaluation and in silico studies of novel compounds as potent TAAR1 agonists that could be used in schizophrenia treatment.

Introduction: Schizophrenia is a serious mental illness that requires effective treatment with minimal adverse effects. As preclinical and clinical research progresses, trace amine-associated receptor 1 (TAAR1) is becoming a potential new target for the treatment of schizophrenia. Methods: We used molecular docking and molecular dynamics (MD) simulations to discover TAAR1 agonists. The agonistic or inhibitory effects of compounds on TAAR1, 5-HT1A, 5-HT2A, and dopamine D2-like receptors were determined. We used an MK801-induced schizophrenia-like behavior model to assess the potential antipsychotic effects of compounds. We also performed a catalepsy assay to detect the adverse effects. To evaluate the druggability of the compounds, we conducted evaluations of permeability and transporter substrates, liver microsomal stability in vitro, human ether-à-go-go-related gene (hERG), pharmacokinetics, and tissue distribution. Results: We discovered two TAAR1 agonists: compounds 50A and 50B. The latter had high TAAR1 agonistic activity but no agonistic effect on dopamine D2-like receptors and demonstrated superior inhibition of MK801-induced schizophrenia-like behavior in mice. Interestingly, 50B had favorable druggability and the ability to penetrate the blood-brain barrier (BBB) without causing extrapyramidal symptoms (EPS), such as catalepsy in mice. Conclusion: These results demonstrate the potential beneficial role of TAAR1 agonists in the treatment of schizophrenia. The discovery of a structurally novel TAAR1 agonist (50B) may provide valuable assistance in the development of new treatments for schizophrenia.

Synthesis and evaluation of piperazinotriazoles. Discovery of a potent and orally bioavailable neurokinin-3 receptor inhibitor.

The neurokinin-3 receptor (NK3R) is one of three receptors that recognize neurokinins. The finding that pharmacological blockade of neurokinin B (NKB) signaling with an oral NK3R antagonist can significantly improve hot flash symptoms independent of any hormonal effect fits strongly suggest that NK3R is a viable drug target and that drugs targeting this receptor could be novel pharmacotherapies. Currently no NK3R ligands have been approved for the treatment of human disorders. Herein, we designed and synthesized a series of novel imidazolepiperazine derivatives (16a-16x, 20a-20f, 29a-29m) and performed molecular docking to confirm the design, among which the target compound 16x exhibited promising inhibitory activity against NK3R (IC50 = 430.60 nM) with excellent membrane permeability (Papp, A-B = 37.6 × 10-6 cm/s, ER < 1) and oral bioavailability (F% = 93.6%). Our in vivo studies demonstrated that 16x was orally active, efficacious, and well-tolerated in ovariectomy (OVX) model to suppress blood luteinizing hormone levels, which suggests that 16x is a viable lead compound for further optimization and development.

The effect of exogenous estrogen on depressive mood in women: A systematic review and meta-analysis of randomized controlled trials.

Sex differences exist in the prevalence of major depressive disorder (MDD). Comparing with males, females are at a higher risk of depression, especially in some reproductive statuses with significant changes in sex hormones. Based on the positive effect on menopausal symptoms in human and on depression-like behaviors in animals, exogenous estrogen was considered as a potential therapeutic approach to the treatment of female depression, however, with inconsistent conclusions in previous studies. In the present systematic review and meta-analysis, 14 eligible randomized controlled trials (RCTs) were included to investigate the effect of exogenous estrogen on depressive mood in women. The results indicated that exogenous estrogens were superior to the control group either alone or in combination with progesterone or antidepressants. Female individuals in perimenopause are more sensitive to estrogen than those in other reproductive statuses, which might be the reason that depressive mood during this stage is more associated with estrogen fluctuations, and exogenous estrogen supplementation can moderate these drastic changes. The finding of meta-regressions that the effect of exogenous estrogen was associated with age in perimenopause and post-menopause rather than the dose or administration of exogenous estrogen, showed again that a stable level of estrogen is more beneficial than a high serum level. This study provides strong evidence of the important role of estrogen fluctuations but not estrogen levels in female depression.

Study on Pharmacokinetics and Metabolic Profiles of Novel Potential PLK-1 Inhibitors by UHPLC-MS/MS Combined with UHPLC-Q-Orbitrap/HRMS.

PLK-1 (Polo-like kinase-1) plays an essential role in cytokinesis, and its aberrant expression is considered to be keenly associated with a wide range of cancers. It has been selected as an appealing target and small-molecule inhibitors have been developed and studied in clinical trials. Unfortunately, most have been declared as failures due to the poor therapeutic response and off-target toxicity. In the present study, a novel potent PLK-1 inhibitor, compound 7a, was designed and synthetized. 1H NMR, 13C NMR, 19F NMR and mass spectrum were comprehensively used for the compound characterization. The compound exhibited higher potency against PLK-1 kinase, HCT-116 and NCI-H2030 cell lines than the positive control. Molecular docking indicated that the binding mode that the ATP binding site of PLK-1 was occupied by the compound. Then, a UHPLC-MS/MS method was established and validated to explore the pharmacokinetic behavior of the drug candidate. The method had good selectivity, high sensitivity and wide linearity. The exposure increased linearly with the dose, but the oral bioavailability was not satisfactory enough. Then, the metabolism was studied using liver microsomes by UHPLC-Q-Orbitrap/HRMS. Our research first studied the pharmacokinetic metabolic characteristics of 7a and may serve as a novel lead compound for the development of PLK-1 inhibitors.

Discovery of the thieno[2,3-d]pyrimidine-2,4-dione derivative 21a: A potent and orally bioavailable gonadotropin-releasing hormone receptor antagonist.

The gonadotropin releasing hormone receptor (GnRH-R) is a G protein-coupled receptor (GPCR) belonging to the rhodopsin family. GnRH-R antagonists suppress testosterone to castrate level more rapidly than gonadotropin releasing hormone agonists but lack the flare phenomenon often seen during the early period of GnRH-R agonist treatment. Recently orgovyx (relugolix) was approved as the first oral GnRH-R antagonist for the treatment of advanced prostate cancer. However, orgovyx has demonstrated poor pharmacokinetic profile with low oral bioavailability and high efflux. Here, we rationally designed and synthesized a series of derivatives (13a-m, 21a-i) through the modification and structure-activity relationship study of relugolix, which led to the discovery of 21a as a highly potent GnRH-R antagonist (IC50 = 2.18 nM) with improved membrane permeability (Papp, A-B = 0.98 × 10-6 cm/s) and oral bioavailability (F % = 44.7). Compound 21a showed high binding affinity (IC50 = 0.57 nM) and potent in vitro antagonistic activity (IC50 = 2.18 nM) at GnRH-R. 21a was well tolerated and efficacious in preclinical studies to suppress blood testosterone levels, which merits further investigation as a candidate novel GnRH-R antagonist for clinical studies.

Improving the treatment of Parkinson's disease: Structure-based development of novel 5-HT2A receptor antagonists/inverse agonists.

Pimavanserin is a selective 5-HT2A receptor antagonist and inverse agonist approved by the FDA in 2016, which is used to treat patients with Parkinson's disease psychosis (PDP). But pimavanserin has potential risk with increasing mortality in elderly patients and also increasing the risk of QT interval prolongation in patients. Therefore, searching for new drugs with high efficacy and low toxicity is urgently needed. Based on the docking study of pimavanserin, a series of novel pimavanserin derivatives (7-1∼7-37) were designed and synthesized. The biological activities were evaluated by cell assays and compound 7-16 exhibited 50-fold higher 5-HT2A receptor antagonist activity (IC50 = 0.54 vs 27.3 nM) and 23-fold higher inverse agonist activity (IC50 = 2.1 vs 50 nM) than pimavanserin. Moreover, 7-16 showed increased potency window between the 5-HT2A and hERG activities than pimavanserin. Furthermore, compound 7-16 demonstrated excellent in vitro and in vivo pharmacokinetics, 4-fold more improvement in functional activity in vivo, and good safety profile. Therefore, compound 7-16 represents a potentially promising candidate as a novel anti-PDP agent that warrants further investigation.

Immunotherapies for Anti-N-M-methyl-D-aspartate Receptor Encephalitis: Multicenter Retrospective Pediatric Cohort Study in China.

Background: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis has been discovered for more than a decade, but the establishment of standardized immunotherapy protocol for pediatric patients still needs more clinical evidence. Methods: A multicenter, retrospective study was conducted on pediatric patients diagnosed with anti-NMDAR encephalitis between November 2011 and December 2018. The clinical records including clinical manifestations, immunotherapy strategies, and outcomes were collected and analyzed. Results: A total of 386 patients were included in our study and the median onset age was 8.00 (IQR 4.83-10.90) years. All patients received first-line immunotherapy and the majority (341, 88.3%) used the standard combination of methylprednisolone pulses (MEP) and intravenous immunoglobulins (IVIG), but 211 patients did not show satisfactory improvement (mRS ≥ 3). Mainly three treatment strategies were applied after first-line immunotherapy: second-line immunotherapy, repetitive first-line immunotherapy, and maintaining oral prednisolone. For patients with mRS ≥ 4 after first-line immunotherapy, the incidence of poor outcome (mRS ≥ 3) in oral prednisolone group was higher than that in other treatment groups (p = 0.039). No difference in complete recovery rate (mRS = 0) was found between patients receiving second-line and repetitive first-line immunotherapy, or patients using long-term and short-term prednisolone. Out of 149 patients who received anti-myelin oligodendrocyte glycoprotein antibody (MOG-Ab) test, 27 (18.12%) were positive. Patients with concomitantly positive MOG-Ab showed milder conditions compared to patients with typical anti-NMDAR encephalitis and were more inclined to relapses. We also identified female, MOG-Ab positive, and not receiving second-line and/or repetitive first-line immunotherapy were risk factors for relapses. Conclusions: For patients with mRS ≥ 4 after first-line immunotherapy and patients with concomitantly positive MOG-Ab, second-line immunotherapy is recommended. When second-line immunotherapy is not applicable, repetitive first-line immunotherapy can be considered as an option. Both second-line and repetitive first-line immunotherapy are beneficial to reduce relapse rate. The duration of sequential oral prednisolone can be shortened after fully evaluating patients' conditions.

Efficacy and tolerability of lamotrigine in the treatment of focal epilepsy among children and adolescents: a meta-analysis.

BACKGROUND: Epilepsy is the most common chronic neurological disease in children, and focal epileptic seizures are the most common subtype. Unlike the data supporting treatment options for adults with epilepsy, evidence regarding the most effective first-line drug therapy for focal epilepsy in children and adolescents is limited. While lamotrigine is a therapeutic option for adults, there are disagreements surrounding its efficacy and tolerability in the younger population. Therefore, we performed a meta-analysis to determine if there was sufficient evidence to support a more definitive recommendation. METHODS: We undertook electronic search strategies using Medline via Ovid SP, Embase via Ovid SP up to February 05, 2021. We also searched relevant articles through Chinese BioMedical Literature (CBM), Chinese National Knowledge Infrastructure (CNKI), WANFANG, and VIP databases up to February 05, 2021. Study selection and data extraction were performed by 2 authors independently. The randomized controlled trials on focal epilepsy in children were included, and we made risk of bias judgments based on the methods endorsed by The Cochrane Collaboration. We used fifty percent or greater reduction in seizure frequency as an indicator of efficacy, the incidence of adverse events and treatment withdrawal as indicators of tolerability. The strength of the correlation was assessed via risk ratios (RRs) and their 95% confidence intervals (95% CIs). RESULTS: A total of 7 randomized trials involving 757 participants fulfilled the eligibility criteria. Of the 7 trials, 3 were placebo-controlled, and 4 compared lamotrigine with carbamazepine or oxcarbazepine. Lamotrigine was significantly more effective than placebo in achieving ≥50% reduction in seizure frequency, but its efficacy was not significantly different from that of carbamazepine or oxcarbazepine (lamotrigine vs. placebo: RR 2.95, 95% CI, 1.88 to 4.61; lamotrigine vs. carbamazepine/oxcarbazepine: RR 0.95, 95% CI, 0.85 to 1.05. There was significant difference in the incidence of overall adverse events between the lamotrigine- and carbamazepine/oxcarbazepine-treated groups (RR 0.64, 95% CI, 0.45 to 0.90). CONCLUSIONS: Lamotrigine was effective in reducing the seizure frequency when used as an add-on treatment in children with focal epilepsy, but current evidence does not suggest that lamotrigine is superior to carbamazepine/oxcarbazepine as monotherapy. For overall adverse events, lamotrigine has significantly fewer than carbamazepine/oxcarbazepine, suggesting that lamotrigine has better tolerability.

Clinical Characteristics and Follow-Up of Seizures in Children With Anti-NMDAR Encephalitis.

Objective: To analyze the seizure characteristics of children with anti-NMDAR encephalitis. Methods: This was a retrospective analysis of 50 children with anti-NMDAR encephalitis between July 1, 2013, and July 1, 2019. Results: Fifty children with anti-NMDAR encephalitis were included in this study, of which 34 (68.0%) had seizures. During the follow-up, three patients with anti-NMDAR encephalitis secondary to herpes simplex virus encephalitis had persistent seizures. The average duration of seizures in the remaining patients was 14.6 days (range 1-47 days). Compared to patients without seizures, those with seizures were more likely to experience consciousness disturbances (p = 0.008) and epileptic form discharge on electroencephalograms (p = 0.002). The Glasgow coma scale scores (p = 0.014), and Rankin scale scores (p = 0.019) were also different. The cranial MRI findings of children were reviewed, and clinical characteristics were compared between children without cranial lesions and those with lesions in the limbic system and neocortex. Compared to children in the non-lesion group, children with lesions in the limbic system and neocortex had a higher incidence of status epilepticus. Further, children in the limbic system and neocortical lesions groups were more likely to be taking anti-seizure medications (ASMs) and receive second-line drugs. Conclusion: Long-term oral ASMs are not recommended for most children with anti-NMDAR encephalitis. Children with involvement of the limbic system and neocortex are prone to status epilepticus, and sequelae of epilepsy may remain when the neocortex is involved.

[Clinical features of children with myelin oligodendrocyte glycoprotein antibody-associated disorders].

OBJECTIVE: To study the clinical features and treatment outcome of children with myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorders (MOGAD). METHODS: A retrospective analysis was performed for the clinical data of 28 children with MOGAD (with 38 demyelinating episodes). RESULTS: Among the disease spectrums of 28 children with MOGAD, optic neuritis was the most common (12 cases, 43%), followed by acute disseminated encephalomyelitis (9 cases, 32%). Among the 38 demyelinating episodes in the 28 children, there were 29 cases (76%) of lesions in the acute stage on head magnetic resonance imaging (MRI), and most of these lesions were extensive or isolated subcortical white matter lesions. A total of 24 cases of spinal MRI results in the acute stage were recorded, among which there were 11 cases (46%) of spinal lesions. MRI abnormalities of the optic nerve were found in 18 cases of optic neuritis in the acute stage. Of the 28 children, 20 (71%) had an increase in white blood cell count in cerebrospinal fluid, with lymphocytes as the most common type of cells, and 3 children had an increase in protein. The titer of serum MOG antibody was 1:10-1:320 in the 28 children. All 28 children were administered with glucocorticoids, along with immunoglobulin in 18 children. The symptoms of 26 children (93%) were alleviated during follow-up, and only 2 children had neurological sequela of the optic function. CONCLUSIONS: The clinical manifestations are diverse in children with MOGAD. Immunotherapy is effective and most children have a good prognosis.

FNDC3B is associated with ER stress and poor prognosis in cervical cancer.

Currently, the occurrence and mortality rate of cervical cancer is high, particularly in low-to-middle-income countries. Therefore, the development of novel diagnostic and treatment strategies for cervical cancer is urgently required. The aim of the present study was to assess the prognostic significance of fibronectin type III domain containing 3B (FNDC3B) expression in patients with cervical cancer and to determine the underlying mechanism of FNDC3 in tumor development. Analysis of the ONCOMINE database revealed that FNDC3B was significantly upregulated in cervical cancer tissue compared with normal tissue. Additionally, FNDC3B expression data and the clinical characteristics of patients with cervical cancer were obtained from the cBioPortal database. Correlations between FNDC3B expression and overall survival were subsequently investigated. The results revealed that increased FNDC3B expression was significantly correlated with a lower overall survival in patients with cervical cancer. A co-expression network was subsequently constructed to elucidate the function of FNDC3B in cervical cancer. Co-expression genes for FNDC3B were obtained from the cBioPortal database and were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. The results demonstrated that the genes were enriched in pathways associated with migration, invasion, endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Furthermore, immunofluorescence results obtained from the Human Protein Atlas revealed that the FNDC3B protein was localized to the ER. The results revealed that upregulated FNDC3B expression may be a biomarker for poor prognosis for patients with cervical cancer. Additionally, the results revealed that FNDC3B may serve an oncogenic role in cancer development via ER stress, UPR, cell migration and invasion. However, further studies are required to determine the exact molecular mechanism of FNDC3B in the development of cervical cancer and to assess its potential as a novel therapeutic target for the treatment of this disease.

Pediatric Autoimmune Encephalitis: Case Series From Two Chinese Tertiary Pediatric Neurology Centers.

Background and purpose: We retrospectively analyzed the clinical characteristics of children with autoimmune encephalitis (AE) in two Chinese tertiary pediatric neurology centers. We also compared anti-NMDAR encephalitis with and without co-positive MOG antibody, as well as specific autoantibody-positive AE and autoantibody-negative but probable AE. Methods: A retrospective study of children (0-18 years old) with AE in Peking University First Hospital and Children's Hospital Affiliated to Capital Institute of Pediatrics was carried out from May 2012 to January 2017. Demographics, clinical features, laboratory, and imaging findings, outcome, and co-positivity with MOG antibody were analyzed. Results: A total of 103 children had AE, 89 (86.4%) had anti-NMDAR encephalitis, 2 (1.9%) had anti-LGI1 encephalitis, 1 (0.9%) had anti-CASPR2 encephalitis, and 11 (10.7%) were diagnosed as autoantibody-negative but probable AE. Among the 89 children with anti-NMDAR encephalitis, 35 were males and 54 were females. The follow-up time was 1-3 years. A total of 15 cases (15/89, 16.9%) with anti-NMDAR encephalitis had co-positive MOG antibody (serum or cerebrospinal fluid or both). These patients were more likely to experience relapse later in life (P = 0.014). We had two cases with anti-LGI1 encephalitis, that is, one with sleep disorder onset, and the other one with seizure onset, both of whom recovered after treatment. One case with anti-CASPR2 encephalitis was treated with an antiepileptic drug and fully recovered. There were 11 cases diagnosed as autoantibody-negative but probable AE who had relatively poorer outcome than those with autoantibody-positive AE (15.2%, 14/89). However, the difference was not significant (P = 0.08). Only one 12-year-old girl with NMDAR-antibody AE had ovarian teratoma. Conclusion: Most subjects with AE in our Chinese cohort had anti-NMDAR AE, which had relatively good prognosis. Children with anti-LGI1 or anti-CASPR2 encephalitis were rare and showed good response on immunotherapy. Co-positive MOG antibody was relatively common in anti-NMDAR encephalitis, which was related to high relapse rate. In our study, the prognosis of autoantibody-negative but probable AE seemed worse than that of specific autoantibody-positive AE.

The Feasibility of Metagenomic Next-Generation Sequencing to Identify Pathogens Causing Tuberculous Meningitis in Cerebrospinal Fluid.

PURPOSE: The application of metagenomic next-generation sequencing (mNGS) in the diagnosis of tuberculous meningitis (TBM) remains poorly characterized. Here, we retrospectively analyzed data from patients with TBM who had taken both mNGS and conventional tests including culture of Mycobacterium tuberculosis (MTB), polymerase chain reaction (PCR) and acid-fast bacillus (AFB) stain, and the sensitivity and specificity of these methods were compared. METHODS: We retrospectively recruited TBM patients admitted to the hospital between December 2015 and October 2018. The first collection of cerebrospinal fluid (CSF) samples underwent both mNGS and conventional tests. In addition, patients with bacterial/cryptococcal meningitis or viral meningoencephalitis were mNGS positive controls, and a patient with auto-immune encephalitis was an mNGS negative control. RESULTS: Twenty three TBM patients were classified as 12 definite and 11 clinical diagnoses, which were based on clinical manifestations, pathogen evidence, CSF parameters, brain imaging, and treatment response. The mNGS method identified sequences of Mycobacterium tuberculosis complex (MBTC) from 18 samples (18/23, 78.26%). In patients with definite TBM, the sensitivity of mNGS, AFB, PCR, and culture to detect MTB in the first CSF samples were 66.67, 33.33, 25, and 8.33%, respectively. The specificity of each method was 100%. Among the four negative mNGS cases (4/23, 17.39%), three turned out positive by repeated AFB stain. The agreement of mNGS with the total of conventional methods was 44.44% (8/18). Combination of mNGS and conventional methods increased the detection rate to 95.65%. One patient was diagnosed as complex of TBM and cryptococcal meningitis, in which AFB stain and cryptococcal antigen enzyme immunoassay were positive and the DNA of Cryptococcus neoformans was detected by mNGS. CONCLUSION: Our study indicates that mNGS is an alternative method to detect the presence of mycobacterial DNA in CSF samples from patients with TBM and deserves to be applied as a front-line CSF test.