ABSTRACT
AIMS: Esophageal squamous cell carcinoma (ESCC) is one of the aggressive and lethal malignancies with an extremely poor prognosis. It is necessary to explore the molecular mechanisms of ESCC invasion. MAIN METHODS: We utilized high-throughput mass spectrometry to analyze the proteomes and phosphorylation profiles of two ESCC cell lines with differing invasion capacities (HK vs TE10). Differentially expressed proteins and phosphorites were identified, followed by comprehensive bioinformatics analyses encompassing function and pathway enrichment, protein-protein interaction (PPI) network analysis, hub gene identification, co-expression analysis, kinase-substrate prediction, and drug-target network analysis. CCK-8 assay, transwell examination, wound-healing assay, and western blot was used to validate the effects of fostamatinib on ESCC cells proliferation, invasion, migration, and LYN expression. KEY FINDINGS: The Q4 cluster of differentially phosphorylated proteins was primarily associated with functions and pathways relevant to tumor metastasis. Phosphorylated hub proteins including ARHGAP35, CTNNA1, and SHC1 were identified through the analysis of PPI network, and their respective regulated kinases were predicted. Among the predicted kinases, LYN was validated to be associated with lymph node metastasis (N0 vs. N1-3) and prognosis in ESCC patients at mRNA levels using TGGA data and protein levels in ESCC tissues (p < 0.05). Validation experiments confirmed the inhibitory effects of fostamatinib on ESCC cells proliferation, migration, invasion, and LYN expression. SIGNIFICANCE: Our multi-omics analysis offers deeper perspectives on ESCC invasiveness and unveils new phosphorylated hub proteins with their regulatory kinase. This study also suggests that fostamatinib may be a potential agent for treating ESCC.
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Humans , Esophageal Neoplasms/metabolism , Esophageal Squamous Cell Carcinoma/metabolism , Proteomics , Cell Movement/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Neoplasm Invasiveness/geneticsABSTRACT
BACKGROUND: Reprogramming lipid metabolism for tumor metastasis is essential in breast cancer, and NUCB2/Nesfatin-1 plays a crucial role in regulating energy metabolism. Its high expression is associated with poor prognosis in breast cancer. Here, we studied whether NUCB2/Nesfatin-1 promotes breast cancer metastasis through reprogramming cholesterol metabolism. METHODS: ELISA was employed to measure the concentration of Nesfatin-1 in the serum of breast cancer patients and the control group. Database analysis suggested that NUCB2/Nesfatin-1 might be acetylated in breast cancer, which was confirmed by treating the breast cancer cells with acetyltransferase inhibitors. Transwell migration and Matrigel invasion assays were conducted, and nude mouse lung metastasis models were established to examine the effect of NUCB2/Nesfatin-1 on breast cancer metastasis in vitro and in vivo. The Affymetrix gene expression chip results were analyzed using IPA software to identify the critical pathway induced by NUCB2/Nesfatin-1. We evaluated the effect of NUCB2/Nesfatin-1 on cholesterol biosynthesis through the mTORC1-SREBP2-HMGCR axis by utilizing mTORC1 inhibitor and rescue experiments. RESULTS: NUCB2/Nesfatin-1 was found to be overexpressed in the breast cancer patients, and its overexpression was positively correlated with poor prognosis. NUCB2 was potentially acetylated, leading to high expression in breast cancer. NUCB2/Nesfatin-1 promoted metastasis in vitro and in vivo, while Nesfatin-1 rescued impaired cell metastasis induced by NUCB2 depletion. Mechanistically, NUCB2/Nesfatin-1 upregulated cholesterol synthesis via the mTORC1 signal pathway, contributing to breast cancer migration and metastasis. CONCLUSIONS: Our findings demonstrate that the NUCB2/Nesfatin-1/mTORC1/SREBP2 signal pathway is critical in regulating cholesterol synthesis, essential for breast cancer metastasis. Thus, NUCB2/Nesfatin-1 might be utilized as a diagnostic tool and also used in cancer therapy for breast cancer in the future.
Subject(s)
Breast Neoplasms , Calcium-Binding Proteins , Animals , Mice , Calcium-Binding Proteins/metabolism , Cholesterol , DNA-Binding Proteins/metabolism , Nucleobindins/genetics , Nucleobindins/metabolism , Up-Regulation , Humans , Female , Breast Neoplasms/metabolism , Breast Neoplasms/pathologyABSTRACT
[This corrects the article DOI: 10.3389/fonc.2022.1037742.].
ABSTRACT
Background: GALAD model is a statistical model used to estimate the possibility of hepatocellular carcinoma (HCC) in patients with chronic liver disease. Many studies with other ethnic populations have shown that it has high sensitivity and specificity. However, whether this model can be used for Chinese patients remains to be determined. Our study was conducted to verify the performance of GALAD model in a Chinese cohort and construct a new model that is more appropriately for Chinese populations. Methods: There are total 512 patients enrolled in the study, which can be divided into training set and validation set. 80 patients with primary liver cancer, 139 patients with chronic liver disease and 87 healthy people were included in the training set. Through the ROC(receiver operating characteristic) curve analysis, the recognition performance of GALAD model for liver cancer was evaluated, and the GAADPB model was established by logistic regression, including gender, age, AFP, DCP, total protein, and total bilirubin. The validation set (75 HCC patients and 130 CLD patients) was used to evaluate the performance of the GAADPB model. Result: The GALAD and GAADPB achieved excellent performance (area under the receiver operating characteristic curve [AUC], 0.925, 0.945), and were better than GAAP, Doylestown, BALAD-2, aMAP, AFP, AFP-L3%, DCP and combined detection of AFP, AFP-L3 and DCP (AUCs: 0.894, 0.870, 0.648, 0.545, 0.879, 0.782, 0.820 and 0.911) for detecting HCC from CLD in the training set. As for early stage of HCC (BCLC 0/A), GAADPB had the best sensitivity compared to GALAD, ADP and DCP (56.3%, 53.1%, 40.6%, 50.0%). GAADPB had better performance than GALAD in the test set, AUC (0.896 vs 0.888). Conclusions: The new GAADPB model was powerful and stable, with better performance than the GALAD and other models, and it also was promising in the area of HCC prognosis prediction. Further study on the real-world HCC patients in China are needed.
ABSTRACT
Health-related quality of life (HRQoL) is an important aspect in the management of patients with hepatitis B (HB), which remains a serious health problem in China. There have been relatively few HRQoL studies involving Chinese patients with HB. The aim of this study was to analyze HRQoL in patients diagnosed with HB living in Zhejiang Province, China. A cross-sectional sample of 98 patients with chronic HB (CHB), 56 patients with advanced HB that have developed cirrhosis, and 48 healthy controls (HCs), all from Zhejiang Province, was used in this study. HRQoL was assessed using Short-Form 36 (SF-36) version 2, European quality of life questionnaire-5 dimensions (EQ-5D), and chronic liver disease questionnaire (CLDQ). Intergroup score differences were detected with U tests. Factors with a significant effect on HRQoL were identified with Spearman correlational analyses. Patients with HB (both groups) had lower SF-36 scores than HCs (p < 0.01), with the exception of general health subscores. Patients with HB cirrhosis had the lowest scores in the EQ-5D visual analog scale (VAS) component. Furthermore, patients with HB cirrhosis had lower (p < 0.01) CLDQ scores than patients with CHB. In our HB patient cohort, disease stage and income level were the factors most associated with HRQoL variables; age, education level, and marital status were, each, also significantly associated with some HRQoL variables in patients with HB in our study (p < 0.05 or p < 0.01). HRQoL is diminished in patients with HB in southeastern China. Disease stage and income emerged as key determinants of HRQoL scores. Augmenting social and medical supports for patients with HB, especially those with a socioeconomic status and an advanced disease stage, may help to enhance HRQoL.
Subject(s)
Hepatitis B, Chronic , Hepatitis B , China/epidemiology , Cross-Sectional Studies , Hepatitis B/epidemiology , Hepatitis B, Chronic/epidemiology , Humans , Quality of Life , Surveys and QuestionnairesABSTRACT
BACKGROUND: Cleavage factor Im 25 (CFIm25) affects the prognosis and progression of cancer by regulating alternative polyadenylation; however, its role in colorectal cancer remains unclear. METHODS: A standard EnVision tissue microarray was used to evaluate the expression of CFIm25 by immunohistochemistry in 363 patients with colorectal cancer. The correlation between CFIm25 expression and clinicopathological characteristics was analyzed using the χ2 test. Univariate analysis was used to study the relationship between clinicopathological characteristics and patient prognosis. Multivariate analysis was performed using the Cox regression model to identify independent prognostic factors for patients with colorectal cancer. RESULTS: Statistical analysis revealed that CFIm25 expression was significantly associated with vascular invasion (P=0.000), serous invasion (P=0.007), pT stage (P=0.016), and clinical stage (P=0.007). Age, vascular invasion, nerve invasion, serosal invasion, differentiation, clinical stage, recurrence, and CFIm25 expression were significantly correlated with the survival time of colorectal cancer patients (P<0.05). The mean overall survival rate in colorectal cancer patients with decreased CFIm25 expression was only 88.53 months, compared with 110.69 months in the high expression group (P=0.000). Decreased CFIm25 expression indicated a worse prognosis in patients with colorectal cancer. Further analysis by the Cox multivariate model showed that CFIm25 (HR, 0.543; 95% CI: 0.372-0.792; P=0.002) and serosa invasion (HR, 1.470; 95% CI: 1.032-2.094; P=0.033) are independent prognostic factors for colorectal cancer. CONCLUSIONS: Decreased CFIm25 expression indicates a worse prognosis of colorectal cancer patients and could be a novel target for the treatment of colorectal cancer in the future. KEYWORDS: Polyadenylation; survival analysis; colorectal cancer (CRC); CFIm25.
ABSTRACT
Background: Chronic HCV infection affects 80 million people globally and may progress to advanced liver disease. The present study aims to investigate the present epidemiology of HCV infection in a southeastern Chinese surgical patient cohort. Methods: Blood samples obtained from 78,484 surgical patients from 18 different city and county hospitals were enrolled. The incidence of serum HCV antibody positivity, HCV RNA load, and HCV genotyping, as well as demographics and relevant clinical history, were investigated. Data were stratified using the multistage cluster random sampling method and further analyzed using the SPSS-20 package. Results: HCV antibody positivity was detected in 0.15% of the population (95% confidence interval (CI): 0.12%-0.18%). Genotype 1b (55.74%) was the dominant type. The HCV infection peaked in the age groups of 16-20, 41-50, and 61-65 years, and it was higher in males than in females (0.19% vs. 0.13%, P < 0.05). The geographical distribution of infection rates differed: 0.19% (95% CI: 0.14%-0.24%), 0.18% (95% CI: 0.13%-0.23%), and 0.06% (95% CI: 0.03-0.09%) in plain areas, islands, and valley regions, respectively. Patients with transfusion history and urban residence were associated with high HCV RNA levels (adjusted odds ratio = 11.24 and 6.20, P < 0.05). Conclusion: The prevalence of HCV infection in this cohort from southeast China was 0.17%, which is lower than the reported 0.43% infection rate in China in 2006. This result can be (partially) explained by the improvement of blood donor screening and the successful campaign for the use of disposable syringes and needles.
Subject(s)
Hepacivirus , Hepatitis C, Chronic/epidemiology , Surgical Procedures, Operative/statistics & numerical data , Adolescent , Adult , Aged , China/epidemiology , Female , Genotype , Hepacivirus/genetics , Hepatitis C Antibodies/blood , Humans , Male , Middle Aged , Preoperative Period , Prevalence , RNA, Viral/blood , Viral Load , Young AdultABSTRACT
The DEAD/DEAH box helicase 11 (DDX11) plays vital roles in regulating the initiation of DNA replication. However, its precise function and regulation in hepatocellular carcinoma (HCC) have never been reported yet. In the current study, we found that DDX11 was overexpressed in HCC tissues. High DDX11 expression was positively correlated with large tumor size, tumor multiplicity, late tumor-node-metastasis (TNM) stage and poor prognosis. Additional, gain-of-function and loss-of-function experimental results revealed that DDX11 overexpression promoted HCC cell proliferation, migration, invasion and inhibited cell apoptosis in vitro. Overexpression of DDX11 also enhanced HCC tumorigenicity in vivo. Furthermore, DDX11 was transcriptionally regulated by transcription factor E2F1 in HCC, as demonstrated by chromatin immunoprecipitation (Ch-IP) and luciferase reporter assays. Mechanistically, E2F1/DDX11 axis promoted HCC cell proliferation, migration and invasion, at least in part, through activating PI3K/AKT/mTOR signaling pathway. Conclusively, our study demonstrates that E2F1-enhanced DDX11 expression promotes HCC progression through PI3K/AKT/mTOR pathway and DDX11 might be a potential therapeutic and prognostic target for HCC treatment.
Subject(s)
Carcinoma, Hepatocellular/genetics , DEAD-box RNA Helicases/metabolism , DNA Helicases/metabolism , E2F1 Transcription Factor/metabolism , Liver Neoplasms/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Transcriptional Activation/genetics , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Movement , Cell Proliferation , Disease Progression , Female , Humans , Liver Neoplasms/pathology , Male , Middle Aged , Signal TransductionABSTRACT
Previous studies have demonstrated that C-C motif chemokine 14 (CCL14) plays an important role in the occurrence and development of cancer. However, the significance of CCL14 in the progression and prognosis of epithelial ovarian cancer (EOC) has not yet been reported. The standard EnVision procedure for tissue microarrays was used to evaluate the immunohistochemical expression of CCL14 protein in 154 patients with EOC who underwent tumor-debulking operations at the Central Cancer Department of Sun Yat-Sen University (Guangzhou, China) or Jiangmen Central Hospital (Jiangmen, China). The association between CCL14 expression and clinicopathological variables was assessed using the χ2 test. For survival status of patients with EOC, Kaplan-Meier survival analysis and a Cox multivariate regression model was used. Expression of CCL14 protein was significantly associated with International Federation of Gynecology and Obstetric stage (P=0.014) and pN status(P=0.005). Kaplan-Meier survival analysis revealed that the survival time of patients with high expression of CCL14 was 136.1 months and that of patients with low expression of CCL14 was 98.9 months (P=0.026). Multivariate analysis demonstrated that CCL14 upregulation was associated with overall survival time (HR, 0.48; 95% CI, 0.261-0.896; P=0.021) and progression-free survival time (HR,0.437; 95% CI, 0.228-0.839; P=0.013). In conclusion, CCL14 is an independent prognostic factor for EOC and upregulation of CCL14 is associated with a more favorable prognosis in patients with EOC.
ABSTRACT
OBJECTIVE: Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1) involves alteration of the structure, function, intracellular localization and/or stability of the phosphorylated protein on serine or threonine residues which relates to inflammation and tumorigenesis. Association between PIN1 promoter polymorphisms and cancer risk were reported in several cancers. We intend to study the relationship between the polymorphism of PIN1 promoter and cervical cancer initiation and development. MATERIALS AND METHODS: We genotyped two common single nucleotide polymorphisms (SNPs) (rs2233678 and rs2233679) in the promoter of the PIN1 gene in healthy controls, patients with CIN or cervical cancer. We used polymerase chain reaction and DNA sequencing methods to analyze these two SNPs in 179 patients and 223 healthy controls. Luciferase activity assay was used to detect PIN1 expression driven by the rs2233679. RESULTS: The results revealed that the carriers of rs2233679 genotypes CT/TT had a significantly increased risk of cervical cancer in patients with CIN compared with genotype CC (odds ration [OR] = 2.924, 95% confidence interval [CI] = 1.093-7.819, P = 0.033). Luciferase activity assay results revealed that PIN1 expression driven by the rs2233679 genotype TT was higher than the genotype CC (P < 0.05). On the other hand, no significant correlation between the healthy controls and patients was found for PIN1 rs2233678 which showed that rs2233678 genotypes CG/GG is 95% in healthy controls and 100% in patients. CONCLUSION: PIN1 rs2233679 genotype CT/TT may be a risk factor of early cervical cancer compared with genotype CC in Hunan populations. Our findings suggest that PIN1 rs2233679 genotype CT/TT might involve in the progression of the precancerous stage developing to early cancer by enhancing PIN1 expression.
Subject(s)
Asian People/genetics , NIMA-Interacting Peptidylprolyl Isomerase/genetics , Polymorphism, Single Nucleotide/genetics , Uterine Cervical Dysplasia/genetics , Uterine Cervical Neoplasms/genetics , Adult , Case-Control Studies , China , Disease Progression , Female , Genetic Predisposition to Disease/ethnology , Genetic Predisposition to Disease/genetics , Genotype , Humans , Middle Aged , Promoter Regions, Genetic/genetics , Sequence Analysis, DNA , Uterine Cervical Neoplasms/ethnology , Uterine Cervical Dysplasia/ethnologyABSTRACT
RING finger protein 187 (RNF187) has been used to predict prognosis of several human carcinomas. However, the clinicopathologic and prognostic implication of RNF187 expression in ovarian carcinomas remains not to be evaluated. The aim of this study was to explore the clinicopathologic and the prognostic significance of RNF187 in patients with ovarian carcinomas. Expression levels of RNF187 protein were investigated by immunohistochemical staining based on tissue-microarray composed of 147 patients with ovarian carcinomas. Receiver operating characteristic curve analysis was used to select the ideal cut-off value of RNF187 expression in ovarian carcinoma, and then analyze the correlation between the status of RNF187 expression and various clinicopathologic variables by chi-square test. Univariate analysis was employed to investigate the association between clinicopathologic variables and prognosis of patients by Kaplan-Meier method. Multivariate analysis was performed to identify the independent prognostic factors by the Cox regression model. Our results demonstrated that high expression of RNF187 was significantly associated with late FIGO stage, high histologic grade and pN1 stage in ovarian carcinoma (P < 0.05). Univariate analysis uncovered patients with the high expression of RNF187 have the worse overall survival and disease-free survival (P < 0.05). More surprisingly, multivariate analysis determined that the RNF187 expression was served as an independent prognostic factor in ovarian carcinoma. The high expression of RNF187 might influence a more aggressive biological behavior in ovarian carcinoma. Therefore, RNF187 expression could be useful to act as a new independent prognostic biomarker for patients with ovarian carcinoma.
Subject(s)
Adenocarcinoma, Mucinous/pathology , Biomarkers, Tumor/metabolism , Cystadenocarcinoma, Serous/pathology , Ovarian Neoplasms/pathology , Trans-Activators/metabolism , Ubiquitin-Protein Ligases/metabolism , Adenocarcinoma, Mucinous/metabolism , Adenocarcinoma, Mucinous/therapy , Adult , Aged , Aged, 80 and over , Cystadenocarcinoma, Serous/metabolism , Cystadenocarcinoma, Serous/therapy , Female , Follow-Up Studies , Humans , Male , Middle Aged , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/therapy , Prognosis , Retrospective Studies , Survival RateABSTRACT
The objective of this study was to investigate the functional role of Rab39a in human cervical cancer (CC) and the underlying molecular mechanisms. We first measured Rab39a mRNA expression in CC tissues and paired non-tumor tissues by quantitative real-time PCR (QRT-PCR). Overall survival of CC patients with different mRNA levels of Rab39a in The Cancer Genome Atlas (TCGA) database was assessed by Kaplan-Meier survival curves analysis. Next methylation-specific PCR (MSP) was performed to determine the expression mechanism of Rab39a. Then cell proliferation, migration and invasion of Rab39a-transfected or mock-transfected cervical cancer cells were determined by CCK-8, flow cytometry, wound healing, transwell migration and invasion assays, respectively. Finally, the molecular mechanism by which Rab39a modulated CC cell epithelial-mesenchymal transition (EMT) was explored. It was found that Rab39a mRNA was significantly down-regulated in the high-risk patients compared to the low-risk patients (pâ¯=â¯0.0054). Six of seven cancer tissues with lymph node metastasis express low Rab39a mRNA compared to the surrounding non-tumor tissues. Cervical cancer patients with low level of Rab39a were showed a poorly clinical outcome (pâ¯=â¯0.004). Loss of Rab39a expression in cervical cancer tissues was associated with the aberrant DNA methylation in the promoter of Rab39a gene. Disrupted Rab39a expression in cervical cancer cells could be restored after treatment with the demethylated agent 5-Aza-2'-deoxycytidine. Furthermore, it was found that Rab39a hardly influenced cell growth but significantly suppressed cell migration, invasion and EMT process. Rab39a exerted its potential suppressor functions through inhibiting AKT phosphorylation. The inhibition effects of Rab39a could be blocked by AKT pathway inhibitor. Collectively, our data shows that Rab39a is a potential epigenetic silenced tumor suppressor inhibiting cancer invasion and migration through modulating the AKT signaling.
Subject(s)
Epigenesis, Genetic , Epithelial-Mesenchymal Transition/genetics , Gene Silencing , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Tumor Suppressor Proteins/genetics , Uterine Cervical Neoplasms/genetics , rab GTP-Binding Proteins/genetics , Cell Line, Tumor , Cell Movement , Down-Regulation , Female , Gene Expression Regulation, Neoplastic , Humans , Methylation , Tumor Suppressor Proteins/metabolism , Uterine Cervical Neoplasms/metabolism , rab GTP-Binding Proteins/metabolismABSTRACT
BACKGROUND: Phospholipid phosphatase 4 (PPAPDC1A or PLPP4) has been demonstrated to be involved in the malignant process of many cancers. The purpose of this study was to investigate the clinical significance and biological roles of PLPP4 in lung carcinoma. METHODS: PLPP4 expression was examined in 8 paired lung carcinoma tissues by real-time PCR and in 265 lung carcinoma tissues by immunohistochemistry (IHC). Statistical analysis was performed to evaluate the clinical correlation between PLPP4 expression and clinicopathological features and survival in lung carcinoma patients. In vitro and in vivo assays were performed to assess the biological roles of PLPP4 in lung carcinoma. Fluorescence-activated cell sorting, Western blotting and luciferase assays were used to identify the underlying pathway through which PLPP4 silencing mediates biological roles in lung carcinoma. RESULTS: PLPP4 is differentially elevated in lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SQC) tissues. Statistical analysis demonstrated that high expression of PLPP4 significantly and positively correlated with clinicopathological features, including pathological grade, T category and stage, and poor overall and progression-free survival in lung carcinoma patients. Silencing PLPP4 inhibits proliferation and cell cycle progression in vitro and tumorigenesis in vivo in lung carcinoma cells. Our results further reveal that PLPP4 silencing inhibits Ca2+-permeable cationic channel, suggesting that downregulation of PLPP4 inhibits proliferation and tumorigenesis in lung carcinoma cells via reducing the influx of intracellular Ca2+. CONCLUSION: Our results indicate that PLPP4 may hold promise as a novel marker for the diagnosis of lung carcinoma and as a potential therapeutic target to facilitate the development of novel treatment for lung carcinoma.
Subject(s)
Calcium Channels/metabolism , Carcinogenesis/metabolism , Lung Neoplasms/chemistry , Lung Neoplasms/metabolism , Phosphatidate Phosphatase/metabolism , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, Neoplastic , Gene Silencing , Humans , Kaplan-Meier Estimate , Lung/chemistry , Lung Neoplasms/mortality , Phosphatidate Phosphatase/genetics , PrognosisABSTRACT
The death receptor, Fas, triggers apoptotic death and is essential for maintaining homeostasis in the peripheral lymphoid organs. RIP1 was originally cloned when searching for Fas-binding proteins and was later shown to associate also with the signaling complex of TNFR1. Although Fas exclusively induces apoptosis, TNFR1 primarily activates the pro-survival/pro-inflammatory NF-κB pathway. Mutations in Fas lead to lymphoproliferative (lpr) diseases, and deletion of TNFR1 results in defective innate immune responses. However, the function of RIP1 in the adult lymphoid system has not been well understood, primarily owing to perinatal lethality in mice lacking the entire RIP1 protein in germ cells. This current study investigated the requirement for RIP1 in the T lineage using viable RIP1 mutant mice containing a conditional and kinase-dead RIP1 allele. Disabling the kinase activity of RIP1 had no obvious impact on the T-cell compartment. However, T-cell-specific deletion of RIP1 led to a severe T-lymphopenic condition, owing to a dramatically reduced mature T-cell pool in the periphery. Interestingly, the immature T-cell compartment in the thymus appeared intact. Further analysis showed that mature RIP1-/- T cells were severely defective in antigen receptor-induced proliferative responses. Moreover, the RIP1-/- T cells displayed greatly increased death and contained elevated caspase activities, an indication of apoptosis. In total, these results revealed a novel, kinase-independent function of RIP1, which is essential for not only promoting TCR-induced proliferative responses but also in blocking apoptosis in mature T cells.
Subject(s)
GTPase-Activating Proteins/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/enzymology , Animals , Apoptosis/drug effects , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Gene Deletion , Lymphocyte Activation/immunology , Mice , Receptors, Antigen, T-Cell/metabolism , Receptors, Death Domain/metabolism , T-Lymphocytes/drug effects , Thymus Gland/cytology , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
To explore the possibility of step-down method and low dose of etanercept for long-term stable remission of patients with juvenile idiopathic arthritis (JIA). Patients with JIA were enrolled into this study between February 2008 and March 2010 and then followed up for 2 years. The inclusion criteria were clinical remission and use of etanercept for therapy. On the first year of the study, the dose of etanercept was kept at 0.4 mg/kg per week, the half dose of what those patients had been used. On the second year, the dose of etanercept was further lowered to 0.4 mg/kg per month. DMARDs were allowed in this study. MR images were performed to observe joint changes. The primary end point was disease flare defined according to clinical and/or radiological data. The flare rate curve was analyzed by Kaplan-Meier, and logistic regression model was used to find factors associating with disease flare. MRI was performed to prove no active changes or progressions of bone erosions on joints. Thirty-one patients were enrolled in this study. There were 4 patients experiencing disease flare during the first 12th month. During the second year, disease flare was not occurred. Thus, the cumulative flare rate was 12.9 % on 12th month and then unchanged on the second year. Logistic regression model indicates there are no differences in sex, age of disease initiation, disease duration, subtypes, DMARDs, HLA-B27, months of etanercept duration and scores on MRI between patients with remission and those experiencing flares. At the end of the study, MRI found no progressions of joints to the patients keeping stable remission. Step-down method can be used for etanercept tapering. Long-term remission and low flare rate can be got by this method.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Juvenile/drug therapy , Immunoglobulin G/therapeutic use , Receptors, Tumor Necrosis Factor/therapeutic use , Adolescent , Arthritis, Juvenile/immunology , Arthritis, Juvenile/pathology , Child , Child, Preschool , Etanercept , Female , HLA-B27 Antigen/analysis , Humans , Logistic Models , Magnetic Resonance Imaging , Male , Prospective StudiesABSTRACT
AIM: To provide a profile of second malignant neoplasms (SMN) in patients with childhood primary malignant brain tumour originating from neuroepithelial tissues with latest data in a population-based study. METHODS: Surveillance, Epidemiology, and End Results (SEER) database (1973-2007) was used to identify above-stated patients. SMN patients were further identified, and standardised incidence ratios (SIRs) and excess absolute risks (EARs) for risk-factor-decided subgroups were calculated. Univariate and multivariate analyses of the association between cumulative incidence of SMN and the risk factors were performed in the whole population. RESULTS: A total of 106 patients were identified as having SMNs. EARs peaked at age at primary diagnosis of 10-14. Males had higher SIRs and EARs than females. Both SIRs and EARs increased after 1990. Age was statistically significant in both univariable and multivariable analyses for cumulative incidence of SMN and RT was not significant in both the analyses, in the whole population of 9075 patients. After follow-up recalculation, matched patients in the ≥1990 group had slightly shorter median interval between primary and secondary cancer than those in the <1990 group, but with no significance. CONCLUSION: The risk of SMN in children with primary malignant brain tumours in a more advanced treatment era might have changed. During making further advances in the treatment of these neoplasms, minimising toxicities while maintaining promising prognostic outcomes will keep being our goal.
Subject(s)
Brain Neoplasms , Neoplasms, Second Primary/epidemiology , Population Surveillance/methods , Adolescent , Child , Child, Preschool , Female , Humans , Incidence , Infant , Male , Risk Assessment , Sex Factors , Time Factors , United States/epidemiology , Young AdultABSTRACT
Near infrared spectroscopy technique combined with chemometrics methods was applied to predict crystallinity of Neosinocalamus affinins. Three improved partial least squares (PLS) methods, including interval partial least squares (iPLS), synergy interval partial least squares (siPLS) and backward interval partial least squares (biPLS), were used to find the most informative ranges and build models with better predictive quality based on multiplicative scatter correction spectra. And then the models were compared with PLS model which was developed on the whole wavelength range 350-2 500 nm. The results showed that the models built by the three improved PLS methods had higher predictive ability than that of PLS model, and the optimal model was obtained by siPLS method that separated the whole spectra into 30 intervals and combined three intervals. The siPLS model had correlation coefficient (R) of 0.88 and root mean standard error of prediction (RMSEP) of 0.011 7. Therefore, through selecting the effective wavelength range, siPLS method could accurately and rapidly predict crystallinity in Neosinocalamus affinins.
Subject(s)
Cellulose/chemistry , Poaceae/chemistry , Least-Squares Analysis , Spectroscopy, Near-Infrared/methodsABSTRACT
Cogan's syndrome (CS) is a rare multisystemic disorder characterized by inflammatory eye diseases and vestibuloauditory dysfunctions. It is prone to be misdiagnosed or overlooked, and the prognosis of those delayed-diagnosed CS is not optimistic. Despite isolated patient responses to systemic treatment including steroids and methotrexate, there is currently no general consensus on an effective treatment for CS. We present a case of Cogan's syndrome remission associated with leflunomide (LEF) in a juvenile patient. To date, there is no such report on CS, especially in children, which is successfully treated by LEF in combination with glucocorticoids.