Repurposing of the FGFR inhibitor AZD4547 as a potent inhibitor of necroptosis by selectively targeting RIPK1.

Necroptosis is a form of regulated necrosis involved in various pathological diseases. The process of necroptosis is controlled by receptor-interacting kinase 1 (RIPK1), RIPK3, and pseudokinase mixed lineage kinase domain-like protein (MLKL), and pharmacological inhibition of these kinases has been shown to have therapeutic potentials in a variety of diseases. In this study, using drug repurposing strategy combined with high-throughput screening (HTS), we discovered that AZD4547, a previously reported FGFR inhibitor, is able to interfere with necroptosis through direct targeting of RIPK1 kinase. In both human and mouse cell models, AZD4547 blocked RIPK1-dependent necroptosis. In addition, AZD4547 rescued animals from TNF-induced lethal shock and inflammatory responses. Together, our study demonstrates that AZD4547 is a potent and selective inhibitor of RIPK1 with therapeutic potential for the treatment of inflammatory disorders that involve necroptosis.

Osimertinib successfully combats EGFR-negative glioblastoma cells by inhibiting the MAPK pathway.

Glioblastoma (GBM) patients have extremely poor prognoses, and currently no effective treatment available including surgery, radiation, and chemotherapy. MAPK-interacting kinases (MNK1/2) as the downstream of the MAPK-signaling pathway regulate protein synthesis in normal and tumor cells. Research has shown that targeting MNKs may be an effective strategy to treat GBM. In this study we investigated the antitumor activity of osimertinib, an FDA-approved epidermal growth factor receptor (EGFR) inhibitor, against patient-derived primary GBM cells. Using high-throughput screening approach, we screened the entire panel of FDA-approved drugs against primary cancer cells derived from glioblastoma patients, found that osimertinib (3 µM) suppressed the proliferation of a subset (10/22) of EGFR-negative GBM cells (>50% growth inhibition). We detected the gene expression difference between osimertinib-sensitive and -resistant cells, found that osimertinib-sensitive GBM cells displayed activated MAPK-signaling pathway. We further showed that osimertinib potently inhibited the MNK kinase activities with IC50 values of 324 nM and 48.6 nM, respectively, against MNK1 and MNK2 kinases; osimertinib (0.3-3 µM) dose-dependently suppressed the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E). In GBM patient-derived xenografts mice, oral administration of osimertinib (40 mg· kg-1 ·d-1, for 18 days) significantly suppressed the tumor growth (TGI = 74.5%) and inhibited eIF4E phosphorylation in tumor cells. Given the fact that osimertinib could cross the blood-brain barrier and its toxicity was well tolerated in patients, our results suggest that osimertinib could be a new and effective drug candidate for the EGFR-negative GBM patients.

Altered resting-state fMRI signals and network topological properties of bipolar depression patients with anxiety symptoms.

BACKGROUND: This study aims to explore the changes in functional neuroimaging in bipolar depression patients with anxiety symptoms (BDP-A). METHODS: Forty-five BDP-A patients, 22 bipolar depression patients without anxiety symptoms (BDP-NA), and 48 healthy controls (HC) were finally involved. The low-frequency oscillation characteristics, functional connectivity (FC), and network properties among the three groups of participants were analyzed. RESULTS: Compared with the BDP-NA group, BDP-A patients exhibited significantly decreased amplitude of low-frequency fluctuation (ALFF) in the left middle frontal gyrus (MFG), superior occipital gyrus, and inferior parietal, but supramarginal and angular gyri (IPL). Enhanced FC from left IPL to middle temporal gyrus, from left precentral gyrus (PreCG) to bilateral angular gyri, medial superior frontal gyrus, and left superior frontal gyrus (SFG)/MFG were also revealed. Compared with HC, the BDP-A group showed remarkably increased ALFF in the left MFG/PreCG, right superior parietal gyrus, while decreased ALFF in the left inferior frontal gyrus, opercular part, and SFG. In addition, higher regional homogeneity in the left MFG/PreCG was found. LIMITATIONS: The limitations are as follows: (1) relatively small sample size; (2) not all the patients were drug-naive; (3) lack of pure anxiety disorder patients as a controlled group; (4) mental health conditions of HC were not systemic evaluated. CONCLUSIONS: BDP-A patients showed significant differences in resting-state fMRI properties when compared with BDP-NA or HC group. These results may infer the dysfunction of the dorsal attention network, the default network, and the fronto-limbic system as well as disrupted brain network efficiency in BDP-A patients.

The relationship between lifestyle factors and clinical symptoms of bipolar disorder patients in a Chinese population.

There is evidence that bipolar disorder (BD) patients with an unhealthy lifestyle have a worse course of illness. This study was designed to examine the extent to which lifestyle could influence the severity of clinical symptoms associated with BD. A total of 113 BD patients were recruited in this study. The lifestyle information including data on dietary patterns, physical activity, and sleep quality were collected using a self-rated questionnaire. The results showed that the consumption of whole grain, seafood, and dairy products were significantly negatively correlated with the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score. The consumption of sugar, soft drinks, and alcohol as well as being a current smoker were positively correlated with the severity of clinical symptoms. Multiple linear regression and binary logistic regression analyses demonstrated an independent negative correlation between both whole grain and dairy product consumption with the HAMD-17 score. The results from the current study suggested that lifestyle factors, especially dietary patterns, might be associated with clinical symptoms of BD. The association between the consumption of specific foods and severity of depressive symptoms may offer some useful information and further understanding of the role of lifestyle factors in the development of BD.

A Self-Organizing Incremental Spatiotemporal Associative Memory Networks Model for Problems with Hidden State.

Identifying the hidden state is important for solving problems with hidden state. We prove any deterministic partially observable Markov decision processes (POMDP) can be represented by a minimal, looping hidden state transition model and propose a heuristic state transition model constructing algorithm. A new spatiotemporal associative memory network (STAMN) is proposed to realize the minimal, looping hidden state transition model. STAMN utilizes the neuroactivity decay to realize the short-term memory, connection weights between different nodes to represent long-term memory, presynaptic potentials, and synchronized activation mechanism to complete identifying and recalling simultaneously. Finally, we give the empirical illustrations of the STAMN and compare the performance of the STAMN model with that of other methods.

Contribution of long duration of undiagnosed bipolar disorder to high frequency of relapse: A naturalistic study in China.

BACKGROUND: With attention to misdiagnosis of bipolar disorder (BP), long duration of undiagnosed bipolar disorder (DUBP) had been reported recently in years. This study aims to investigate the contributions of long DUBP to the frequency of relapse in bipolar patients, and explore affect factors of DUBP. METHOD: From 26 hospitals throughout China, 3896 participants diagnosed with BP according to International Classification of Diseases 10th criteria were enrolled in this study. Socio-demographic and clinical data were collected from medical records and specific questionnaires through clinical interviews with patients and their relatives. RESULTS: (1) Our results showed that the mean of DUBP was 40.52months. In total, 779 patients (19.995%) reported DUBP greater than 5years, and 1931 patients (49.564%) reported their DUBP greater than 2years. The number of mood episodes was averaged 5.44, and the frequency ratio of (hypo) mania to depressive episodes was 1.49 (3.27/2.19). (2) Multiple linear regression analysis revealed that DUBP was significantly contributed to the number of relapse (Beta=0.072, p<0.001) after considering the confounding including gender, age at study entry, age of onset, age of first (hypo) manic episodes, age of first depressive episodes, type of first episodes and family history of mental illness. (3) Factors including age at the study entry (Beta=0.526, p<0.001), age of onset (Beta=-1.654, p<0.001), age of first (hypo) manic episode (Beta=0.348, p<0.001), age of first depressive episode (Beta=0.983, p<0.001), depression as the type of first episode (Beta=0.058, p<0.001) and family history of mental illness (Beta=0.029, p<0.05) were significantly contributed to long DUBP. CONCLUSION: It was concluded that long DUBP might lead to high frequent relapse in bipolar patients. The factors correlated with long DUBP include older age, early age of onset, depression as the type of first episode and family history of mental illness. The findings of our study suggest emergency task to early reorganization of bipolar disorder, and improving clinicians' recognition of bipolar disorder from patients with depressive episodes, especially in children and adolescents.

[Correlation between Expression of Peripheral IL-17 Protein and Aggression of Bipolar Mania].

OBJECTIVE: To explore the correlation between the interleukin-17 (IL-17) level of peripheral blood and aggression of bipolar mania. METHODS: Thirty-six patients of bipolar mania were selected as experimental group by DSM-IV-TR and received treatment with quetiapine and lithium. Thirty-six healthy volunteers with similar age and gender were selected as control group. The level of IL-17 at baseline in each group and the level of IL-17 in the experimental group after treatment for 2, 4 and 8 weeks were detected by ELISA. RESULTS: The level of IL-17 in experimental group at baseline, after treatment for 2 and 4 weeks were all significantly higher than that in control group. After 8 weeks treatment, there was no significant difference between the two groups (P > 0.05). After 2, 4 and 8 weeks treatment, the total score and aggression score of Young Mania Rating Score (YMRS) were significantly lower than the baseline level (P < 0.05). In experimental group, the level of IL-17 was positively correlated with the two scores of YMRS at baseline (P < 0.05). CONCLUSION: Bipolar mania may be related to the up-regulation of IL-17. The level of IL-17 is related to the severity of manic symptoms at baseline, especially aggression symptom.

Effectiveness of Antipsychotic Drugs for 24-Month Maintenance Treatment in First-Episode Schizophrenia: Evidence From a Community-Based "Real-World" Study.

OBJECTIVE: Maintenance treatment of schizophrenia with antipsychotic medications has become a standard for the prevention of psychotic relapse. However, little is known about the effectiveness of antipsychotic drugs for maintenance treatment in "real-world" populations with schizophrenia. We carried out a prospective study to assess the effectiveness of the most frequently prescribed antipsychotic drugs in the maintenance treatment of schizophrenia from 2 community settings. METHODS: This study was conducted from October 2011 to December 2014. All participants were diagnosed with schizophrenia according to DSM-IV, were treated with an antipsychotic monotherapy, and were registered in a case management program with monthly monitoring for 24 months. The primary outcome measure, Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales were used to evaluate symptom severity and treatment response. The Personal and Social Performance scale (PSP) was used to evaluate the patients' social functioning. The Medication Adherence Rating Scale (MARS) was used to assess medication adherence behavior. On the basis of antipsychotic used at baseline, patients were clustered into 7 groups: aripiprazole (n = 21), clozapine (n = 84), chlorpromazine (n = 61), olanzapine (n = 34), perphenazine (n = 21), quetiapine (n = 27), and risperidone (n = 99). RESULTS: Of the 347 patients enrolled in the study, 312 completed the 24-month follow-up. There were no significant differences among the treatment groups in the PANSS total and subscale scores or the CGI-S and CGI-I scores over 24 months (all P values > .05). There were also no significant differences in interactions between PSP scores and antipsychotic drugs (P = .17). The remission rates increased as the follow-time lapsed in all groups, but no significant difference was observed in remission rates at each time point among the 7 groups (P values > .05). At the endpoint, MARS total scores were over 6, but did not significantly differ among the studied drugs (P = .24). CONCLUSIONS: These findings suggest that antipsychotic drugs can achieve equivalent effectiveness in maintenance treatment of first-episode schizophrenia through a well-organized case management program and family participation.

Serum DHEAS levels are associated with the development of depression.

The aim of study was to evaluate the association between serum DHEAS levels and depression with a case-control study together with a meta-analysis. Radioimmunoassay (RIA) was performed to measure the serum DHEAS levels of all participants before and after treatment. Depression Patients were divided into mild depression and severe depression based on Hamilton depression scale (HAMD24) and received 5-hydroxytryptamine (5-HT) and citalopram (20mg/d) for 8 weeks. Case-control studies related to our study theme were enrolled for meta-analysis and Comprehensive Meta-analysis 2.0 (CMA 2.0) was used for statistical analysis. After treatment, DHEAS levels in depression patients were significantly increased, while before and after treatment, DHEAS levels were all lower in depression patients than in controls (all P<0.001); further analysis on age revealed that DHEAS levels were decreased with the rising of age. Meta-analysis results suggested that serum DHEAS levels (ng/mL) were significantly higher in healthy controls compared to depression patients (SMD=0.777, 95%CI=0.156-1.399, P=0.014). In conclusion, our study suggests that serum DHEAS levels are associated with the development of depression and it decreased with the rising of age.

[Microsurgical management of tuberculum sellae meningiomas].

OBJECTIVE: To explore the approach and efficacy of microsurgery for tuberculum sellae meningiomas. METHODS: The clinical data of 56 patients with tuberculum sellae meningiomas treated at our department from 1991 - 2009 were analyzed retrospectively. There were 20 males and 36 females with an age range of 32 - 65 years old (mean: 46). All patients underwent microsurgery through pterional, unilateral subfrontal, orbitozygomatic or supraorbital keyhole approach. RESULTS: Among these patients, there were total resection (n = 51) and subtotal resection (n = 5). Postoperatively, 53 patients recovered well, 2 had a mild disability, 1 suffered a severe disability and there was no mortality. CONCLUSION: Most cases of tuberculum sellae meningiomas can be removed safely and totally. Several approaches may be employed to achieve the best outcomes. Microsurgery can markedly boost the total resection rate of tuberculum salle meningiomas and lower the postoperative complications and mortality.

[Association between depression and G72 gene polymorphism].

OBJECTIVE: To investigate the association between G72 gene polymorphisms and depression,and to probe the difference of G72 gene polymorphisms between depression with and without mixed family history. METHODS: The polymorphisms of G72 gene (rs947267 and rs2181953) were detected by PCR technique in 100 depressive patients without mixed family history, 50 depressive patients with mixed family history and 86 normal controls. RESULTS: (1) The frequencies of rs947267 genotypes and alleles in female depressive patients without mixed family history were significant different to the controls (P=0.017 and P=0.008), the OR scores were 0.300 (A/A, P=0.010), 0.456(A, P=0.008) and 2.195(C, P=0.008) respectively; but in male patients there were no significant differences to the controls (P>0.05). (2) The frequencies of rs2181953 genotypes and alleles in the depressive patients without mixed family history were not significantly different to the controls regardless of sex (P>0.05). (3) The frequencies of rs947267 and rs2181953 genotypes and alleles in the depressive patients with mixed family history were not significantly different to the controls regardless of sex (P>0.05). CONCLUSION: The G72 gene polymorphism may be associated with female depressive patients without mixed family history,C allele of rs947267 may be the risk factor.

[Association study of NOTCH4 gene polymorphisms with schizophrenia and mood disorders in mixed pedigrees].

This study was to explore the relationships between NOTCH4 gene and schizophrenia (SP) and mood disorders (MD), and to search for a common susceptible gene for SP and MD in Chinese Han population. We collected 61 mixed pedigrees of SP and MD in Chinese Han population. NOTCH4 polymorphisms -1725T/G and-25T/C were genotyped by applying PCR-RLFP technique, then transmission disequilibrium test (TDT) and haplotype-based haplotype relative risk analysis(HHRR) were performed. The results showed that -1725T/G was not associated with SP or MD (P>0.05), -25T/C was not associated with SP (P>0.05), but associated significantly with MD for female or early-onset (age of onset0.05). Our results suggested NOTCH4 or neighboring gene might be a common susceptible gene for SP and MD in the pedigrees studied.