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Objective: To assess the effectiveness and clinical value of case-cohort design and determine prognostic factors of breast cancer patients in Xinjiang on the basis of case-cohort design. Methods: The survival data with different sample characteristics were simulated by using Cox proportional risk models. To evaluate the effectiveness for the case-cohort, entire cohort, and simple random sampling design by comparing the mean, coefficient of variation, etc., of covariate parameters. Furthermore, the prognostic factors of breast cancer patients in Xinjiang were determined based on case-cohort sampling designs. The models were comprehensively evaluated by likelihood ratio test, the area under the receiver operating characteristic curve (AUC), and Akaike Information Criterion (AIC). Results: In a simulations study, the case-cohort design shows better stability and improves the estimation efficiency when the censored rate is high. In the breast cancer data, molecular subtypes, T-stage, N-stage, M-stage, types of surgery, and postoperative chemotherapy were identified as the prognostic factors of patients in Xinjiang. These models based on the different sampling designs both passed the likelihood ratio test (p<0.05). Moreover, the model constructed under the case-cohort design had better fitting effect (AIC=3,999.96) and better discrimination (AUC=0.807). Conclusion: Simulations study confirmed the effectiveness of case-cohort design and further determined the prognostic factors of breast cancer patients in Xinjiang based on this design, which presented the practicality of case-cohort design in actual data.
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Objective: To examine the factors that affect the prognosis and survival of breast cancer patients who were diagnosed at the Affiliated Cancer Hospital of Xinjiang Medical University between 2015 and 2021, forecast the overall survival (OS), and assess the clinicopathological traits and risk level of prognosis of patients in various subgroups. Method: First, nomogram model was constructed using the Cox proportional hazards models to identify the independent prognostic factors of breast cancer patients. In order to assess the discrimination, calibration, and clinical utility of the model, additional tools such as the receiver operating characteristic (ROC) curve, calibration curve, and clinical decision curve analysis (DCA) were used. Finally, using two-step cluster analysis (TCA), the patients were grouped in accordance with the independent prognostic factors. Kaplan-Meier survival analysis was employed to compare prognostic risk among various subgroups. Result: T-stage, N-stage, M-stage, molecular subtyping, type of operation, and involvement in postoperative chemotherapy were identified as the independent prognostic factors. The nomogram was subsequently constructed and confirmed. The area under the ROC curve used to predict 1-, 3-, 5- and 7-year OS were 0.848, 0.820, 0.813, and 0.791 in the training group and 0.970, 0.898, 0.863, and 0.798 in the validation group, respectively. The calibration curves of both groups were relatively near to the 45° reference line. And the DCA curve further demonstrated that the nomogram has a higher clinical utility. Furthermore, using the TCA, the patients were divided into two subgroups. Additionally, the two groups' survival curves were substantially different. In particular, in the group with the worse prognosis (the majority of patients did not undergo surgical therapy or postoperative chemotherapy treatment), the T-, N-, and M-stage were more prevalent in the advanced, and the total points were likewise distributed in the high score side. Conclusion: For the survival and prognosis of breast cancer patients in Xinjiang, the nomogram constructed in this paper has a good prediction value, and the clustering results further demonstrated that the selected factors were important. This conclusion can give a scientific basis for tailored treatment and is conducive to the formulation of focused treatment regimens for patients in practical practice.
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Purpose: The neuronal ELAV-like proteins (nElavls; Elavl2, Elavl3, Elavl4) have been known to regulate neuronal differentiation, maintenance, and axonogenesis in the brain. However, the specific role of nElavls in retina remains unclear. Here, we attempted to identify the expression pattern of Elavl2 during retinogenesis and aimed to decipher the function of Elavl2 in the retina. Methods: We have used the Cre-loxP system to conditionally inactivate Elavl2 in order to examine its role in developing retina. Eyes were collected for histology, immunohistochemistry, and TUNEL analysis to identify the structure of retina, and examined by RNA sequencing to analyze the function and pathway enrichment of differentially expressed genes in transgenic mice. Moreover, the mechanism by which Elavl2 regulates the differentiation of amacrine cells (ACs) was explored by RNA immunoprecipitation assays. Finally, eyes were functionally assessed by whole-cell patch-clamp, electroretinography (ERG) and optomotor response. Results: Elavl2 was expressed in retinal progenitor cells and retinal ganglion cells (RGCs), ACs, and horizontal cells. Retina-specific ablation of Elavl2 led to the loss of ACs and the transcription factors involved in ACs differentiation were also downregulated. In addition, the spontaneous activities of RGCs were obviously increased in Elavl2-deficient mice. Meanwhile, the loss of ACs that induced by Elavl2 deficiency lead to a decrease in ERG responses and visual acuity. Conclusions: Elavl2 is an intrinsic factor that involved in the differentiation of ACs subtype during retinogenesis, and essential for maintaining the normal retinal function.
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Células Amácrinas/fisiologia , Proteína Semelhante a ELAV 2/genética , Proteínas do Tecido Nervoso/genética , Neurogênese/genética , Retina , Animais , Diferenciação Celular , Eletrorretinografia/métodos , Regulação da Expressão Gênica no Desenvolvimento , Interneurônios/fisiologia , Camundongos , Camundongos Transgênicos , Técnicas de Patch-Clamp/métodos , Retina/embriologia , Retina/crescimento & desenvolvimento , Retina/fisiologia , Células Ganglionares da Retina/fisiologia , TranscriptomaRESUMO
RATIONALE: The management of complete obstruction of anastomosis following colorectal surgery is challenging. Some modified minimally invasive methods have been reported to be successfully implemented in some cases. In this case report, we present a case to share our experience. PATIENT CONCERNS: A 64-year-old man underwent low anterior resection and single barrel ileostomy for rectal cancer 5 months ago. Completely obstructed anastomotic stenosis was found during colonoscopy. DIAGNOSIS: Colonoscopy showed the anastomosis at 8âcm from the anal verge was completely obstructed. INTERVENTIONS: A small incision was made by a needle knife, and then the stenosis was sequentially dilated by using a wire-guided balloon dilator. OUTCOMES: The luminal continuity was reestablished. The patient underwent successful ileostomy closure 2 months later. At 18-months follow-up, no restenosis of the anastomosis was observed during colonoscopy. LESSONS: Endoscopic small incision with a needle knife along with balloon dilation could be an alternative method for patients with complete obstruction of anastomosis after colorectal resection. But this procedure should be performed with great caution in selected patients and performed only by highly experienced endoscopists.
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Colonoscopia , Neoplasias Colorretais/cirurgia , Obstrução Intestinal/terapia , Complicações Pós-Operatórias/terapia , Anastomose Cirúrgica , Terapia Combinada , Constrição Patológica , Dilatação/instrumentação , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Choroidal neovascularization (CNV) is a hallmark of exudative age-related macular degeneration (exAMD) and a major cause of visual loss in AMD. Despite the widespread use of anti-VEGF therapy, serious adverse effects arise from repeated intravitreal injection of anti-VEGF antibodies, which warrant alternative strategy. We report herein that in a CNV murine model created by krypton red laser, intravenous injection of a serine racemase inhibitor, l-Aspartic acid ß-hydroxamate (L-ABH), significantly reduced CNV at the dose 6â¯mg/kg on the first day before and followed by 3â¯mg/kg on the third day after laser injury. The CNV volumes were analyzed with isolectin GS-IB4 staining on choroidal/RPE flat mounts on the seventh day after laser injury. Injection of L-ABH did not produce negative effects on retinal function and visual behavior. To dissect the mechanism in vitro, pretreatment with L-ABH in primary RPE cultures significantly reduced production of vascular endothelial growth factor (VEGF) and macrophage chemotactic protein 1 (MCP-1) by TNFα-primed RPEs. Consistent with these observations, L-ABH pretreatment significantly attenuated macrophage migration mediated by TNFα-primed RPE. Collectively, intravenous injection of L-ABH significantly reduced CNV volumes via reducing production of VEGF and MCP-1 by inflammation-primed RPEs.
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Inibidores da Angiogênese/administração & dosagem , Asparagina/análogos & derivados , Neovascularização de Coroide/tratamento farmacológico , Inflamação/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Asparagina/administração & dosagem , Células Cultivadas , Corioide/patologia , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Inflamação/metabolismo , Inflamação/patologia , Injeções Intravenosas , Injeções Intravítreas , Camundongos , Camundongos Endogâmicos C57BL , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade VisualRESUMO
Although the inhibitor of apoptosis proteinlike protein2 (ILP2) has been shown as a serological biomarker for breast cancer, its effect on breast cancer cell growth remains elusive. The present study aimed to determine the role of ILP2 in breast cancer cell growth. We used immunohistochemistry to analyze ILP2 expression in 59 tissue paraffinembedded blocks, which included 35 breast cancer tissues and 24 galactophore hyperplasia tissues. Western blot analysis was used to detect protein expression levels of ILP2 in breast cancer cell lines such as HCC1937, MX1 and MCF7 as well as breast gland cell line MCF 10A. ILP2 was silenced by siRNA in HCC1937, MX1 and MCF7 cell lines. MTT assays, scratch assays and AOEB double staining analysis were conducted to evidence the role of ILP2 on breast cancer cell growth. Results from this study showed increased ILP2 expression in breast cancer tissues and breast cancer cell lines such as HCC1937, MX1 and MCF7. Cell viability or rate of cell migration of HCC1937, MX1 and MCF7 cell lines was significantly inhibited when ILP2 was knocked down by siRNA. The apoptosis rate of HCC1937, MX1 and MCF7 cell lines was increased when compared with that of the control group. Thus, ILP2 plays an active role in the growth of breast cancer cells.
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Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Proliferação de Células , Hiperplasia/patologia , Proteínas Inibidoras de Apoptose/metabolismo , Adulto , Apoptose , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Movimento Celular , Feminino , Humanos , Hiperplasia/metabolismo , Pessoa de Meia-Idade , Prognóstico , Células Tumorais CultivadasRESUMO
Sex steroid hormones play an important role in mediating physiological responses and developmental processes through their receptors across all vertebrates. Chinese alligator (Alligator sinensis) is a critically endangered reptile species unique to China. In this study, we have cloned one of the sex steroid hormone receptor genes, androgen receptor (AR) from the brain of Chinese alligator for the first time. The full-length AR cDNA is 2717â¯bp in length with an open reading frame (ORF) encoding 722 amino acids. Amino acid alignment analyses indicated that the ARs exhibit highly conserved functional domains. Especially, the P-box and D-box, which are essential to ensure that receptor binding to the androgen response elements, are completely conserved in selected species. Using the quantitative real-time PCR (qPCR), the spatial expression of four receptor mRNAs in all newborn brain tissues and temporal expression of them in the cerebrum during the embryonic development in Chinese alligators were investigated. The results of qPCR showed ubiquitous expression of the four receptor mRNAs in all newborn brain tissues examined and significant changes in the expression levels of these receptor mRNAs in the embryonic development. These results suggest that sex steroid hormones might play an important role in the regulation of complex neuroendocrine activities in newborn Chinese alligator. Furthermore, these data provide an important foundation for further studies on endocrinology and molecular biology of non-mammalian sex steroid hormone receptors.
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Encéfalo/metabolismo , Receptores Androgênicos/genética , Receptores de Esteroides/metabolismo , Jacarés e Crocodilos/embriologia , Jacarés e Crocodilos/genética , Jacarés e Crocodilos/crescimento & desenvolvimento , Jacarés e Crocodilos/metabolismo , Animais , Animais Recém-Nascidos , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Clonagem Molecular , Feminino , Expressão Gênica , Masculino , Filogenia , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Alinhamento de SequênciaRESUMO
Apoptosis plays an important role in neuron loss in Alzheimer's disease (AD). SET, an endogenous inhibitor of protein phosphatase-2A, is phosphorylated in AD brains and positively correlates with cell apoptosis. However, the mechanism underlying phosphorylated SET association with apoptosis remains unknown. Here, we show that mimetic phosphorylation of SET (S9E) induced apoptosis of primary cultured neurons. To investigate its mechanism, we overexpressed SET (S9E) in HEK293/tau cells and observed apoptosis accompanied with a marked increase of cleaved caspase-3 and cytoplasmic SET (S9E) retention with enhanced protein phosphatase-2A inhibition, which subsequently caused p53 hyperphosphorylation and activation. In addition, it caused the release of nucleoside diphosphate kinase A isoform a, a positive regulator of p53 with a DNase activity from SET/nucleoside diphosphate kinase A isoform a complex, and migration into the nucleus, resulting in DNA damage. Besides, it reduced nuclear tau accumulation leading to DNA protection deficiency. These findings suggest that SET phosphorylation is involved in the neuronal apoptotic pathway in AD and provide a new insight into the mechanism of this pathology.
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Transporte Ativo do Núcleo Celular , Doença de Alzheimer/metabolismo , Apoptose , Proteínas de Transporte/metabolismo , Chaperonas de Histonas/metabolismo , Nucleosídeo NM23 Difosfato Quinases/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Proteínas Reguladoras de Apoptose , Córtex Cerebral/metabolismo , Proteínas de Ligação a DNA , Células HEK293 , Humanos , Fosforilação , Cultura Primária de Células , Ratos Sprague-Dawley , Proteínas tau/metabolismoRESUMO
Choroidal neovascularization (CNV) is a leading cause of blindness in age-related macular degeneration. Production of vascular endothelial growth factor (VEGF) and macrophage recruitment by retinal pigment epithelial cells (RPE) significantly contributes to the process of CNV in an experimental CNV model. Serine racemase (SR) is expressed in retinal neurons and glial cells, and its product, d-serine, is an endogenous co-agonist of N-methyl-d-aspartate receptor. Activation of the receptor results in production of nitric oxide (. NO), a molecule that promotes retinal and choroidal neovascularization. These observations suggest possible roles of SR in CNV. With laser-injured CNV mice, we found that inactivation of SR-coding gene (Srrnull ) significantly reduced CNV volume, neovascular density, and invading macrophages. We exploited the underlying mechanism in vivo and ex vivo. RPE from wild-type (WT) mice expressed SR. To explore the possible downstream target of SR inactivation, we showed that choroid/RPE homogenates extracted from laser-injured Srrnull mice contained less inducible nitric oxide synthase and decreased phospho-VEGFR2 compared to amounts in WT mice. In vitro, inflammation-primed WT RPEs expressed more inducible NOS, produced more. NO and VEGF than did inflammation-primed Srrnull RPEs. When co-cultured with inflammation-primed Srrnull RPE, significantly fewer RF/6A-a cell line of choroidal endothelial cell, migrated to the opposite side of the insert membrane than did cells co-cultured with pre-treated WT RPE. Altogether, SR deficiency reduces RPE response to laser-induced inflammatory stimuli, resulting in decreased production of a cascade of pro-angiogenic cytokines, including. NO and VEGF, and reduced macrophage recruitment, which contribute synergistically to attenuated angiogenesis.