RESUMO
Objective: Double pituitary adenomas (DPA) are a rare clinical condition, and our knowledge of them is limited. Missing the second lesion leading to incomplete biochemical remission after surgery is an important challenge in DPA management. This study aims to analyze independent prognostic factors in DPA patients and summarize clinical experiences to prevent surgical failure. Methods: Two cases of DPA patients with Cushing's disease diagnosed and surgically treated at Peking Union Medical College Hospital are reported. A literature review was performed on the online database Pubmed, and 57 DPA patients from 22 retrieved articles were included. Demographic characteristics, endocrine manifestations, diagnostic methods, tumor size, and immunohistochemical features of 59 patients were analyzed. Binary logistic regression models were used to identify independent prognostic factors affecting postoperative biochemical remission. Results: Among 59 DPA patients, the mean ± SD age was 43.64 ± 14.42 years, with 61.02% being female (n = 36). The most common endocrine manifestations were Cushing's syndrome (23/59, 38.98%) and acromegaly (20/59, 33.90%). The most prevalent immunohistochemical types were ACTH-immunopositive (31/118, 26.27%) and GH-immunopositive (31/118, 26.27%) tumors. Microadenomas (<1cm) were the most frequent in terms of tumor size (62/92, 67.39%). The detection rate for double lesions on 3.0T MRI was 50.00% (14/28), which significantly higher than 1.5T MRI (P = 0.034). Univariate analysis revealed that female, Cushing's syndrome and only single lesion detected by surgical exploration were associated with significantly worse prognosis (P<0.05). Multivariate analysis identified double lesion detected by surgical exploration (OR = 0.08, P = 0.003) and contiguous type tumor (OR = 0.06, P = 0.017) as independent protective factors for DPA patients. Conclusions: The double lesion detected by surgical exploration is independently associated with a better prognosis for DPA patients. Comprehensive intraoperative exploration are crucial measures to avoid missing causative lesions.
Assuntos
Acromegalia , Adenoma , Síndrome de Cushing , Hipersecreção Hipofisária de ACTH , Neoplasias Hipofisárias , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Acromegalia/complicações , Adenoma/diagnóstico , Síndrome de Cushing/diagnóstico , Hipersecreção Hipofisária de ACTH/complicações , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/cirurgia , Neoplasias Hipofisárias/complicaçõesRESUMO
Cytosolic double-stranded DNA surveillance by cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) signaling triggers cellular senescence, autophagy, biased mRNA translation, and interferon-mediated immune responses. However, detailed mechanisms and physiological relevance of STING-induced senescence are not fully understood. Here, we unexpectedly found that interferon regulatory factor 3 (IRF3), activated during innate DNA sensing, forms substantial endogenous complexes in the nucleus with retinoblastoma (RB), a key cell cycle regulator. The IRF3-RB interaction attenuates cyclin-dependent kinase 4/6 (CDK4/6)-mediated RB hyperphosphorylation that mobilizes RB to deactivate E2 family (E2F) transcription factors, thereby driving cells into senescence. STING-IRF3-RB signaling plays a notable role in hepatic stellate cells (HSCs) within various murine models, pushing activated HSCs toward senescence. Accordingly, IRF3 global knockout or conditional deletion in HSCs aggravated liver fibrosis, a process mitigated by the CDK4/6 inhibitor. These findings underscore a straightforward yet vital mechanism of cGAS-STING signaling in inducing cellular senescence and unveil its unexpected biology in limiting liver fibrosis.
Assuntos
Neoplasias da Retina , Retinoblastoma , Camundongos , Animais , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , DNA/metabolismo , Interferons/metabolismoRESUMO
BACKGROUND: Anoikis is a speed-limited procedure to inhibit tumor metastasis during epithelial-mesenchymal transition (EMT). Previous studies have explored anoikis-related genes (ARG) in predicting prognosis and distinguishing tumoral immunity in many types of cancer. However, the role of ARGs in regulating NK cell exhaustion (NKE) and in predicting chemotherapy sensitivity is not clear. Therefore, it is necessary to work on it. METHODS: Gene expression profiles and clinical features are collected from TCGA and GEO, and data analysis is performed in R4.2.0. RESULTS: The ARGs-based no-supervised learning algorithm identifies three ARG subgroups, amongst which the prognosis is different. WCGNA and Artificial intelligence (AI) are applied to construct an NKE-related drug sensitivity stratification and prognosis identification model in digestive system cancer. Pathways association analysis screens out GLI2 is a key gene in regulating NKE by non-classic Hedgehog signaling (GLI2/TGF-ß/IL6). In vitro experiments show that down-regulation of GLI2 enhances the CAPE-mediated cell toxicity and accompanies with down-regulation of PD-L1, tumor-derive IL6, and snial1 whereas the expression of cleaved caspas3, cleaved caspase4, cleaved PARP, and E-cadherin are up-regulated in colorectal cancer. Co-culture experiments show that GLI2- decreased colorectal tumor cells lead to down-regulation of TIM-3 and PD1 in NK cells, which are restored by TGF-bate active protein powder. Besides, the Elisa assay shows that GLI2-decreased colorectal tumor cells lead to up-regulation of IFN-gamma in NK cells.
Assuntos
Anoikis , Neoplasias Colorretais , Proteínas Hedgehog , Proteína Gli2 com Dedos de Zinco , Humanos , Anoikis/genética , Inteligência Artificial , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Interleucina-6 , Proteínas Nucleares/genética , Fator de Crescimento Transformador beta , Proteína Gli2 com Dedos de Zinco/genéticaRESUMO
BACKGROUND: Venous thromboembolism (VTE) can occur in children with COVID-19, and the efficacy and safety of prophylactic anticoagulant therapy are uncertain. This study aimed to assess the incidence of VTE in pediatric patients with COVID-19, the association of D-dimer with thrombus formation, and the effectiveness and safety of prophylactic anticoagulation treatment. METHODS: We systematically searched databases from January 2020 to February 2023. A systematic review and meta-analysis were conducted to determine the incidence of VTE in children and evaluate the efficacy and safety of prophylactic anticoagulant therapy. RESULTS: Thirteen cohort studies and one clinical trial were included. The pooled incidence rate of VTE in affected children was 1.5% (95% CI 0.4-2.9%). Children with D-dimer levels five times higher than normal had a higher risk of VTE (OR 4.92, 95% CI 1.60-15.11). Prophylactic anticoagulant therapy did not significantly reduce the risk of VTE (OR 1.35, 95% CI 0.74-2.49). The safety of prophylactic anticoagulant therapy was relatively high, with major bleeding and all-cause mortality rates below 0.1% (95% CI 0.0-0.2%). CONCLUSIONS: The incidence of VTE in children with COVID-19 is low, and prophylaxis based on ISTH standards is reasonable. Low-molecular-weight heparin (LMWH) for VTE prevention has a high level of safety. However, more high-quality studies are needed to understand the impact of anticoagulant therapy on VTE incidence in pediatric patients with COVID-19.
Assuntos
COVID-19 , Trombose , Tromboembolia Venosa , Humanos , Criança , Heparina de Baixo Peso Molecular/efeitos adversos , COVID-19/complicações , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , Anticoagulantes/efeitos adversos , Trombose/epidemiologia , Trombose/etiologia , Trombose/prevenção & controle , Heparina/efeitos adversosRESUMO
Intracranial germ cell tumors (IGCTs) are a rare subtype of central nervous system neoplasms that predominantly affect young individuals and exhibit a higher incidence in East Asia. IGCTs can be pathologically divided into two main categories: germinomas and non-germinomatous germ cell tumors (NGGCTs). Despite the scarcity of this disease, recent advancements in molecular biology techniques have facilitated the discovery of the inherent genetic and molecular characteristics of IGCTs. Somatic mutations that result in the activation of the KIT/RAS/MAPK and PI3K/AKT/mTOR pathways, chromosomal instability leading to characteristic changes in chromosomal fragments (notably 12p gain), and potentially diagnostic miRNAs (such as miR-371a-3p) may provide valuable insights for the efficient diagnosis, targeted therapy, and prognosis evaluation of IGCTs. Additionally, transcriptomic and methylomic analyses have provided new perspectives on the intrinsic development of IGCTs, further elucidating their equivalence with GCTs at other sites. The evaluation of the tumor immune landscape may guide prognosis prediction and immunotherapy for IGCT patients. Nevertheless, current research still faces challenges such as the absence of basic laboratory research systems, a single source of large sample research data, and a limited overall volume of research. The incorporation of larger sample sizes, the implementation of more innovative evaluation systems, and the employment of novel experimental methods are urgently required to become the focus of future research.
Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , MicroRNAs , Neoplasias Embrionárias de Células Germinativas , Humanos , Neoplasias Encefálicas/patologia , Neoplasias Embrionárias de Células Germinativas/genética , Fosfatidilinositol 3-Quinases/genética , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Epigênese GenéticaRESUMO
B-cell lymphoma 2-related protein A1 (BCL2A1) is a member of the BCL-2 family. Previous studies have shown that BCL2A1 is closely related to the tumorigenesis and resistance to chemotherapy of multiple solid tumors, such as breast cancer. However, the expression pattern and potential biological function of BCL2A1 in glioma remain unknown. For the first time, we found that the expression of BCL2A1 was higher in human glioma tissues than in normal brain tissues (NBTs) in both public datasets and an in-house cohort. High BCL2A1 expression was associated with advanced WHO grade, IDH 1/2 wild type and the mesenchymal (ME) subtype, and its overexpression in glioma predicted resistance to temozolomide (TMZ) chemotherapy and unfavorable prognosis. In addition, Gene set enrichment analysis (GSEA), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that BCL2A1 was significantly correlated with the immune response and immune-related pathways, and BCL2A1 expression was positively correlated with microenvironmental parameters (immune, stromal, and ESTIMATE scores) and macrophage infiltration. Interestingly, bioinformatic prediction and immunohistochemical/immunofluorescence staining analysis revealed that BCL2A1 expression was obviously associated with the tumor-associated macrophages (TAMs) markers CD68 and CCL2. Notably, knockdown of BCL2A1 significantly inhibited cell proliferation of U87 and U251 in vitro, induced smaller tumor size and prolonged survival time of mice in vivo. Co-culture experiments of macrophages and GBM cells showed that BCL2A1 knockdown inhibited macrophage migration. Meanwhile, knockdown of BCL2A1 was associated with low expression of CD68 and CCL2 in intracranial xenograft model. This may suggest that BCL2A1 promotes the progression of glioma and influences the prognosis of patients by participating in TAMs infiltration. In conclusion, these findings suggest that BCL2A1 could serve as a promising prognostic indicator and immunotherapy target in gliomas.
Assuntos
Neoplasias da Mama , Glioma , Animais , Feminino , Humanos , Camundongos , Glioma/genética , Macrófagos , Prognóstico , Macrófagos Associados a TumorRESUMO
As a protector of human health, the gut microbiota plays an important role in the development of the immune system during childhood, and the regulation of dietary habits, metabolism and immune system during adulthood. Dysregulated gut flora is not pathogenic, but it can weaken the protective effect of the immune system and cause various diseases. The tumor microenvironment is a physiological environment formed during tumor growth, which provides nutrients and growth factors necessary for tumor growth. As an important factor affecting the tumor microenvironment, the intestinal microflora affects the development of tumors through the mechanisms of gut and microflora metabolites, gene toxins and signaling pathways. The present article aimed to review the components and mechanisms of action, clinical applications, and biological targets of gut microbiota in the regulation of the tumor microenvironment. The present review provides novel insights for the future use of intestinal flora, to regulate the tumor microenvironment, to intervene in the occurrence, development, treatment and prognosis of tumors.
Assuntos
Microbioma Gastrointestinal , Humanos , Adulto , Microambiente TumoralRESUMO
Glioblastoma multiforme (GBM) is the most common intracranial malignant tumor and is notorious for its poor prognosis. An important element in the short overall survival of GBM patients is the lack of understanding the pathogenesis and progression of tumor and deficiency biomarkers that can be used for early diagnosis and therapeutic sensitivity monitoring. Studies have shown that transmembrane protein 2 (TMEM2) is participated in tumorigenesis of various human tumors, including rectal and breast cancers. Although Qiuyi Jiang et al. have reported that TMEM2 combined with IDH1/2 and 1p19q can predict the survival time of glioma patients based on bioinformatics, its expression and biological role of glioma remain unclear. In our study, we investigated the effect of TMEM2 expression level on glioma malignancy in public datasets and an independent internal dataset. We revealed TEMM2 expression was higher in GBM tissues than in non-tumor brain tissues (NBT). Moreover, the increase in TMEM2 expression level was closely related to tumor malignancy. The survival analysis showed that TMEM2 high expression reduces survival time in all glioma patients, including GBM and LGG patients. Subsequent experiments demonstrated that knockdown TMEM2 inhibited proliferation of GBM cells. In addition, we analyzed TMEM2 mRNA levels in different GBM subtypes, and demonstrated that TMEM2 expression was upregulated in mesenchymal subtype. Meanwhile, bioinformatics analysis and transwell assay indicated that knockdown TMEM2 suppressed epithelial-mesenchymal transition (EMT) in GBM. Importantly, Kaplan-Meier analysis demonstrated that TMEM2 high expression reduced the treatment response to TMZ in GBM patients. Knockdown of TMEM2 alone did not reduce apoptosis GBM cells, but significant apoptotic cells were observed in the group treated with additional TMZ. These studies may contribute to improving the accuracy of early diagnosis and evaluating the effectiveness of TMZ treatment in GBM patients.
RESUMO
The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial showed improvement in overall survival (OS) and other efficacy endpoints with apalutamide plus androgen deprivation therapy (ADT) versus ADT alone in patients with metastatic castration-sensitive prostate cancer (mCSPC). As ethnicity and regional differences may affect treatment outcomes in advanced prostate cancer, a post hoc final analysis was conducted to assess the efficacy and safety of apalutamide in the Asian subpopulation. Event-driven endpoints were OS, and time from randomization to initiation of castration resistance, prostate-specific antigen (PSA) progression, and second progression-free survival (PFS2) on first subsequent therapy or death. Efficacy endpoints were assessed using the Kaplan-Meier method and Cox proportional-hazards models without formal statistical testing and adjustment for multiplicity. Participating Asian patients received once-daily apalutamide 240 mg ( n = 111) or placebo ( n = 110) plus ADT. After a median follow-up of 42.5 months and despite crossover of 47 placebo recipients to open-label apalutamide, apalutamide reduced the risk of death by 32% (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.42-1.13), risk of castration resistance by 69% (HR: 0.31; 95% CI: 0.21-0.46), PSA progression by 79% (HR: 0.21; 95% CI: 0.13-0.35) and PFS2 by 24% (HR: 0.76; 95% CI: 0.44-1.29) relative to placebo. The outcomes were comparable between subgroups with low- and high-volume disease at baseline. No new safety issues were identified. Apalutamide provides valuable clinical benefits to Asian patients with mCSPC, with an efficacy and safety profile consistent with that in the overall patient population.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/patologia , Antagonistas de Androgênios/uso terapêutico , Antígeno Prostático Específico , Castração , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológicoRESUMO
Glioblastoma multiforme (GBM) is the most common and fatal primary malignant central nervous system tumor in adults. Although there are multiple treatments, the median survival of GBM patients is unsatisfactory, which has prompted us to continuously investigate new therapeutic strategies, including new drugs and drug delivery approaches. Ferroptosis, a kind of regulated cell death (RCD), has been shown to be dysregulated in various tumors, including GBM. Fatostatin, a specific inhibitor of sterol regulatory element binding proteins (SREBPs), is involved in lipid and cholesterol synthesis and has antitumor effects in a variety of tumors. However, the effect of fatostatin has not been explored in the field of ferroptosis or GBM. In our study, through transcriptome sequencing, in vivo experiments, and in vitro experiments, we found that fatostatin induces ferroptosis by inhibiting the AKT/mTORC1/GPX4 signaling pathway in glioblastoma. In addition, fatostatin inhibits cell proliferation and the EMT process through the AKT/mTORC1 signaling pathway. We also designed a p28-functionalized PLGA nanoparticle loaded with fatostatin, which could better cross the blood-brain barrier (BBB) and be targeted to GBM. Our research identified the unprecedented effects of fatostatin in GBM and presented a novel drug-targeted delivery vehicle capable of penetrating the BBB in GBM.
Assuntos
Neoplasias Encefálicas , Ferroptose , Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Proteínas Proto-Oncogênicas c-akt , Alvo Mecanístico do Complexo 1 de Rapamicina , Linhagem Celular Tumoral , Transdução de Sinais , Neoplasias Encefálicas/tratamento farmacológicoRESUMO
BACKGROUND: Mitochondria represent a major source of reactive oxygen species (ROS) in cells, and the direct increase in ROS content is the primary cause of oxidative stress, which plays an important role in tumor proliferation, invasion, angiogenesis, and treatment. However, the relationship between mitochondrial oxidative stress-related genes and glioblastoma (GBM) remains unclear. This study aimed to investigate the value of mitochondria and oxidative stress-related genes in the prognosis and therapeutic targets of GBM. METHODS: We retrieved mitochondria and oxidative stress-related genes from several public databases. The LASSO regression and Cox analyses were utilized to build a risk model and the ROC curve was used to assess its performance. Then, we analyzed the correlation between the model and immunity and mutation. Furthermore, CCK8 and EdU assays were utilized to verify the proliferative capacity of GBM cells and flow cytometry was used to analyze apoptosis rates. Finally, the JC-1 assay and ATP levels were utilized to detect mitochondrial function, and the intracellular ROS levels were determined using MitoSOX and BODIPY 581/591 C11. RESULTS: 5 mitochondrial oxidative stress-related genes (CTSL, TXNRD2, NUDT1, STOX1, CYP2E1) were screened by differential expression analysis and Cox analysis and incorporated in a risk model which yielded a strong prediction accuracy (AUC value = 0.967). Furthermore, this model was strongly related to immune cell infiltration and mutation status and could identify potential targeted therapeutic drugs for GBM. Finally, we selected NUDT1 for further validation in vitro. The results showed that NUDT1 was elevated in GBM, and knockdown of NUDT1 inhibited the proliferation and induced apoptosis of GBM cells, while knockdown of NUDT1 damaged mitochondrial homeostasis and induced oxidative stress in GBM cells. CONCLUSION: Our study was the first to propose a prognostic model of mitochondria and oxidative stress-related genes, which provided potential therapeutic strategies for GBM patients.
Assuntos
Genes Mitocondriais , Glioblastoma , Estresse Oxidativo , Humanos , Glioblastoma/genética , Glioblastoma/patologia , Estresse Oxidativo/genética , Prognóstico , Espécies Reativas de Oxigênio/metabolismoRESUMO
Early transition metals based 2D carbides, nitrides and carbonitrides nanomaterials are known as MXenes, a novel and extensive new class of 2D materials family. Since the first accidently synthesis based discovery of Ti3 C2 in 2011, more than 50 additional compositions have been experimentally reported, including at least eight distinct synthesis methods and also more than 100 stoichiometries are theoretically studied. Due to its distinctive surface chemistry, graphene like shape, metallic conductivity, high hydrophilicity, outstanding mechanical and thermal properties, redox capacity and affordable with mass-produced nature, this diverse MXenes are of tremendous scientific and technological significance. In this review, first we'll come across the MXene based nanomaterials possible synthesis methods, their advantages, limitations and future suggestions, new chemistry related to their selected properties and potential sensing applications, which will help us to explain why this family is growing very fast as compared to other 2D families. Secondly, problems that help to further improve commercialization of the MXene nanomaterials based sensors are examined, and many advances in the commercializing of the MXene nanomaterials based sensors are proposed. At the end, we'll go through the current challenges, limitations and future suggestions.
RESUMO
Glioma is a common type of brain tumor with high incidence and mortality rates. Iron plays an important role in various physiological and pathological processes. Iron entry into the cell is promoted by binding the transferrin receptor 2 (TFR2) to the iron-transferrin complex. This study was designed to assess the association between TFR2 and ferroptosis in glioma. Lipid peroxidation levels in glioma cells were assessed by determination of lipid reactive oxygen species (ROS), glutathione content, and mitochondrial membrane potential. The effect of TFR2 on TMZ sensitivity was examined by cell viability assays, flow cytometry, and colony formation assays. We found that Low TFR2 expression predicted a better prognosis for glioma patients. And overexpression of TFR2 promoted the production of reactive oxygen species and lipid peroxidation in glioma cells, thereby further promoting ferroptosis. This could be reversed by the ferroptosis inhibitors Fer-1 and DFO (both inhibitors of ferroptosis). Moreover, TFR2 potentiated the cytotoxic effect of TMZ (temozolomide) via activating ferroptosis. In conclusion, we found that TFR2 induced ferroptosis and enhanced TMZ sensitivity in gliomas. Our findings might provide a new treatment strategy for glioma patients and improve their prognosis.
Assuntos
Ferroptose , Glioma , Humanos , Temozolomida/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Apoptose , Linhagem Celular Tumoral , Glioma/tratamento farmacológico , Glioma/genética , Glioma/metabolismo , Ferro/metabolismo , Receptores da Transferrina/genéticaRESUMO
RNA-binding proteins (RBP) regulate several aspects of co- and post-transcriptional gene expression in cancer cells. CSTF2 is involved in the expression of many cellular mRNAs and involved in the 3'-end cleavage and polyadenylation of pre-mRNAs to terminate transcription. However, the role of CSTF2 in human glioblastoma (GBM) and the underlying mechanisms remain unclear. In the present study, CSTF2 was found to be upregulated in GBM, and its high expression predicted poor prognosis. Knockdown CSTF2 induced GBM cell apoptosis both in vitro and in vivo. Specific mechanism studies showed that CSTF2 unstabilized the mRNA of the BAD protein by shortening its 3' UTR. Additionally, an increase in the expression level of CSTF2 decreased the expression level of BAD. In conclusion, CSTF2 binds to the mRNA of the BAD protein to shorten its 3'UTR, which negatively affects the BAD mediated apoptosis and promotes GBM cell survival.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/genética , Glioblastoma/metabolismo , Proteína de Morte Celular Associada a bcl/genética , Proteína de Morte Celular Associada a bcl/metabolismo , Apoptose/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismoRESUMO
Sirtuin-6 (SIRT6), a member of the sirtuins family of NAD ( +) dependent deacetylases, has been shown to have beneficial effects in ischemic stroke. However, the role of SIRT6 in intracerebral haemorrhage (ICH) has not reported. We observed that SIRT6 expression was down-regulated in human ICH patients and down-regulated in ICH-induced rat cortical neurons. We subsequently found that SIRT6 overexpression reduced brain tissue damage and increased neuronal survival in the ICH model of rats and hemin-induced cortical neurons. Our further study found that overexpression of SIRT6 can reduce inflammatory response by down-regulating the expression of NF-kB and thus promote the recovery of neurological function in ICH animals. In conclusion, SIRT6 can inhibit the expression of NF-kB and plays a neuroprotective role in ICH by inhibiting the NF-kB-mediated inflammatory response.SIRT6 could be a novel therapeutic target for ICH.
Assuntos
NF-kappa B , Sirtuínas , Ratos , Humanos , Animais , NF-kappa B/metabolismo , Hemorragia Cerebral/genética , Hemorragia Cerebral/metabolismo , Neuroproteção , Sirtuínas/genéticaRESUMO
BACKGROUND: Bipolar disorder is among the top 10 causes of disability worldwide. The Short-Form Six-Dimension (SF-6D) is a frequently used measure of preference-based health-related quality of life (HRQOL). However, this measure's psychometric performance has not been tested in outpatient patients with bipolar disorder. AIMS OF THE STUDY: This study assessed the psychometric properties of the SF-6D, including convergent validity, known-groups validity, and responsiveness. METHODS: We examined convergent validity between the SF-6D and four condition-specific measures of functioning (LIFE-RIFT), life satisfaction (QLESQ), depressive symptoms (MADRS), and manic symptoms (YMRS). We used known-groups validity tests to compare the SF-6D health utility values estimated for patients in different clinical states, including depression, mania, hypomania, and recovered. We assessed the responsiveness of the SF-6D by comparing the sensitivity of the SF-6D utility values to longitudinal changes in the four condition-specific measures during the same period of time. We conducted all analyses using data from 2,627 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) clinical trial. RESULTS: The SF-6D demonstrated moderate (0.3-0.7) convergence with the LIFE-RIFT, QLESQ, and MADRS measures. Convergence with the manic symptoms measure (YMRS) was weak (<0.3). For known-groups validity, the SF-6D distinguished the recovered state from the three symptomatic clinical states. For responsiveness, the measure did not show floor or ceiling effects. The SF-6D utility value increased when mental health improved, with a small ES of 0.3 over the 1-year period, which was comparable to the four condition-specific measures. DISCUSSION: The SF-6D demonstrated moderate convergent validity, moderate responsiveness, and it can distinguish the differences between known-groups that had been identified in literature. The SF-6D may be a suitable measure of preference-based HRQOL for patients with bipolar disorder, but caution is needed due to its lower convergence with the YMRS mania scale. LIMITATIONS: The subsample of patients in manic episode was small, which may reduce the reliability of study findings regarding this specific clinical state. In terms of generalizability, the STEP-BD study sample is based on patients who received treatment in bipolar specialty clinics affiliated with academic medical centers, which may be different from other outpatient clinics. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: The mean health utility value for patients with hypomania is significantly lower than the mean value for recovered patients. This finding emphasizes the importance of treating hypomania. IMPLICATION FOR HEALTH POLICIES: This study validates an existing approach toward generating health utility values for bipolar disorder. These utility values can be used to create quality-adjusted life years (QALYs), which are the most commonly used measure of health benefit in cost-effectiveness studies. IMPLICATIONS FOR FURTHER RESEARCH: Studies with larger samples of patients with mania are needed to study measures of health utility in this patient population.
Assuntos
Transtorno Bipolar , Qualidade de Vida , Humanos , Psicometria/métodos , Mania , Pacientes Ambulatoriais , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
Lower-grade glioma (LGG) is a common malignant primary tumour in the central nervous system, and most patients eventually develop highly aggressive gliomas despite comprehensive traditional treatment. Tumour molecular subtypes and prognostic biomarkers play a crucial role in LGG diagnosis and treatment. Therefore, the identification of novel biomarkers in LGG patients is crucial for predicting the prognosis of glioma. Immunogenic cell death (ICD) is defined as regulated cell death that is sufficient to activate the adaptive immune response of immunocompetent hosts. The combination of ICD and immunotherapy might exert a greater and more persistent antitumour effect in gliomas. In our study, we explored the expression, function, and genetic alterations of 34 ICD-related genes. Using 12 ICD-related genes, including IL17RA, IL1R1, EIF2AK3, CD4, PRF1, CXCR3, CD8A, BAX, PDIA3, CASP8, MYD88, and CASP1, we constructed and validated an ICD-related risk signature via least absolute shrinkage and selection operator (LASSO) Cox regression analysis. All the information was obtained from public databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and the Chinese Glioma Genome Atlas (CGGA) databases. Our results revealed that ICD-high risk groups have a poor prognosis and might be more sensitive to immune checkpoint blockade (ICB) immunotherapy. In addition, ICD-high risk groups were associated with 1p19q noncodeletion, higher WHO grade, wild type IDH, and an immunosuppressive tumour microenvironment. We verified the prognostic value of 12 ICD-related genes in TCGA and CGGA databases. Immunohistochemistry was performed to verify the expression of several ICD-related genes at the protein level. Our study provides a novel and comprehensive perspective to elucidate the underlying mechanisms of LGG prognosis and direction for future individualized cancer immunotherapy.
Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patologia , Microambiente Tumoral/genética , Morte Celular Imunogênica , Transcriptoma , Glioma/genética , Glioma/terapia , Glioma/metabolismo , PrognósticoRESUMO
Gliomas are one of the most frequent types of nervous system tumours and have significant morbidity and mortality rates. As a result, it is critical to fully comprehend the molecular mechanism of glioma to predict prognosis and target gene therapy. The goal of this research was to discover the hub genes of glioma and investigate their prognostic and diagnostic usefulness. In this study, we collected mRNA expression profiles and clinical information from glioma patients in the TCGA, GTEx, GSE68848, and GSE4920 databases. WGCNA and differential expression analysis identified 170 DEGs in the collected datasets. GO and KEGG pathway analyses revealed that DEGs were mainly enriched in gliogenesis and extracellular matrix. LASSO was performed to construct prognostic signatures in the TCGA cohort, and 17 genes were used to build risk models and were validated in the CGGA database. The ROC curve confirmed the accuracy of the prognostic signature. Univariate and multivariate Cox regression analyses showed that all independent risk factors for glioma except gender. Next, we performed ssGSEA to demonstrate a high correlation between risk score and immunity. Subsequently, 7 hub genes were identified by the PPI network and found to have great drug targeting potential. Finally, RPL39, as one of the hub genes, was found to be closely related to the prognosis of glioma patients. Knockdown of RPL39 in vitro significantly inhibited the proliferation and migration of glioma cells, whereas overexpression of RPL39 had the opposite effect. And we found that knockdown of RPL39 inhibited the polarization and infiltration of M2 phenotype macrophages. In conclusion, our new prognosis-related model provides more potential therapeutic strategies for glioma patients.