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Patients with treatment-resistant schizophrenia (TRS), particularly those resistant to clozapine (CTRS), pose a clinical challenge due to limited response to standard antipsychotic treatments. Inflammatory factors like tumor necrosis factor-alpha (TNF-α), interleukin 2 (IL-2), and interleukin 6 (IL-6) are implicated in schizophrenia's pathophysiology. Our study examines cognitive function, psychopathological symptoms and inflammatory factors in TRS patients, focusing on differences between CTRS and non-CTRS individuals, as well as healthy controls. A cohort of 115 TRS patients and 84 healthy controls were recruited, assessing IL-2, IL-6 and TNF-α. The Positive and Negative Syndrome Scale (PANSS) was applied to assess psychopathological symptoms, while the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was applied to assess cognitive functioning. CTRS patients showed lower visuospatial constructional score (p = 0.015), higher PANSS scores, higher levels of IL-2 and reduced TNF-α than non-CTRS patients (p < 0.05). Notably, IL-2 was independently associated with psychopathology symptoms in CTRS patients (Beta = 0.268, t = 2.075, p = 0.042), while IL-6 was associated with psychopathology symptoms in non-CTRS patients (Beta = - 0.327, t = - 2.109, p = 0.042). Sex-specific analysis in CTRS patients revealed IL-2 associations with PANSS total and positive symptoms in females, and TNF-α associations with PANSS positive symptoms in males. Furthermore, IL-2, IL-6, and TNF-α displayed potential diagnostic value in TRS patients and CTRS patients (p < 0.05). Clozapineresistant symptoms represent an independent endophenotype in schizophrenia with distinctive immunoinflammatory characteristics, potentially influenced by sex.
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OBJECTIVE: To observe the effect of acupuncture on gastroesophageal reflux disease (GERD) based on the "heart-stomach connection" theory, and to explore its possible mechanisms. METHODS: Seventy patients with GERD were randomly divided into an acupuncture group (35 cases, 2 cases dropped out) and a medication group (35 cases, 1 case dropped out). The patients in the acupuncture group received acupuncture at bilateral Shenmen (HT 7), Neiguan (PC 6), Burong (ST 19), Tianshu (ST 25), Zusanli (ST 36), Gongsun (SP 4), and Zhongwan (CV 12), with needles retained for 30 min, every other day, three times a week. The patients in the medication group were treated with oral omeprazole capsules, once daily, 20 mg each time. Both groups were treated for 8 weeks. Before and after treatment, the GERD questionnaire (GERDQ), GERD-quality of life scale (GERD-QOL), Hamilton depression scale-24 (HAMD-24), Zung self-rating depression scale (SDS), and Zung self-rating anxiety scale (SAS) scores were observed. Serum levels of gastrointestinal hormones (gastrin [GAS], motilin [MTL], and vasoactive intestinal peptide [VIP]) were measured, and the clinical efficacy of both groups was evaluated. Correlation between pre-treatment GERDQ score and GERD-QOL score, HAMD-24 score, SDS score, and SAS score was analyzed. RESULTS: After treatment, the scores of GERDQ, HAMD-24, SDS, and SAS were decreased (P<0.001) and the scores of GERD-QOL were increased (P<0.001), serum levels of GAS and MTL were increased (P<0.001) in both groups, while the serum level of VIP in the acupuncture group was decreased (P<0.001) compared with those before treatment. The acupuncture group had higher GERD-QOL score and lower SAS score than the medication group (P<0.05), with lower serum VIP level (P<0.05). The total effective rate was 75.8% (25/33) in the acupuncture group, and 76.5% (26/34) in the medication group, with no significant difference between the two groups (P>0.05). GERDQ score was negatively correlated with GERD-QOL scores (r =-0.762, P<0.01) and positively correlated with HAMD-24 score, SDS score, and SAS score (r =0.709, 0.649, 0.689, P<0.01) before treatment. CONCLUSION: Based on the "heart-stomach connection" theory, acupuncture could effectively improve clinical symptoms, quality of life, and negative emotions in patients with GERD. Its mechanism may be related to the regulation of gastrointestinal hormone levels, thereby promoting the contraction of the lower esophageal sphincter.
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Terapia por Acupuntura , Refluxo Gastroesofágico , Humanos , Refluxo Gastroesofágico/terapia , Refluxo Gastroesofágico/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Hormônios Gastrointestinais/sangue , Pontos de Acupuntura , Adulto Jovem , Estômago/fisiopatologia , Coração/fisiopatologia , Motilina/sangueRESUMO
BACKGROUND: Sleep disturbances are a common occurrence in patients with schizophrenia, yet the underlying pathogenesis remain poorly understood. Here, we performed a targeted metabolomics-based approach to explore the potential biological mechanisms contributing to sleep disturbances in schizophrenia. METHODS: Plasma samples from 59 drug-naïve patients with schizophrenia and 36 healthy controls were subjected to liquid chromatography-mass spectrometry (LC-MS) targeted metabolomics analysis, allowing for the quantification and profiling of 271 metabolites. Sleep quality and clinical symptoms were assessed using the Pittsburgh Sleep Quality Index (PSQI) and the Positive and Negative Symptom Scale (PANSS), respectively. Partial correlation analysis and orthogonal partial least squares discriminant analysis (OPLS-DA) model were used to identify metabolites specifically associated with sleep disturbances in drug-naïve schizophrenia. RESULTS: 16 characteristic metabolites were observed significantly associated with sleep disturbances in drug-naïve patients with schizophrenia. Furthermore, the glycerophospholipid metabolism (Impact: 0.138, p<0.001), the butanoate metabolism (Impact: 0.032, p=0.008), and the sphingolipid metabolism (Impact: 0.270, p=0.104) were identified as metabolic pathways associated with sleep disturbances in drug-naïve patients with schizophrenia. CONCLUSIONS: Our study identified 16 characteristic metabolites (mainly lipids) and 3 metabolic pathways related to sleep disturbances in drug-naïve schizophrenia. The detection of these distinct metabolites provide valuable insights into the underlying biological mechanisms associated with sleep disturbances in schizophrenia.
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Metabolômica , Esquizofrenia , Transtornos do Sono-Vigília , Humanos , Esquizofrenia/sangue , Esquizofrenia/complicações , Metabolômica/métodos , Feminino , Masculino , Adulto , Transtornos do Sono-Vigília/sangue , Transtornos do Sono-Vigília/metabolismo , Cromatografia Líquida , Espectrometria de Massas , Esfingolipídeos/sangue , Esfingolipídeos/metabolismo , Estudos de Casos e Controles , Adulto Jovem , Glicerofosfolipídeos/sangueRESUMO
Clozapine-resistant treatment-refractory schizophrenia (CR-TRS) patients face significant clinical challenges. While links between metabolic syndrome (MetS) and inflammatory cytokines in schizophrenia have been established, the relationship between MetS and cytokine levels in CR-TRS patients remains unexplored. This study aimed to investigate the relationship between cytokines levels, clinical symptoms and cognitive impairments in CR-TRS patients, both with and without MetS. The study included 69 CR-TRS patients (31with MetS and 38 without MetS) and 84 healthy controls. The levels of IL-2, IL-6, TNF-α and routine biochemical parameters were measured. Psychopathological symptoms and cognitive function were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), respectively. We found that CR-TRS patients with MetS displayed lower cognitive function scores compared to those without MetS, even when accounting for potential confounders. TNF-α levels were significantly higher in CRTRS patients with MetS compared to those without MetS, demonstrating substantial pathophysiological potential for CR-TRS patients with MetS via receiver operating characteristic curve (ROC). In CR-TRS patients without MetS, IL-2 independently contributed to the total score and general psychopathology subscore of PANSS. Additionally, IL-6 exhibited an independent contribution to the positive subscore of PANSS. In terms of cognition function, IL-6 independently contributed to the delayed memory of RBANS in CR-TRS patients without MetS. TNF-α could potentially serve as a predictive marker for distinguishing between CR-TRS patients with/without MetS, while IL-2 and IL-6 could independently contribute to psychopathological symptoms or cognitive function in CRTRS patients without MetS. Our study provided insights into the potential interplay between cytokines, clinical symptoms and cognitive impairments in CR-TRS patients with/without MetS.
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BACKGROUND: Inflammatory processes could potentially impact both mood and suicide risk, however, the relationship between cytokines and suicidal ideation remains unclear. This study aimed to investigate the association between plasma levels of cytokines and suicidal ideation in population with major depressive disorders (MDD). METHODS: A cross-sectional study was performed to assess the peripheral plasma levels of interleukin-1ß (IL-1ß), IL-2, IL-6, IL-8, IL-10 and tumor necrosis factor-α (TNF-α) in 88 Chinese Han first-episode drug-naïve MDD patients. Suicidal ideation in the past week were identified using the Beck Scale for Suicide Ideation-Chinese Version (BSI-CV). The Hamilton Depression Rating Scale-17 (HAMD-17), the Hamilton Anxiety Rating Scale-14 (HAMA-14) and the Childhood Trauma Questionnaire (CTQ) was used to assess depression, anxiety and childhood trauma. Multivariable logistic regression models were used to estimate the association between cytokines and suicidal ideation. Interaction and stratified analyses were conducted according to age, sex, marital status, education, smoking status, BMI and physical activity. RESULTS: Among the 88 participants, 42 individuals (47.7%) reported suicidal ideation within the past week. In the fully adjusted model, a statistically significant trend was observed in the association between IL-2 level and suicidal ideation (OR: 1.40, 95% CI: 1.00-1.97). The stratified analysis showed a statistically significant association between IL-6 level and suicidal ideation among younger people (OR: 1.17, 95% CI: 1.01-1.36) and a significant positive association between IL-8 (OR: 1.59, 95% CI: 1.03-2.44) and IL-10 (OR: 2.51, 95% CI: 1.27-4.96) levels and suicide ideation among higher educated populations. LIMITATIONS: The cross-sectional design, residual confounding effects and small sample size CONCLUSION: Our findings indicate a significant positive association between plasma IL-2 level and suicidal ideation in MDD patients. IL-2 has the potential to be a biomarker of suicidal ideation in patients with depression.
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Citocinas , Transtorno Depressivo Maior , Interleucina-2 , Ideação Suicida , Humanos , Masculino , Feminino , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/psicologia , Adulto , Estudos Transversais , Citocinas/sangue , Interleucina-2/sangue , Pessoa de Meia-Idade , Interleucina-6/sangue , Fator de Necrose Tumoral alfa/sangue , Interleucina-10/sangue , Interleucina-8/sangue , Interleucina-1beta/sangue , China , Escalas de Graduação Psiquiátrica , Adulto JovemRESUMO
BACKGROUND: Major depressive disorder (MDD) is one of the global burdens of disease, and its pathogenesis remains unclear. An increasing amount of research indicates that ghrelin regulates mood in patients with MDD. Still, current results are inconsistent, and the mechanisms underlying how ghrelin modulates depressive symptoms are inconclusive, especially in first-episode drug-naïve MDD patients. Therefore, this study aims to investigate the relationship and potential mechanism between ghrelin and first-episode drug-naïve MDD. METHODS: Ninety first-episode drug-naïve MDD patients and 65 healthy controls (HCs) were included. Hamilton Depression Scale (HAMD-17) as a measure of depressive symptoms. Plasma levels of ghrelin and hypothalamic-pituitary-adrenal axis (HPA-axis) hormones were measured in all participants. RESULTS: Compared to HCs, the ghrelin levels were higher in the MDD (p < .001) and still showed significance after covarying for sex, age, and Body Mass Index (BMI). Ghrelin was positively related to corticotropin-releasing-hormone (CRH) levels (r = .867, p < .001), adrenocorticotropic hormone (ACTH) levels (r = .830, p < .001), and cortisol levels (r = .902, p < .001) in partial correlation analysis. In addition, there was a positive correlation between HAMD total score and ghrelin levels (r = .240, p = .026). Other than that, the HAMD total score also had a positive correlation with the CRH (r = .333, p = .002) and cortisol (r = .307, p = .004) levels. Further mediation analysis demonstrated that the relationship between ghrelin and HAMD total score was mediated by CRH (ab-path; ß = .4457, 95% CI = 0.0780-1.0253, c-path; ß = .2447, p = .0260, c'-path; ß = -.2009, p = .3427). CONCLUSIONS: These findings revealed that plasma ghrelin provides a pivotal link to depressive symptoms in first-episode drug-naive MDD patients. CRH mediated the relationship between ghrelin and HAMD total score. It might provide new insights into understanding the pathogenesis of MDD, contributing to intervention and treatment from this approach.
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Transtorno Depressivo Maior , Humanos , Depressão , Sistema Hipotálamo-Hipofisário , Hidrocortisona , Grelina , Sistema Hipófise-SuprarrenalRESUMO
Purpose: Major depressive disorder (MDD) is associated with worse cognitive functioning. We aim to examine the association between baseline cognitive functioning and the reduction rate in HDRS-17 total scores and to highlight the predictors of the reduction rate in HDRS-17 total scores in MDD with first-episode, drug-naïve (FED) patients. Patients and Methods: Ninety FED patients were recruited consecutively and evaluated using the 17-item Hamilton Depression Rating Scale (HDRS-17), the 14-item Hamilton Anxiety Scale (HAMA-14), the Functioning Assessment Short Test (FAST) and the MATRICS Consensus Cognitive Battery (MCCB) at baseline and again at week 8. Results: Eighty-four FED patients completed the study. Comparison showed that response group had significantly higher T scores in TMT-A, BACS-SC, WMS-III, BVMT-R, MSCEI and CPT-IP, but showed significantly lower scores in FAST total scores including autonomy, occupational functioning, cognitive functioning, interpersonal relationship than non- response group (all p's< 0.05). Partial correlation analysis also found that the reduction rate in HDRS-17 total scores could be negatively associated with autonomy, cognitive functioning and interpersonal relationship domains as well as total FAST scores, also was further positively associated with T-scores of BACS-SC, CPT-IP and MSCEI in MCCB, even when accounting for potential confounders. Furthermore, the levels of cognitive function domain, autonomy domain in FAST, and BACS-SC, CPT-IP in MCCB may predict the reduction rate in HDRS-17 total scores in FED patients (all p's< 0.05). Conclusion: Our findings underscore significant correlations between baseline functioning and the reduction rate in HDRS-17 total scores in FED patients. Moreover, better baseline cognitive function, autonomy, speed of processing and attention/vigilance are more likely to predict patients' response to antidepressant treatment, indicating pre-treatment better cognitive functioning may be predictors to treatment response in FED.
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Background: Risperidone is a commonly prescribed antipsychotic drug with a potential side effect of weight gain. However, the pathophysiological mechanism is still poorly understood. Here, we sought to identify potential biomarkers of risperidone-induced weight gain by using a targeted metabolomics approach. Methods: We enrolled 30 subjects who received risperidone monotherapy for 8 weeks from a prospective longitudinal cohort study for drug-naïve schizophrenia patients. Plasma metabolites were measured by targeted metabolomics Biocrates MxP® Quant 500 Kit at baseline and 8-week follow-up. Results: After 8 weeks of risperidone treatment, the levels of 48 differential metabolites were upregulated, including lysophosphatidylcholines (2), phosphatidylcholines (PC) (8), cholesteryl esters (CE) (3), and triglycerides (35), while 6 differential metabolites namely PC aa C38:6, methionine (Met), α-aminobutyric acid (AABA), TrpBetaine, CE (22:6), and Taurocholic acid (TCA) were downregulated. Interestingly, the reduction of PC aa C38:6, AABA and CE (22:6) was linearly related with increased BMI. Further multiple regression analysis showed that the changes of PC aa C38:6 and AABA were independent contributors of increased BMI. In addition, baseline levels of PC aa C36:5, CE (20:5) and AABA had positive relationships with the change of BMI. Conclusion: Our findings indicate phosphatidylcholines and amino acids may serve as biomarkers for risperidone-induced weight gain.
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Alzheimer's disease (AD) is a chronic neurodegenerative disease, which leads to impairment of cognition and memory. The heat shock protein 70 (HSP70) family plays an important role in the pathogenesis of AD. It is known to regulate protein misfolding in a variety of diseases, including inhibition of Aß aggregation and NFT formation in AD. As yet, the diagnostic molecular markers of AD remain unclear. Herein, we sought to investigate molecular markers of HSP70 family that can affect diagnosis and treatment in AD through computational analysis. In this study, the intersection between HSP70 family members and immune molecules was taken to screen immune-related HSP70 family genes. Based on the datasets from the NCBI-Gene Expression Omnibus (GEO) database, we found that the expression levels of HSPA1A and HSPA2 were significantly increased in AD samples, while HSPA8 significantly decreased. Surprisingly, the combination of the 3 hub genes had a good diagnosis of AD via receiver operating characteristic curve (ROC). Moreover, the clinical value of the 3 hub genes was further assessed by the Spearman correlation analysis with AD-related genes, ß-secretase activity, and γ-secretase activity. In terms of immune cell infiltration, we showed that the distribution of seven immune cell types (macrophages M2, neutrophils, T cells CD4 memory activated, macrophages M0, NK cells activated, plasma cells, and T cells follicular helper) was associated with the occurrence of AD by CIBERSORT. Furthermore, our data suggested that EP300, MYC, TP53, JUN, CREBBP, and ESR1 might be key transcription factors (TFs) for the 3 hub genes. In general, these findings suggest that HSPA1A, HSPA2, and HSPA8 are potential molecular biomarkers for prognosis among HSP70 family in AD, and it provides a new perspective on diagnostic and therapeutic targets for AD.
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Doença de Alzheimer , Doenças Neurodegenerativas , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Biomarcadores , Proteínas de Choque Térmico HSC70/metabolismo , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Prognóstico , Fatores de TranscriçãoRESUMO
There is a shared problem in current optical imaging technologies of how to obtain the optical parameters of biological tissues with complex profiles. In this work, an imaging system for obtaining the optical parameters of biological tissues with complex profile was presented. Firstly, Fourier transformation profilometry was used for obtaining the profile information of biological tissues, and then the difference of incident light intensity at different positions on biological tissue surface was corrected with the laws of illumination, and lastly the optical parameters of biological tissues were achieved with the spatial frequency domain imaging technique. Experimental results indicated the proposed imaging system could obtain the profile information and the optical parameters of biological tissues accurately and quickly. For the slab phantoms with height variation less than 30 mm and angle variation less than 40º, the maximum relative errors of the profile uncorrected optical parameters were 46.27% and 72.18%, while the maximum relative errors of the profile corrected optical parameters were 6.89% and 10.26%. Imaging experiments of a face-like phantom and a human's prefrontal lobe were performed respectively, which demonstrated the proposed imaging system possesses clinical application value for the achievement of the optical parameters of biological tissues with complex profiles. Besides, the proposed profile corrected method can be used to combine with the current optical imaging technologies to reduce the influence of the profile information of biological tissues on imaging quality.
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Diagnóstico por Imagem , Luz , Humanos , Imagem Óptica , Imagens de FantasmasRESUMO
BACKGROUND: Depression affects more than 350 million people worldwide. In China, 4.2% (54 million people) of the total population suffers from depression. Psychotherapy has been shown to change cognition, improve personality, and enhance the ability to cope with difficulties and setbacks. While pharmacotherapy can reduce symptoms, it is also associated with adverse reactions and relapse after drug withdrawal. Therefore, there has been an increasing emphasis placed on the use of non-pharmacological therapies for depression. The hypothesis of this study was that acupuncture at ghost points combined with fluoxetine would be more effective than fluoxetine alone for the treatment of depression. AIM: To investigate the efficacy of acupuncture at ghost points combined with fluoxetine for the treatment of patients with depression. METHODS: This randomized controlled trial included patients with mild to moderate depression (n = 160). Patients received either acupuncture at ghost points combined with fluoxetine (n = 80) or fluoxetine alone (control group, n = 80). Needles were retained in place for 30 min, 5 times a week; three treatment cycles were administered. The Mann-Whitney U test was used to compare functional magnet resonance imaging parameters, Hamilton depression rating scale (HAMD) scores, and self-rating depression scale (SDS) scores between the acupuncture group and control group. RESULTS: There were no significant differences in HAMD or SDS scores between the acupuncture group and control group, before or after 4 wk of treatment. The acupuncture group exhibited significantly lower HAMD and SDS scores than the control group after 8 wk of treatment (P < 0.05). The acupuncture group had significantly lower fractional Amplitude of Low Frequency Fluctuations values for the left anterior wedge leaf, left posterior cingulate gyrus, left middle occipital gyrus, and left inferior occipital gyrus after 8 wk. The acupuncture group also had significantly higher values for the right inferior frontal gyrus, right insula, and right hippocampus (P < 0.05). After 8 wk of treatment, the effective rates of the acupuncture and control groups were 51.25% and 36.25%, respectively (P < 0.05). CONCLUSION: The study results suggest that acupuncture at ghost points combined with fluoxetine is more effective than fluoxetine alone for the treatment of patients with mild to moderate depression.
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Pheochromocytoma/paraganglioma (PPGL) is an endocrine tumor of the chromaffin cells in the adrenal medulla or the paraganglia. Currently, about 70% of PPGLs can be explained by germline or somatic mutations in several broadly expressed susceptibility genes including RET, VHL, and SDHB, while for the remaining, mainly sporadic cases, the pathogenesis is still unclear. Even for known susceptible genes, how mutations in these mostly ubiquitous genes result in tissue-specific pathogenesis remains unanswered, and why RET-mutated tumors almost always occur in the adrenal while SDHB-mutated tumors mostly occur extra-adrenal remains a mystery. By analyzing 22 sporadic PPGLs using SNP 6.0 genotyping arrays combined with expression profiling of 4 normal and 4 tumor tissues, we identified GIPC2, a gene located at 1p31.1 with preferential expression in adrenal and inducible by adrenal glucocorticoid, as a novel putative tumor suppressor gene for PPGLs. Copy number deletion and GIPC2 promoter hypermethylation but not GIPC2 mutation, accompanied with reduced GIPC2 expression, were observed in 39 of 55 PPGLs in our cohort. Examination of a published expression database consisting of 188 PPGLs found little GIPC2 expression in Cluster 1A (SDHx-associated) and Cluster 2A (NF1/RET-associated) tumors, but less pronounced reduction of GIPC2 expression in Cluster 1B (VHL-associated) and Cluster 2B/2C tumors. GIPC2 induced p27, suppressed MAPK/ERK and HIF-1É pathways as well as cancer cell proliferation. Overexpressing GIPC2 in PC12 cells inhibited tumor growth in nude mice. We found GIPC2 interacted with the nucleoprotein NONO and both proteins regulated p27 transcription through the same GGCC box on p27 promoter. Significantly, low expression of both GIPC2 and p27 was associated with shorter disease-free survival time of PPGLs patients in the TCGA database. We found that PPGL-causing mutations in RET and in SDHB could lead to primary rat adrenal chromaffin cell proliferation, ERK activation, and p27 downregulation, all requiring downregulating GIPC2. Notably, the RET-mutant effect required the presence of dexamethasone while the SDHB-mutant effect required its absence, providing a plausible explanation for the tumor location preference. In contrast, the PPGL-predisposing VHL mutations had no effect on proliferation and GIPC2 expression but caused p53 downregulation and reduced apoptosis in chromaffin cells compared with wild-type VHL. Thus, our study raises the importance of cortical hormone in PPGL development, and GIPC2 as a novel tumor suppressor provides a unified molecular mechanism for the tumorigenesis of both sporadic and hereditary tumors of Clusters 1A and 2A concerning SDHB and RET, but not tumors of Cluster 1B concerning VHL and other clusters.
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Neoplasias das Glândulas Suprarrenais/genética , Proteínas de Transporte/metabolismo , Genes Supressores de Tumor/fisiologia , Feocromocitoma/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Succinato Desidrogenase/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Humanos , Feocromocitoma/patologia , TransfecçãoRESUMO
p97/VCP, an evolutionarily concerned ATPase, partakes in multiple cellular proteostatic processes, including the endoplasmic reticulum (ER)-associated protein degradation (ERAD). Elevated expression of p97 is common in many cancers and is often associated with poor survival. Here we report that the levels of p97 positively correlated with the histological grade, tumor size, and lymph node metastasis in breast cancers. We further examined p97 expression in the stem-like cancer cells or cancer stem cells (CSCs), a cell population that purportedly underscores cancer initiation, therapeutic resistance, and recurrence. We found that p97 was consistently at a higher level in the CD44+/CD24-, ALDH+, or PKH26+ CSC populations than the respective non-CSC populations in human breast cancer tissues and cancer cell lines and p97 expression also positively correlated with that of SOX2, another CSC marker. To assess the role of p97 in breast cancers, cancer proliferation, mammosphere, and orthotopic growth were analyzed. Similarly as p97 depletion, two pharmacological inhibitors, which targets the ER-associated p97 or globally inhibits p97's ATPase activity, markedly reduced cancer growth and the CSC population. Importantly, depletion or inhibition of p97 greatly suppressed the proliferation of the ALDH+ CSCs and the CSC-enriched mammospheres, while exhibiting much less or insignificant inhibitory effects on the non-CSC cancer cells. Comparable phenotypes produced by blocking ERAD suggest that ER proteostasis is essential for the CSC integrity. Loss of p97 gravely activated the unfolded protein response (UPR) and modulated the expression of multiple stemness and pluripotency regulators, including C/EBPδ, c-MYC, SOX2, and SKP2, which collectively contributed to the demise of CSCs. In summary, p97 controls the breast CSC integrity through multiple targets, many of which directly affect cancer stemness and are induced by UPR activation. Our findings highlight the importance of p97 and ER proteostasis in CSC biology and anticancer therapy.
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Neoplasias da Mama/genética , Células-Tronco Neoplásicas/metabolismo , Resposta a Proteínas não Dobradas/imunologia , Proteína com Valosina/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos NusRESUMO
An amendment to this paper has been published and can be accessed via the original article.
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BACKGROUND: Vogesella species are common aquatic, Gram-negative rod-shaped bacteria, originally described in 1997. Vogesella perlucida was first isolated from spring water in 2008. Furthermore, bacterial pathogenicity of Vogesella perlucida has never been reported. Here, we report the first case of rare Vogesella perlucida-induced bacteremia in an advanced-age patient with many basic diseases and history of dexamethasone abuse. CASE PRESENTATION: A 71-year-old female was admitted with inflamed upper and lower limbs, rubefaction, pain and fever (about 40 °C). She had been injured in a fall at a vegetable market and then touched river snails with her injury hands. A few days later, soft tissue infection of the patient developed and worsened. Non-pigmented colonies were isolated from blood cultures of the patient. Initially, Vogesella perlucida was wrongly identified as Sphingomonas paucimobilis by Vitek-2 system with GN card. Besides, we failed to obtain an acceptable identification by the MALDI-TOF analysis. Finally, the isolated strain was identified as Vogesella perlucida by 16S rRNA gene sequences. In addition, the patient recovered well after a continuous treatment of levofloxacin for 12 days. CONCLUSION: Traditional microbiological testing system may be inadequate in the diagnosis of rare pathogenic bacteria. Applications of molecular diagnostics techniques have great advantages in clinical microbiology laboratory. By using 16S rRNA gene sequence analysis, we report the the first case of rare Vogesella perlucida-induced bacteremia.
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Bacteriemia/microbiologia , Betaproteobacteria/patogenicidade , Infecções dos Tecidos Moles/microbiologia , Idoso , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Técnicas de Tipagem Bacteriana , Betaproteobacteria/classificação , Betaproteobacteria/genética , Betaproteobacteria/isolamento & purificação , Feminino , Humanos , Levofloxacino/uso terapêutico , RNA Ribossômico 16S/genética , Infecções dos Tecidos Moles/tratamento farmacológico , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Vancomicina/uso terapêuticoRESUMO
Based on transformation optics, we propose a device to detect the presence of a carpet cloaking structure at near field. By using complementary media, the detective device can optically cancel a certain volume of reflective metal and reveal the hidden medium inside the metal. The detective performance of this device is confirmed by full-wave finite-element simulations. It is shown that the detective device is invisible when there is no carpet cloak in the system, yet it becomes visible with the presence of the carpet cloak. The device works at near field, but the response can be found even at the far field. Furthermore, it is shown that the device can detect both anisotropic and isotropic carpet cloaking structures. The investigation may provide a unique method to detect a carpet cloak and contribute to the design of novel optical devices, such as far field detectors for a nanoscale medium.