BRAF V600E mutation has been thought to be a valuable molecular marker that may predict a worse prognosis for papillary thyroid cancer (PTC). But whether BRAF V600E mutation is associated with lymph node metastasis (LNM) remains controversial. Different surgical strategies may bring a bias in demonsstrating the association between them. In order to delineate a risk stratification to guide a tailored initial approach to tumors that express BRAF V600E mutation, we performed this meta-analysis by using the articles in which total or near-total thyroidectomy plus bilateral central lymph node dissection was routinely performed to avoid the bias from the surgical strategy. We searched the Medline, Embase and CNKI database for eligible studies from January 2003 to May 2018. Meta-analysis was performed using the STATA 12.0 software. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under fixed-effects or randomeffects models. Fifteen clinical studies were included with a total of 4909 PTC patients. Our meta-analysis results reported that BRAFV600E mutation was associated with LNM (OR=1.34; 95% CI: 1.09-1.65; P=0.005), as well as central LNM (OR=1.59; 95% CI: 1.35-1.88; P<0.00001). Moreover, in patients with papillary thyroid microcarcinoma, we also confirmed the predictive value of BRAF V600E mutation for LNM (OR=3.49; 95% CI: 2.02-6.02; P<0.00001). This meta-analysis demonstrates that BRAF V600E mutation is closely related to LNM in PTC patients. The results suggest that BRAF V600E mutation can be considered as a risk factor for LNM in PTC. Moreover, combining BRAF V600E mutation with other risk factors to determine the initial surgical treatment may bring benefits for PTC patients.
A549 Cells, Apoptosis drug effects, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Cell Proliferation drug effects, Cisplatin administration & dosage, Cisplatin adverse effects, Disease-Free Survival, Drug Resistance, Neoplasm genetics, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, Male, Paclitaxel administration & dosage, Paclitaxel adverse effects, Aurora Kinase B genetics, Carcinoma, Non-Small-Cell Lung drug therapy, Drug Resistance, Neoplasm drug effects, Prognosis
Abstract
Objective: Aurora kinase B (Aurora-B) is a crucial regulator of accurate mitosis. Abnormal Aurora-B expression is associated with aneuploidy and has been implicated in the pathogenesis and drug resistance in a variety of human cancers. However, little evidence is available regarding the role of Aurora-B in regulating drug response in non-small cell lung cancer (NSCLC), which is the most common type of lung cancer, and is characterized with poor prognosis and high mortality., Method: In the current study, we investigated the association of Aurora-B with the prognosis of NSCLC patients, and we also used the latest CRISPR/Cas9 system to explore the regulatory role of Aurora-B in NSCLC cells developing resistance to cisplatin (CDDP) and paclitaxel., Results: We found that Aurora-B was correlated with significantly reduced overall survival and disease-free survival in NSCLC patients. Aurora-B overexpression was also observed in NSCLC cells developing impaired response to both CDDP and paclitaxel. Moreover, we found, for the first time, that Aurora-B may impair NSCLC drug response by disturbing cell proliferation and inhibiting p53-related DNA damage response and apoptotic pathway, while the knockout of Aurora-B resensitized NSCLC cells to chemo drugs by ensuring correct chromosome segregation and restoring p53 expression., Conclusions: Our results demonstrated the association of Aurora-B with chemoresistance in NSCLC, which may finally contribute to the poor prognosis of NSCLC patients. We also suggested Aurora-B as a promising therapeutic target in NSCLC treatment.
In recent years, many researches have shown that OCT4 is overexpressed in both germ cell tumors and somatic cancers. Meanwhile, OCT4 has relationship with poor prognosis in a lot of solid tumors, such as hepatocellular carcinoma, gastric cancer, and esophageal cancer. In our study, we investigated the expression status of OCT4 and its clinical significance in patients with acute myeloid leukemia (AML) using real-time quantitative PCR. The receiver operating characteristic (ROC) curve reveals that the level of OCT4 expression could be available for a potential diagnostic biomarker for differentiating AML from controls with an area under the ROC curve (AUC) of 0.915 (95 % confidence interval (CI) 0.837-0.992; P < 0.001). At the cutoff value of 0.56, the sensitivity and the specificity are 75.9 and 81.2 %, respectively. The amount of white blood cell (WBC) of patients with high OCT4 expression is higher than that of patients with low OCT4 expression (18.2 × 10(9) versus 2.7 × 10(9) L(-1), P = 0.001). Among those patients who are less than 70 years old, patients with OCT4 high expression have significantly shorter overall survival (OS) than those without OCT4 high expression (P = 0.048). These findings suggest that OCT4 high expression is a common event and may have an adverse impact on prognosis in AML.
Axelrod, Margaret L, Nixon, Mellissa J, Gonzalez-Ericsson, Paula I, Bergman, Riley E, Pilkinton, Mark A, McDonnell, Wyatt J, Sanchez, Violeta, Opalenik, Susan R, Loi, Sherene, Zhou, Jing, Mackay, Sean, Rexer, Brent N, Abramson, Vandana G, Jansen, Valerie M, Mallal, Simon, Donaldson, Joshua, Tolaney, Sara M, Krop, Ian E, Garrido-Castro, Ana C, Marotti, Jonathan D, Shee, Kevin, Miller, Todd W, Sanders, Melinda E, Mayer, Ingrid A, Salgado, Roberto, and Balko, Justin M
Subjects
CD8-Positive T-Lymphocytes, Lymphocytes, Tumor-Infiltrating, Humans, Neoplasm Recurrence, Local, Paclitaxel, Albumins, Neoplasm Proteins, Antineoplastic Combined Chemotherapy Protocols, Prognosis, Treatment Outcome, Neoadjuvant Therapy, Gene Expression Regulation, Neoplastic, Adult, Aged, Middle Aged, Female, Tumor Microenvironment, Programmed Cell Death 1 Receptor, Triple Negative Breast Neoplasms, B7-H1 Antigen, Progression-Free Survival, Clinical Research, Genetics, Breast Cancer, Cancer, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract
PurposeThe recent approval of anti-programmed death-ligand 1 immunotherapy in combination with nab-paclitaxel for metastatic triple-negative breast cancer (TNBC) highlights the need to understand the role of chemotherapy in modulating the tumor immune microenvironment (TIME).Experimental designWe examined immune-related gene expression patterns before and after neoadjuvant chemotherapy (NAC) in a series of 83 breast tumors, including 44 TNBCs, from patients with residual disease (RD). Changes in gene expression patterns in the TIME were tested for association with recurrence-free (RFS) and overall survival (OS). In addition, we sought to characterize the systemic effects of NAC through single-cell analysis (RNAseq and cytokine secretion) of programmed death-1-high (PD-1HI) CD8+ peripheral T cells and examination of a cytolytic gene signature in whole blood.ResultsIn non-TNBC, no change in expression of any single gene was associated with RFS or OS, while in TNBC upregulation of multiple immune-related genes and gene sets were associated with improved long-term outcome. High cytotoxic T-cell signatures present in the peripheral blood of patients with breast cancer at surgery were associated with persistent disease and recurrence, suggesting active antitumor immunity that may indicate ongoing disease burden.ConclusionsWe have characterized the effects of NAC on the TIME, finding that TNBC is uniquely sensitive to the immunologic effects of NAC, and local increases in immune genes/sets are associated with improved outcomes. However, expression of cytotoxic genes in the peripheral blood, as opposed to the TIME, may be a minimally invasive biomarker of persistent micrometastatic disease ultimately leading to recurrence.
Breast Cancer, Cancer, Clinical Research, Adult, Aged, Aged, 80 and over, Antigens, Neoplasm, BRCA1 Protein, Breast Neoplasms, Carcinogenesis, Cyclin D1, Disease-Free Survival, Female, Gene Expression Regulation, Neoplastic, Genomic Instability, Humans, Lymphocyte Activation, Middle Aged, Prognosis, RNA, Messenger, T-Lymphocytes, Breast cancer, BRCA1, CCND1, T cell activation score, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract
BackgroundEffector CD8+ T cell activation and its cytotoxic function to eradicate tumor cells depend on the T cell recognition of tumor neoantigens, and are positively associated with improved survival in breast cancer. Tumor suppressor BRCA1 and cell cycle regulator CCND1 play a critical role in maintaining genome integrity and tumorigenesis, respectively. However, it is still unclear how BRCA1 and CCND1 expression levels affect the effect of T cell activation on breast cancer patient survival.MethodsThe interactions between T cell activation status and either BRCA1 or CCND1 expression were evaluated using Kaplan-Meier survival curves and multivariate Cox regression models in a public dataset with 1088 breast cancer patients.ResultsAmong the patients with low BRCA1 or CCND1 expression, the Activation group showed better overall survival than the Exhaustion group. Adjusted hazards ratios were 0.43 (95% CI: 0.20-0.93) in patients with a low BRCA1 level, and 0.39 (95% CI: 0.19-0.81) in patients with a low CCND1 level, respectively. There was a significant trend in both subgroups (p-trend = 0.011 in the low BRCA1 group, and p-trend = 0.009 in the low CCND1 group). In contrast, there is no significant association in patients with either high BRCA1 or high CCND1 levels. There is a significant interaction between T cell activation status and BRCA1 level (p = 0.009), but not between T cell activation status and CCND1 level (p = 0.135).ConclusionsBRCA1 expression modified the effect of T cell activation status on patient survival in breast cancer, suggesting that the existence of neoantigens and the enhancement of neoantigen presentation in combination with immune checkpoint blockade may have synergistic effects on patient outcome.
Background: Non‑intestinal adenocarcinoma of the nasal cavity and paranasal sinuses (non‑ITAC) is a heterogeneous tumour that has rarely been reported in previous studies. We compared and analysed the symptoms, radiographic and pathological features, treatment methods, and prognosis of patients with low-grade (G1) and high-grade (G3) tumours. Methods: This was a retrospective study included 22 patients with pathologically confirmed non-ITAC of the nasal cavity and paranasal sinuses who were treated between January 2008 and December 2021 at a single centre. Of these, 11 patients had G1 tumours, and 11 patients had G3 tumours. Clinicopathological features, treatment methods, and survival outcomes were analysed. Results: The median follow-up period was 48.5 months. Nasal congestion was the most common initial symptom, and the nasal cavity was the most frequently involved site. For G1 tumours, the main treatment was simple surgery, 1 and 3‑year overall survival (OS) rates were 100 and 88.9%, while the 1 and 3‑year local control (LC) rates were 100 and 100%, respectively. For G3 tumours, the main treatments were surgery combined with radiotherapy and/or chemotherapy,1 and 3‑year OS rates were 72.7 and 72.7%, while the 1 and 3‑year LC rates were 100 and 90.91%, respectively. G3 tumours was associated with significantly shorter overall survival than G1 tumours (P = 0.035). Patients with stage III-IV showed shorter overall survival compared to stage I-II patients (P = 0.035). Conclusions: Non-ITAC of the nasal cavity and paranasal sinuses may frequently occur in the nasal cavity. The main treatment modality is surgery, supplemented by radiotherapy and chemotherapy. Pathological grade and tumour stage were poor prognostic factors for the disease. [ABSTRACT FROM AUTHOR]
Background: Although several studies have confirmed the prognostic value of the consolidation to tumor ratio (CTR) in non-small cell lung cancer (NSCLC), there still remains controversial about it. Methods: We systematically searched the PubMed, Embase, and Web of Science databases from inception to April, 2022 for eligible studies that reported the correlation between CTR and prognosis in NSCLC. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were extracted and pooled to assess the overall effects. Heterogeneity was estimated by I2 statistics. Subgroup analysis based on the cut-off value of CTR, country, source of HR and histology type was conducted to detect the sources of heterogeneity. Statistical analyses were performed using STATA version 12.0. Results: A total of 29 studies published between 2001 and 2022 with 10,347 patients were enrolled. The pooled results demonstrated that elevated CTR was associated with poorer overall survival (HR = 1.88, 95% CI 1.42–2.50, P < 0.01) and disease-free survival (DFS)/recurrence-free survival (RFS)/progression-free survival (PFS) (HR = 1.42, 95% CI 1.27–1.59, P < 0.01) in NSCLC. According to subgroup analysis by the cut-off value of CTR and histology type, both lung adenocarcinoma and NSCLC patients who had a higher CTR showed worse survival. Subgroup analysis stratified by country revealed that CTR was a prognostic factor for OS and DFS/RFS/PFS in Chinese, Japanese, and Turkish patients. Conclusions: In NSCLC patients with high CTR, the prognosis was worse than that with low CTR, indicating that CTR may be a prognostic factor. [ABSTRACT FROM AUTHOR]
Zhang, Han, Lv, Qing-Wei, Zheng, Zi-Qiang, Shen, Liang-Jun, Zhou, Jing, and Guo, Mi
Subjects
INTRACEREBRAL hematoma, BRAIN injuries, HEPATITIS A virus cellular receptors, GLIAL fibrillary acidic protein
Abstract
(C) Relationship between serum soluble T cell immunoglobulin and mucin domain-3 levels and Rotterdam computed tomography scores of patients after severe traumatic brain injury. Serum C-reactive protein levels, Glasgow coma scale scores and Rotterdam computed tomography scores were independently correlated with serum soluble T cell immunoglobulin and mucin domain-3 levels after severe traumatic brain injury (all P 0.05). HT
Table 4 Factors in Relation to Extended Glasgow Outcome Scale Scores at 180 Days After Severe Traumatic Brain Injury
ht HT
Figure 7 Serum soluble T cell immunoglobulin and mucin domain-3 levels and 180-day extended Glasgow outcome scale scores after severe traumatic brain injury. Serum soluble T cell immunoglobulin and mucin domain-3 levels after severe traumatic brain injury were significantly highest in patients with Glasgow coma scale score 3, followed by scores 4, 5, 6 and 7, and were substantially lowest in those with score 8 (P 0.001). [Extracted from the article]
Gu, Yu, Xu, Zi-jun, Zhou, Jing-dong, Wen, Xiang-mei, Jin, Ye, Yuan, Qian, Xia, Pei-hui, Feng, Yuan, Yang, Lei, Lin, Jiang, and Qian, Jun
Subjects
ACUTE myeloid leukemia, ORGANIC cation transporters, GENE expression, BONE marrow cells, P16 gene, PROGNOSIS, DNA methylation, GENE silencing
Abstract
Background: We screened out several hypermethylated solute carrier (SLC) family genes in acute myeloid leukemia by reduced representation bisulfite sequencing. SLC22A3 encodes an organic cation transport protein, which is critical for drug transportation and cellular detoxification. SLC22A3 is significantly downregulated and associated with tumor progression and worse prognosis in a variety of solid tumors. However, there are no data available regarding the role of SLC22 in AML. This study aimed to explore the regulatory mechanism of DNA methylation on SLC22A3 expression, as well as its clinical significance in AML prognosis. Results: SLC22A3 was identified as the sole prognosis-associated gene among SLCs based on TCGA and Beat AML databases. Bone marrow mononuclear cells (BMMNCs) from AML, MDS patients, and healthy donors were enrolled in this study. SLC22A3 methylation was significantly increased in AML compared with controls and MDS patients; meanwhile, the expression level of SLC22A3 was decreased. SLC22A3 hypermethylation presented an obvious association with some specific clinical characteristics and affected the survival time of AML patients as an independent risk indicator. SLC22A3 expression changed regularly as the disease complete remissions and relapses. Demethylation drug 5-aza-2′-deoxycytidine (DAC) activated transcription and increased mRNA expression of SLC22A3 in leukemia cell lines and AML fresh BMMNCs. Knockdown of SLC22A3 in leukemia cells enhanced cell proliferation and suppressed cell apoptosis. Data from public programs were used for auxiliary screening of probable molecular mechanisms of SLC22A3 in the antileukemia effect. Conclusions: Our results showed that increased methylation and decreased expression of SLC22A3 may be indicators of poor prognosis in AML. Methylation-silenced SLC22A3 expression may have potential guiding significance on antileukemia effect of DAC. [ABSTRACT FROM AUTHOR]
acute myeliod leukemia, recurrence, immune system diseases, hemic and lymphatic diseases, expression, prognosis, MCL-1, neoplasms, OncoTargets and Therapy, Original Research
Abstract
Xi-xi Li,1,2,* Jing-dong Zhou,1,3,4,* Xiang-mei Wen,3,5,* Ting-juan Zhang,1,3,4 De-hong Wu,6 Zhao-qun Deng,3,5 Zhi-hui Zhang,1,3,4 Xin-yue Lian,1,3,4 Pin-fang He,1,3,4 Xin-yu Yao,7 Jiang Lin,3,5 Jun Qian1,3,4*These authors contributed equally to this work1Department of Hematology, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, People’s Republic of China; 2Department of Hematology, The Second Affiliated Hospital, Soochow University, Suzhou, Jiangsu, People’s Republic of China; 3Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People’s Republic of China; 4The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People’s Republic of China; 5Laboratory Center, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, People’s Republic of China; 6Department of Hematology, The Third People’s Hospital of KunShan City, 215300 Kunshan, People’s Republic of China; 7School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People’s Republic of ChinaBackground:Altered expression of the BCL-2 family member MCL-1 has been linked to the progression and outcome of various malignancies. Recently, MCL-1 inhibitor S63845 was reported to kill MCL-1-dependent cancer cells and has potential value in clinical application.Purpose: Herein, we reported MCL-1 expression pattern in Chinese de novo acute myeloid leukemia (AML) and its impact on prognosis and may provide theoretical basis for AML patients using MCL-1 inhibitor in clinics. Real-time quantitative PCR was carried out to detect the transcript of MCL-1 in AML patients.Results: MCL-1 expression was significantly up-regulated in AML compared with controls (P=0.042). We divided the patients into two groups (higher and lower expression of MCL-1) based on the median level. Among both non-acute promyelocytic leukemia (APL) and cytogenetically normal AML (CN-AML), patients with higher expression of MCL-1 correlated with lower complete remission (CR) rate (P=0.031 and 0.004, respectively) and shorter overall survival (OS) time (P=0.008 and 0.004, respectively) compared with those with lower expression of MCL-1. Meanwhile, Cox regression analyses revealed that overexpression of MCL-1 acted as an independent risk factor for OS in non-APL patients and CN-AML patients (P=0.011 and 0.045, respectively). In follow-up patients, MCL-1 expression level decreased after CR compared with newly diagnosis time (P=0.020) and increased after relapse (P=0.004).Conclusion: Our findings suggest that higher expression of MCL-1 predicts poor prognosis and can be used for disease monitoring.Keywords: MCL-1, expression, prognosis, recurrence, acute myeliod leukemia
Colorectal cancer (CRC) is one of the most common and malignant carcinomas. Many long noncoding RNAs (lncRNAs) have been reported to play important roles in the tumorigenesis of CRC by influencing the expression of some mRNAs via competing endogenous RNA (ceRNA) networks and interacting with miRNAs. Pseudogene is one kind of lncRNA and can act as RNA sponges for miRNAs and regulate gene expression via ceRNA networks. However, there are few studies about pseudogenes in CRC. In this study, 31 differentially expressed (DE) pseudogenes, 17 DE miRNAs and 152 DE mRNAs were identified by analyzing the expression profiles of colon adenocarcinoma obtained from The Cancer Genome Atlas. A ceRNA network was constructed based on these RNAs. Kaplan–Meier analysis showed that 7 pseudogenes, 4 miRNAs and 30 mRNAs were significantly associated with overall survival. Then multivariate Cox regression analysis of the ceRNA-related DE pseudogenes was performed and a 5-pseudogene signature with the greatest prognostic value for CRC was identified. Moreover, the results were validated by the Gene Expression Omnibus database, and quantitative real-time PCR in 113 pairs of CRC tissues and colon cancer cell lines. This study provides a pseudogene-associated ceRNA network, 7 prognostic pseudogene biomarkers, and a 5-pseudogene prognostic risk signature that may be useful for predicting the survival of CRC patients. [ABSTRACT FROM AUTHOR]
• The relation between metagenomic next-generation sequencing (mNGS) and the prognosis of intensive care unit patients is not clear. • mNGS assay is associated with a better prognosis in intensive care unit for infectious diseases. • Absence of mNGS assay was an independent risk factor for increased mortality. • mNGS can improve the range of pathogens detection. To evaluate the relation between metagenomic next-generation sequencing (mNGS) and the prognosis of patients with infectious diseases undergoing mechanical ventilation in the intensive care unit (ICU). This is a single-center observational study, comparing nonrandomly assigned diagnostic approaches. We analyzed the medical records of 228 patients with suspected infectious diseases undergoing mechanical ventilation in the ICU from March 2018 to May 2020. The concordance of pathogen results was also assessed for the results of mNGS, culture, and polymerase chain reaction assays. The 28-day mortality of the patients in the mNGS group was lower after the baseline difference correction (19.23% (20/104) vs 29.03% (36/124) , P = 0.039). Subgroup analysis showed that mNGS assay was associated with improved 28-day mortality of patients who are not immunosuppressed (14.06% vs 29.82%, P = 0.018). Not performing mNGS assay, higher acute physiology and chronic health evaluation II score, and hypertension are independent risk factors for 28-day mortality. The mNGS assay presented an advantage in pathogen positivity (69.8% double-positive and 25.0% mNGS-positive only), and the concordance between these two assays was 79.0%. mNGS survey may be associated with a better prognosis by reducing 28-day mortality of patients with infectious diseases on mechanical ventilation in the ICU. This technique presented an advantage in pathogen positivity over traditional methods. [ABSTRACT FROM AUTHOR]
(1) Background: The reasons for changes in the inflammatory markers of patients with surgically resected hepatocellular carcinoma are unclear. We aimed to investigate the association of an inflammatory status with the prognosis of patients with hepatocellular carcinoma, who underwent surgical resection. (2) Methods: We retrospectively enrolled 91 patients with Child A hepatocellular carcinoma, who had received surgical resection, to explore the influence of preoperative inflammatory markers and postoperative changes on the prognosis. (3) Results: The platelet-to-lymphocyte ratio (PLR) and its alteration were independent prognostic factors. Patients with a low PLR had a significantly better recurrence-free survival (RFS) than those with a high PLR (1-year RFS of 88.5% versus 50.0%; 3-year RFS of 62.1% versus 25.0%, p = 0.038). The patients with a low PLR showed a significantly better overall survival (OS) than those with a high PLR (1-year OS of 98.9% versus 75.0%; 3-year OS of 78.2% versus 25.0%, p = 0.005). The patients whose PLR had increased at 6 months after operation showed a worse OS than patients whose PLR had decreased (1-year OS of 96.3% versus 98.4%; 3-year OS of 63.0% versus 79.7%, p = 0.048). However, neither the neutrophil-to-lymphocyte ratio nor Onodera's prognostic nutritional index had any prognostic significance. (4) Conclusions: The PLR and its alteration are significant prognostic factors for the RFS and OS of patients with Child A hepatocellular carcinoma who had received curative surgery. [ABSTRACT FROM AUTHOR]
Sheng Li, Liu Yajiao, Zhu Yingying, Zhou Jingfen, and Hua Haiying
Subjects
acute myeloid leukemia, ptpn11 mutations, prevalence, clinical characteristics, prognosis, Medicine
Abstract
We discuss the clinical characteristics and prognostic significance of adult individuals with PTPN11 mutations who have developed acute myeloid leukemia (AML) (none acute promyelocytic leukemia). Next generation sequencing and Sanger sequencing were used to detect 51 gene mutations, and multiplex-PCR was used to detect 41 fusion genes from 232 de novo adult AML patients retrospectively. About 7.76% patients harbored PTPN11 mutations, 20 PTPN11 alterations were identified, all of which were missense mutations in the N-SH2 (n = 16) and PTP (n = 4) domains located in exon 3. Patients with PTPN11 mut had significantly higher platelet counts and hemoglobin levels (p < 0.001), which were mainly detected in M5 (n = 12, 66.67%, p < 0.001) subtype. Patients with MLL-AF6 positive showed a higher frequency of PTPN11 mut (p = 0.018) in the 118 AML cases. PTPN11 mut were accompanied by other mutations, which were NPM1 (44.44%), DNMT3A (38.89%), FLT3 (38.89%), and NRAS (17.2%). PTPN11 mut had a negative impact on the complete remission rate in M5 subtype patients (p < 0.001). However, no statistically significant effect on overall survival (OS) with PTPN11 mut patients in the whole cohort and age group (p > 0.05) was observed. Further analysis revealed no significant difference in OS among NPM1 mut/PTPN11 mut, NPM1 mut/PTPN11 wt, DNMT3A mut/PTPN11 mut, and DNMT3A mut/PTPN11 wt patients (p > 0.05). Multivariate analysis showed the proportion of bone marrow blasts ≥65.4% was a factor significantly affecting OS in PTPN11 mut patients (p = 0.043).
CANCER prognosis, RENAL cell carcinoma, ONLINE information services, NEPHRECTOMY, META-analysis, MEDICAL information storage & retrieval systems, SYSTEMATIC reviews, SURGERY, PATIENTS, URINARY organs, MEDLINE, PROGRESSION-free survival, NUTRITIONAL status
Abstract
In recent years, the controlling nutritional status (CONUT) score has increasingly became an effective indicator associated with tumor prognosis. This study was conducted to synthesise data on the prognostic value of CONUT score on patients with upper tract urothelial carcinoma (UTUC) or renal cell carcinoma (RCC) undergoing nephrectomy. We designed and performed a systematic analysis of studies that verified the correlation between preoperative CONUT score and prognosis for UTUC and RCC using PubMed, Web of Science and Embase. The conclusion was clarified by pooled hazard ratios (HR) and 95% confidence intervals (95% CI). Subgroup analysis were further conducted in accordance with different primary tumor. Six studies involving 3529 patients were included in this evidence synthesis, which revealed that the CONUT score had a potential role to predict the survival of UTUC and RCC patients accepting surgery. Pooled analysis showed that the overall survival (OS, HR 2·32, p < 0·0001), cancer-specific survival (CSS, HR 2·68, p < 0·0001) and disease-free survival (DFS, HR 1·62, p < 0·00001) were inferior in the high CONUT score group when compared with low score group. Subgroup analysis revealed that this result was in line with UTUC (OS: HR 1·86, p = 0·02; CSS: HR 2·24, p = 0·01; DFS: HR 1·54, p < 0·00001) and RCC (OS: HR 3·05, p < 0·00001; CSS: HR 3·47, p < 0·00001; DFS: HR 2·21, p = 0·0005) patients respectively. Consequently, the CONUT score is a valuable preoperative index to predict the survival of patients with UTUC or RCC undergoing nephrectomy. [ABSTRACT FROM AUTHOR]
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with variable outcomes. In this study, data of 84 DLBCL patients, who were tested EBV DNA in peripheral blood, were retrospectively analyzed. Patients were divided into three subgroups according to EBV copy number (EBV-CN) values: the negative (<500 copies/ml), low (500–104 copies/ml), and high EBV-CN group (≥104 copies/ml). The higher EBV-CN was associated with male and elderly patients. No significant difference was found between the three subgroups regarding immunophenotype, cytogenetic features, and molecular features. Patients of the high EBV-CN group had significantly worse progression-free and overall survival (OS) compared to other groups. After adjusting conventional risk factors, high EBV-CN was an independent prognostic factor for OS in multivariate analysis. Taken together, peripheral blood EBV-CN can predict outcomes of patients with DLBCL and 104 copies/ml is a more suitable boundary value than the traditional normal value in predicting prognosis. [ABSTRACT FROM AUTHOR]
Background: Globally, non-small-cell lung cancer (NSCLC) is one of the most prevalent tumors. Various studies have investigated its etiology, but the molecular mechanism of NSCLC has not been elucidated.Methods: The GSE19804, GSE118370, GSE19188, GSE27262, and GSE33532 microarray datasets were obtained from the Gene Expression Omnibus (GEO) database for the identification of genes involved in NSCLC development as well as progression. Then, the identified differentially expressed genes (DEGs) were subjected to functional enrichment analyses. The protein-protein interaction (PPI) network was built after which module analysis was conducted via the Search Tool for Retrieval of Interacting Genes/Proteins (STRING) and Cytoscape. There were 562 DEGs: 98 downregulated genes and 464 upregulated. These DEGs were established to be enriched in p53 signaling pathway, transendothelial leukocyte migration, cell adhesion molecules, contractions of vascular smooth muscles, coagulation and complement cascades, and axon guidance. Assessment of tumor immunity was performed to determine the roles of hub genes.Results: There were 562 dysregulated genes, while 12 genes were hub genes. NUF2 was established to be a candidate immunotherapeutic target with potential clinical implications. The 12 hub genes were highly enriched in the p53 signaling pathway, the cell cycle, progesterone-associated oocyte maturation, cellular senescence, and oocyte meiosis. Survival analysis showed that NUF2 is associated with NSCLC occurrence, invasion, and recurrence.Conclusion: The NUF2 gene discovered in this study helps us clarify the pathomechanisms of NSCLC occurrence as well as progression and provides a potential diagnostic and therapeutic target for NSCLC. [ABSTRACT FROM AUTHOR]
CANCER prognosis, HEPATOCELLULAR carcinoma, GENOMICS, MYELOID-derived suppressor cells, T cell receptors, PROGNOSIS
Abstract
Background: As a crucial constituent part of Polycomb repressive complex 2, PHD finger protein 19 (PHF19) plays a pivotal role in epigenetic regulation, and acts as a critical regulator of multiple pathophysiological processes. However, the exact roles of PHF19 in cancers remain enigmatic. The present research was primarily designed to provide the prognostic landscape visualizations of PHF19 in cancers, and study the correlations between PHF19 expression and immune infiltration characteristics in tumor microenvironment. Methods: Raw data in regard to PHF19 expression were extracted from TCGA and GEO data portals. We examined the expression patterns, prognostic values, mutation landscapes, and protein-protein interaction network of PHF19 in pan-cancer utilizing multiple databases, and investigated the relationship of PHF19 expression with immune infiltrates across TCGA-sequenced cancers. The R language was used to conduct KEGG and GO enrichment analyses. Besides, we built a risk-score model of hepatocellular carcinoma (HCC) and validated its prognostic classification efficiency. Results: On balance, PHF19 expression was significantly higher in cancers in comparison with that in noncancerous samples. Increased expression of PHF19 was detrimental to the clinical prognoses of cancer patients, especially HCC. There were significant correlations between PHF19 expression and TMB or MSI in several cancers. High PHF19 levels were critically associated with the infiltration of myeloid-derived suppressor cells (MDSCs) and Th2 subsets of CD4+ T cells in most cancers. Enrichment analyses revealed that PHF19 participated in regulating carcinogenic processes including cell cycle and DNA replication, and was correlated with the progression of HCC. Intriguingly, GSEA suggested that PHF19 was correlated with the cellular components including immunoglobulin complex and T cell receptor complex in HCC. Based on PHF19-associated functional gene sets, an eleven-gene prognostic signature was constructed to predict HCC prognosis. Finally, we validated pan-cancer PHF19 expression, and its impacts on immune infiltrates in HCC. Conclusion: The epigenetic related regulator PHF19 participates in the carcinogenic progression of multiple cancers, and may contribute to the immune infiltration in tumor microenvironment. Our study suggests that PHF19 can serve as a carcinogenic indicator related to prognosis in pan-cancer, especially HCC, and shed new light on therapeutics of cancers for clinicians. [ABSTRACT FROM AUTHOR]
Objective: The aim of this study was to evaluate the survival outcomes of radical prostatectomy (RP), external beam radiotherapy plus brachytherapy (EBRT + BT), and EBRT alone among elderly men (aged 70 years and above) with very high-risk (VHR) prostate cancer (PCa). Methods: We identified elderly men diagnosed with VHR PCa between 2004 and 2015 in the Surveillance, Epidemiology, and End Results database. The propensity score-matching method was adopted to balance the covariates and generate new cohorts. -Kaplan-Meier and Cox analyses were conducted to build up survival curves and evaluate the overall survival (OS) and PCa-specific survival (PCSS) outcomes. Results: A total of 9,818 patients were identified. Of them, 5,839 were in the EBRT group, 725 in the EBRT + BT group, and 3,254 in the RP group. The survival curves of the overall cohort showed that RP was associated with the best OS, followed by EBRT + BT and EBRT (p < 0.001). As for the PCSS, RP shared similar outcomes with EBRT + BT (hazard ratio [HR]: 1.25 [0.93–1.69], p = 0.175). EBRT was associated with significantly worse PCSS than both RP (HR: 1.88, 95% confidence interval [95% CI] [1.64–2.15], p < 0.001) and EBRT + BT (HR: 1.48, 95% CI [1.19–1.85], p = 0.002). In the matched cohorts, RP presented better OS (HR: 1.41, 95% CI [1.07–1.86], p = 0.041) and similar PCSS with EBRT + BT (HR: 1.50, 95% CI [0.91–2.47], p = 0.12). RP was associated with significantly better OS and PCSS outcomes than EBRT alone (OS HR: 1.58, 95% CI [1.59–2.12], p < 0.001; PCSS HR: 2.08 [1.60–2.72], p < 0.001). EBRT + BT also had significantly better OS and PCSS outcomes than EBRT alone (OS HR: 1.33, 95% CI [1.11–1.60], p < 0.001; PCSS HR: 1.57 [1.13–2.19], p = 0.003). Conclusions: For patients above 70 years with VHR PCa, RP was associated with better OS and similar PCSS than EBRT + BT. Both RP and EBRT + BT have better OS and PCSS than EBRT alone. [ABSTRACT FROM AUTHOR]
Acute leukemia with ambiguous lineage (ALAL) is a rare and highly aggressive malignancy with limited molecular characterization and therapeutic recommendations. In this study, we retrospectively analyzed 1635 acute leukemia cases in our center from January 2012 to June 2018. The diagnose of ALAL was based on either EGIL or 2016 WHO criteria, a total of 39 patients were included. Four patients diagnosed as acute undifferentiated leukemia (AUL) by both classification systems. Among the patients underwent high-throughput sequencing, 89.5% were detected at least one mutation and the median number of gene mutation was 3 (0–8) per sample. The most frequently mutated genes were NRAS (4, 21%), CEBPA (4, 21%), JAK3 (3, 16%), RUNX1 (3, 16%). The mutations detected in mixed-phenotype acute leukemia (MPAL) enriched in genes related to genomic stability and transcriptional regulation; while AUL cases frequently mutated in genes involved in signaling pathway. The survival analysis strongly suggested that mutation burden may play important roles to predict the clinical outcomes of ALAL. In addition, the patients excluded by WHO criteria had even worse clinical outcome than those included. The association of the genetic complexity of blast cells with the clinical outcomes and rationality of the diagnostic criteria of WHO system need to be evaluated by more large-scale prospective clinical studies. [ABSTRACT FROM AUTHOR]
ACUTE myeloid leukemia, GENE expression, PROGNOSIS, LEUCOCYTES, BONE marrow
Abstract
Background: There is mounting evidence that demonstrated the association of aberrant NEDD4L expression with diverse human cancers. However, the expression pattern and clinical implication of NEDD4L in acute myeloid leukemia (AML) remains poorly defined. Methods: We systemically determined NEDD4L expression with its clinical significance in AML by both public data and our research cohort. Moreover, biological functions of NEDD4L in leukemogenesis were further tested by in vitro experiments. Results: By the public data, we identified that low NEDD4L expression was correlated with AML among diverse human cancers. Expression of NEDD4L was remarkably decreased in AML compared with controls, and was confirmed by our research cohort. Clinically, low expression of NEDD4L was correlated with greatly lower age, higher white blood cells, and higher bone marrow/peripheral blood blasts. Moreover, NEDD4L underexpression was positively correlated with normal karyotype, FLT3 and NPM1 mutations, but negatively associated with complex karyotype and TP53 mutations. Importantly, the association between NEDD4L expression and survival was also discovered in cytogenetically normal AML patients. Finally, a number of 1024 RNAs and 91 microRNAs were identified to be linked to NEDD4L expression in AML. Among the negatively correlated microRNAs, miR-10a was also discovered as a microRNA that may directly target NEDD4L. Further functional studies revealed that NEDD4L exhibited anti-proliferative and pro-apoptotic effects in leukemic cell line K562. Conclusions: Our findings indicated that NEDD4L underexpression, as a frequent event in AML, was associated with genetic abnormalities and prognosis in AML. Moreover, NEDD4L expression may be involved in leukemogenesis with potential therapeutic target value. [ABSTRACT FROM AUTHOR]
Ferroptosis is a newly discovered, iron‐dependent, nonapoptotic form of programmed cell death that plays an important role in the development of lung adenocarcinoma (LUAD). In this study, ferroptosis‐related genes (FRGs) were identified from the FerrDb dataset, and the mRNA expression profiles and corresponding clinical data of LUAD patients were downloaded from the University of California, Santa Cruz (UCSC) databases. Data from LUAD patients from the Gene Expression Omnibus (GEO) dataset were used as the verification set. Cox and Lasso regression analyses were used to screen the FRGs with prognostic value, and six prognostic‐related FRGs were selected to construct prognostic risk score signatures. Immunohistochemistry was utilized to manifest the differential expression of six FRGs in tumor and normal tissues at the protein level. Functional enrichment analysis indicated that FRGs were mainly enriched in ferroptosis‐related pathways. Patients were divided into high‐ and low‐risk groups based on the median risk score. The Kaplan–Meier survival curves confirmed that patients with a high score had significantly worse overall survival. Receiver operating characteristic (ROC) curves proved that the prognostic signature has good sensitivity and specificity for predicting the prognosis of LUAD patients. Nomogram analysis showed that the prognostic signature has potential independent prognostic value. Moreover, the prognostic signature has been shown to be significantly associated with some clinical features (T stage, N stage, tumor stage, and survival status) as well as many immune‐activity‐related genes and immune‐checkpoint‐related genes. In conclusion, we constructed a prognostic signature consisting of six FGRs, which can provide a reference for predicting the prognosis of LUAD patients. [ABSTRACT FROM AUTHOR]
Although liver transplantation is considered to be the best choice for patients with end-stage liver diseases, postoperative immune rejection still cannot be overlooked. Patients with liver transplantation have to take immunosuppressive drugs for a long time or even their entire lives, in which heavy economic burden and side effects caused by the drugs have become the major impediment for liver transplantation. There is a growing body of evidences indicating that mesenchymal stem cell (MSC) transplantation, a promising tool in regenerative medicine, can be used as an effective way to induce immune tolerance after liver transplantation based on their huge expansion potential and unique immunomodulatory properties. MSCs have been reported to inhibit innate immunity and adaptive immunity to induce a tolerogenic microenvironment. In in vitro studies, transplanted MSCs show plasticity in immune regulation by altering their viability, migration, differentiation, and secretion in the interactions with the surrounding host microenvironment. In this review, we aim to provide an overview of the current understanding of immunomodulatory properties of MSCs in liver transplantation, to elucidate the potential mechanisms behind MSCs regulating immune response, especially in vivo and the influence of the microenvironment, and ultimately to discuss the feasible strategies to improve the clinical prognosis of liver transplantation. Only after exhaustive understanding of potential mechanisms of the MSC immunomodulation can we improve the safety and effectiveness of MSC treatment and achieve better therapeutic effects. [ABSTRACT FROM AUTHOR]
It was previously reported that PRR34‐AS1 was overexpressed in some solid tumors. PRR34‐AS1 promoter was shown to have a differential methylation region (DMR), and was hypomethylated in acute myeloid leukemia (AML). Therefore, the present study used real‐time quantitative PCR (RQ‐PCR) to explore the expression characteristics of PRR34‐AS1 in AML. In addition, the correlation between the expression of PRR34‐AS1 and clinical prognosis of AML was determined. The findings of this study indicated that high PRR34‐AS1 expression was bound up with shorter overall survival (OS) in AML patients (p = 0.002). Moreover, patients with high expression of PRR34‐AS1 had significantly lower complete remission (CR) rate compared with those with low expression of PRR34‐AS1 after induction chemotherapy. Furthermore, multivariate analysis confirmed that PRR34‐AS1 expression was an independent factor affecting CR in whole‐AML, non‐APL‐AML, and CN‐AML patients (p = 0.032, 0.039, and 0.036, respectively). Methylation‐specific PCR (MSP) and bisulfite sequencing PCR (BSP) were used to explore the methylation status of PRR34‐AS1. PRR34‐AS1 promoter showed a pattern of hypomethylation in AML patients compared with normal controls (p = 0.122). Notably, of whole‐AML and non‐APL‐AML patients, PRR34‐AS1 hypomethylated patients presented a significantly shorter OS than those with a hypermethylated PRR34‐AS1 (p = 0.010 and 0.037, respectively). Multivariate analysis confirmed that the hypomethylation of PRR34‐AS1 served as an independent prognostic indicator in both whole‐cohort AML and non‐APL‐AML categories (p = 0.057 and 0.018, respectively). In summary, the findings of this study showed that abnormalities in PRR34‐AS1 are associated with poor prognosis in AML. Therefore, monitoring this index may be important in the prognosis of AML and can provide information on effective chemotherapy against the disease. [ABSTRACT FROM AUTHOR]
Objective: Diffuse large B-cell lymphoma (DLBCL) is the most common histopathological type of non-Hodgkin's lymphoma, which may arise from various extranodal sites. Little is known about the clinical characteristics and survival outcomes of primary DLBCL of the urinary tract (UT). Thus, we conducted this study to explore the independent prognostic factors of patients with UT-DLBCL using the Surveillance, Epidemiology, and End Results (SEER) database. Materials and Methods: We searched the Surveillance, Epidemiology, and End Results (SEER) database for the data of patients diagnosed with UT-DLBCL between 1975 and 2016. Data, including demographic tumour stage and therapeutic strategies, such as surgical resection, radiation therapy, and chemotherapy, were collected. The impact of these factors on survival outcomes, including overall survival (OS) and disease-specific survival (DSS), was analysed using Kaplan–Meier curves. Results: Four-hundred and eighty-nine patients who met the inclusion criteria were enrolled in the data analysis. The median age was 69 years old. Most cases of UT-DLBCL (72.39%) originated from the kidney, followed by the urinary bladder (24.95%). Both surgical resection and chemotherapy can significantly improve OS and DSS. Patients older than 75 years had the worst survival outcomes. Stage IV DLBCL may be a poor prognostic factor. Conclusion: To the best of our knowledge, this is the largest population-based study of UT-DLBCL. Advanced age, male gender, lack of surgical resection or chemotherapy, and stage IV DLBCL were poor prognostic factors. [ABSTRACT FROM AUTHOR]
PROGNOSIS, BRAIN tumors, SMALL interfering RNA, GENES, GLIOBLASTOMA multiforme
Abstract
Glioblastoma (GBM) is a malignant brain tumour with poor prognosis. The potential pathogenesis and therapeutic target are still need to be explored. Herein, TCGA expression profile data and clinical information were downloaded, and the WGCNA was conducted. Hub genes which closely related to poor prognosis of GBM were obtained. Further, the relationship between the genes of interest and prognosis of GBM, and immune microenvironment were analysed. Patients from TCGA were divided into high‐ and low‐risk group. WGCNA was applied to the high‐ and low‐risk group and the black module with the lowest preservation was identified which could distinguish the prognosis level of these two groups. The top 10 hub genes which were closely related to poor prognosis of patients were obtained. GO analysis showed the biological process of these genes mainly enriched in: Cell cycle, Progesterone‐mediated oocyte maturation and Oocyte meiosis. CDCA5 and CDCA8 were screened out as the genes of interest. We found that their expression levels were closely related to overall survival. The difference analysis resulted from the TCGA database proved both CDCA5 and CDCA8 were highly expressed in GBM. After transfection of U87‐MG cells with small interfering RNA, it revealed that knockdown of the CDCA5 and CDCA8 could influence the biological behaviours of proliferation, clonogenicity and apoptosis of GBM cells. Then, single‐gene analysis was performed. CDCA5 and CDCA8 both had good correlations with genes that regulate cell cycle in the p53 signalling pathway. Moreover, it revealed that high amplification of CDCA5 was correlated with CD8+ T cells while CDCA8 with CD4+ T cells in GBM. These results might provide new molecular targets and intervention strategy for GBM. [ABSTRACT FROM AUTHOR]
• Admission serum CXCL12 levels are significantly elevated in patients with IMAEs after head trauma. • Admission serum CXCL12 levels are related to the number of IMAEs after head trauma. • Admission serum CXCL12 is a determinant for IMAEs after head trauma. • Admission serum CXCL12 has a better predictive ability for IMAEs after head trauma. CXC chemokine ligand-12 (CXCL12) is associated with brain inflammation. We attempted to discern whether serum CXCL12 is a promising predictor for in-hospital major adverse events (IMAEs) after traumatic brain injury (TBI), including death, acute lung injury, acute traumatic coagulopathy, progressive hemorrhagic injury and posttraumatic cerebral infarction. In this prospective, observational study, serum CXCL12 levels were quantified among 117 severe TBI patients. We investigated the relation of CXCL12 levels to IMAEs using a multivariate analysis. Median value of serum CXCL12 concentrations was substantially higher in patients with IMAEs than in other remainders (21.1 vs. 11.6 ng/ml). With an increasing number of IMAEs, serum CXCL12 concentrations were significantly increased (r = 0.702). Serum CXCL12 independently predicted IMAEs (odds ratio, 1.253; 95% CI, 1.100–1.428). Serum CXCL12 concentrations discriminated risk of IMAEs with area under receiver operating characteristic curve of 0.759 (95% CI, 0.672–0.834), its concentrations >16.0 ng/ml distinguished IMAEs with 83.9% sensitivity and 67.2% specificity and its combination with Glasgow coma scale scores produced the best predictive ability compared with each one alone (p = 0.0116 or 0.0004). Serum CXCL12 concentrations are independently associated with IMAEs following TBI, substantializing serum CXCL12 as a useful prognostic biomarker for head trauma patients. [ABSTRACT FROM AUTHOR]
PANCREATIC tumors, RESEARCH, COMBINATION drug therapy, CLINICAL trials, HETEROCYCLIC compounds, RESEARCH methodology, ANTINEOPLASTIC agents, DEOXYCYTIDINE, CANCER relapse, PROGNOSIS, EVALUATION research, MEDICAL cooperation, ANTIMETABOLITES, FLUOROURACIL, COMPARATIVE studies, RANDOMIZED controlled trials, COST effectiveness, COMBINED modality therapy, QUALITY-adjusted life years
Abstract
Purpose: This study aimed to investigate the cost-effectiveness of adjuvant treatments in resected pancreatic cancer.Methods: A Markov model was developed to mimic the disease process of postoperative pancreatic cancer, encompassing three health states (relapse-free survival, recurrent disease, and death). Health outcomes and utility scores were derived from the phase III trial and available literature. Cost data were calculated using standard fee data from the West China Hospital for 2017. One-way sensitivity analyses and probabilistic sensitivity analyses were developed to explore model uncertainty.Results: Treatment with S-1 was estimated to yield 1.61 quality-adjusted life-years (QALYs) at a cost of $25,696, whereas treatment with gemcitabine yielded 1.27 QALYs at a cost of $28,930. The incremental cost-effectiveness ratio of S-1 versus gemcitabine was $-9,490 per QALY. Based on the willingness-to-pay threshold of $25,841 per QALY, the net monetary benefit (NMB) was $15,786 for S-1 and $3,727 for gemcitabine, generating the incremental NMB of $12,059. A probabilistic sensitivity analysis revealed that the probabilities of S-1 and gemcitabine being cost-effective were 92% and 8%, respectively. Results were robust to changes in parameters.Conclusion: Adjuvant therapy using S-1 is a cost-effective alternative compared to gemcitabine in patients with postoperative pancreatic cancer from the Chinese societal perspective. [ABSTRACT FROM AUTHOR]
Ma, Fenglong, Wang, Yaqing, Xiao, Houping, Yuan, Ye, Chitta, Radha, Zhou, Jing, and Gao, Jing
Subjects
MEDICAL coding, ARTIFICIAL neural networks, MEDICAL informatics, RECURRENT neural networks, ELECTRONIC health records, NURSING informatics, DIAGNOSIS, RESEARCH, RESEARCH methodology, ACQUISITION of data, PROGNOSIS, EVALUATION research, MEDICAL cooperation, COMPARATIVE studies, FORECASTING, STATISTICAL models, HEART failure
Abstract
Background: Diagnosis aims to predict the future health status of patients according to their historical electronic health records (EHR), which is an important yet challenging task in healthcare informatics. Existing diagnosis prediction approaches mainly employ recurrent neural networks (RNN) with attention mechanisms to make predictions. However, these approaches ignore the importance of code descriptions, i.e., the medical definitions of diagnosis codes. We believe that taking diagnosis code descriptions into account can help the state-of-the-art models not only to learn meaning code representations, but also to improve the predictive performance, especially when the EHR data are insufficient.Methods: We propose a simple, but general diagnosis prediction framework, which includes two basic components: diagnosis code embedding and predictive model. To learn the interpretable code embeddings, we apply convolutional neural networks (CNN) to model medical descriptions of diagnosis codes extracted from online medical websites. The learned medical embedding matrix is used to embed the input visits into vector representations, which are fed into the predictive models. Any existing diagnosis prediction approach (referred to as the base model) can be cast into the proposed framework as the predictive model (called the enhanced model).Results: We conduct experiments on two real medical datasets: the MIMIC-III dataset and the Heart Failure claim dataset. Experimental results show that the enhanced diagnosis prediction approaches significantly improve the prediction performance. Moreover, we validate the effectiveness of the proposed framework with insufficient EHR data. Finally, we visualize the learned medical code embeddings to show the interpretability of the proposed framework.Conclusions: Given the historical visit records of a patient, the proposed framework is able to predict the next visit information by incorporating medical code descriptions. [ABSTRACT FROM AUTHOR]
Male, Rural Population, China, Pediatric Obesity, Incidence, Infant, Newborn, Observational Study, Infant, Prognosis, Weight Gain, Body Mass Index, Double-Blind Method, Risk Factors, Child, Preschool, Electric Impedance, Humans, Female, Micronutrients, Prospective Studies, Child, Research Article, Follow-Up Studies
Abstract
Obesity is increasing in developing countries. This study aimed to identify the association between rapid infancy weight gain and obesity risk among early school-age children. A total of 581 singletons (349 boys, 232 girls) whose mothers participated in an antenatal multiple micronutrient supplement trial in rural western China were followed from birth to between 7 and 9 years of age. Height and weight were measured at birth, 1.5 years, and between 7 and 9 years. At the 7- to 9-year time point, body composition was determined using bioelectrical impedance analysis. Multilevel mixed analysis was used to test the associations between rapid weight gain in infancy (from birth to age 1.5 years) and body size and composition or overweight/obesity among early school-age children. Overall, 31.2% (181 of 581) of the infants showed a weight-for-age Z score gain greater than 0.67 between birth and 1.5 years, indicating rapid weight gain. Approximately 5.7% (33 of 579) of the subjects were overweight (BMI-for-age Z scores [BAZ] >1 and ≤2) or obese (BAZ >2). Rapid infancy weight gain was associated with a higher BAZ (P
Background: Downstream of tyrosine kinase 6 (DOK6), which is specifically expressed in the nervous system, was previously recognized as an adapter only in neurite outgrowth. Recent studies also demonstrated the potential role of DOK6 in solid tumors such as gastric cancer and breast cancer. However, previous studies of DOK6 have not dealt with its roles in myeloid malignancies. Herein, we verified the promoter methylation status of DOK6 and further explored its clinical implication in de novo acute myeloid leukemia (AML). Methods: A total of 100 newly diagnosed adult AML patients were involved in the current study. DOK6 expression and methylation were detected by real‐time qPCR and methylation‐specific PCR (MSP), respectively. Bisulfite sequencing PCR (BSP) was performed to assess the methylation density of the DOK6 promoter. Results: Downstream of tyrosine kinase 6 promoter methylation was significantly increased in AML patients compared to controls (P = .037), whereas DOK6 expression significantly decreased in AML patients (P < .001). The expression of DOK6 was markedly up‐regulated after treated by 5‐aza‐2′‐deoxycytidine (5‐aza‐dC) in THP‐1 cell lines. The methylation status of the DOK6 promoter was associated with French‐American‐British classifications (P = .037). There was no significant correlation existed between DOK6 expression and its promoter methylation (R = .077, P = .635). Interestingly, of whole‐AML and non‐APL AML patients, both have a tendency pertaining to the DOK6 methylation group and a significantly longer overall survival (OS) than the DOK6 unmethylation group (P = .042 and.036, respectively). Conclusion: Our study suggested that DOK6 promoter hypermethylation was a common molecular event in de novo AML patients. Remarkably, DOK6 promoter methylation could serve as an independent and integrated prognostic biomarker not only in non‐APL AML patients but also in AML patients who are less than 60 years old. [ABSTRACT FROM AUTHOR]
The current study was aimed to investigate integrin beta‐like 1 (ITGBL1) methylation pattern and its clinical relevance in patients with acute myeloid leukemia (AML). Real‐time methylation‐specific polymerase chain reaction (PCR; RQ‐MSP) and bisulfite sequencing PCR (BSP) were performed to detect the methylation of ITGBL1 promoter. Real‐time quantitative PCR (RT‐qPCR) was performed to analyze ITGBL1 transcript level. The results showed that ITGBL1 methylation level in 131 patients with AML was significantly higher than 29 controls (p < 0.001). The ITGBL1‐hypermethylated group tended to have a higher bone marrow (BM) blasts (p = 0.076). Meanwhile, ITGBL1‐hypermethylated patients tended to have a lower complete remission (CR) rate (p = 0.102). ITGBL1‐hypermethylated patients had significantly shorter overall survival (OS) and leukemia‐free survival (LFS) than ITGBL1 hypomethylated patients in whole AML cohort (p = 0.009 and 0.043, respectively) and patients with nonacute promyelocytic leukemia (APL ; p = 0.023 and 0.039, respectively). Multivariate analysis confirmed that the ITGBL1 methylation served as an independent prognostic factor in both patients with whole‐cohort AML (p = 0.030) and patients with non‐APL (p = 0.020). Furthermore, the ITGBL1 methylation level was significantly decreased in follow‐up AML patients who achieved complete remission after induction therapy (P = 0.001). ITGBL1 methylation negatively correlated with ITGBL1 expression in patients with AML (R = −0.328, p = 0.008). Moreover, demethylation of ITGBL1 could increase the ITGBL1 expression in the K562 leukemic cell line (p < 0.05). In conclusion, the ITGBL1 hypermethylation is a potential biomarker for predicting prognosis and monitoring disease status in patients with AML. The results showed that ITGBL1 methylation level in patients with AML was significantly higher than controls. ITGBL1‐hypermethylated patients had significantly shorter overall survival (OS) and leukemia‐free survival (LFS) than ITGBL1 hypomethylated patients in patients with whole AML cohort and nonacute promyelocytic leukemia (APL). Multivariate analysis confirmed that ITGBL1 methylation served as an independent prognostic factor in both patients with whole‐cohort AML and patients with non‐APL. [ABSTRACT FROM AUTHOR]
Previous studies have been indicated that integrin α2 (ITGA2) may be important in cell migration, invasion, survival, and angiogenesis. However, the correlation between ITGA2 expression and acute myeloid leukemia (AML) is still unclear. Real‐time quantitative polymerase chain reaction was carried out to analyze ITGA2 messenger RNA level. Methylation‐specific polymerase chain reaction (PCR) and bisulfite sequencing PCR were performed to detect the methylation of ITGA2 promoter. ITGA2 expression was significantly upregulated in 134 de novo AML patients compared with 33 controls (p = 0.007). ITGA2high group had markedly lower complete remission (CR) rate than ITGA2low group (p = 0.011). Furthermore, the overall survival in ITGA2high patients was significantly shorter than ITGA2low patients throughout AML cohort, non–acute promyelocytic leukemia (APL) and cytogenetic normal‐AML (p = 0.001, 0.002, and 0.044, respectively). Multivariate analysis confirmed that ITGA2 overexpression served as an independent prognostic factor in both whole‐cohort AML patients (p = 0.018) and non‐APL AML patients (p = 0.021). Besides, ITGA2 expression level was significantly decreased in AML patients after CR (p = 0.011), and was returned at the time of relapse phase (p = 0.021). Moreover, unmethylated ITGA2 promoter was identified in normal controls, leukemia cell lines, and primary leukemia cells with low or high ITGA2 expression. In conclusions, methylation‐independent ITGA2 overexpression is associated with poor prognosis in AML. Integrin α2 (ITGA2) expression was significantly upregulated in 134 de novo acute myeloid leukemia (AML) patients compared with 33 controls (p = 0.007). Furthermore, the overall survival in high ITGA2 expression patients was significantly shorter than low ITGA2 expression patients throughout AML cohort, non–acute promyelocytic leukemia (APL), and cytogenetic normal‐AML (p = 0.001, 0.002, and 0.044, respectively). Multivariate analysis confirmed that ITGA2 overexpression served as an independent prognostic factor in both whole‐cohort AML patients (p = 0.018) and non‐APL AML patients (p = 0.021). [ABSTRACT FROM AUTHOR]
This study was designed to learn the expression status of miR-24 and its clinical relevance in patients with acute myeloid leukemia (AML). We detected the miR-24 expression levels using real-time quantitative PCR in 84 AML patients and investigated the clinical significance of miR-24 expression in AML. There was no difference in clinical parameters between cases with miR-24 high expression and with miR-24 low expression. The frequency of miR-24 high expression was higher in patients with t(8;21) than in others (82% (9/11) versus 44% (32/72), P=0.026). The levels of miR-24 expression had no correlation with the mutations of nine genes (FLT3-ITD, NPM1, C-KIT, IDH1/IDH2, DNMT3A, N/K-RAS and C/EBPA). Meanwhile, among the group who obtained CR, the cases with miR-24 high expression had no difference in overall survival (OS) and relapse-free survival (RFS) than those with miR-24 low expression (P=0.612 and 0.665, respectively). These findings implicated that miR-24 high regulation is a common event in AML with t(8;21), and it might serve as a novel and selective therapeutic target for the treatment of AML with t(8;21).
DNA methylation, P16 gene, DYSPLASIA, SQUAMOUS cell carcinoma, CANCER invasiveness, TUMOR markers, PROGRESSION-free survival, POLYMERASE chain reaction, PROTEIN metabolism, ALLELES, DNA, EPITHELIAL cells, LONGITUDINAL method, MOUTH tumors, ORAL mucosa, PROGNOSIS, PROTEINS, RESEARCH funding, DISEASE progression, NEOPLASTIC cell transformation, DIAGNOSIS
Abstract
Background: Total P16 methylation (P16M), including P16 hydroxymethylation (P16H) and true-P16M, correlates with malignant transformation of oral epithelial dysplasia (OED). Both true-P16M and P16H are early events in carcinogenesis. The aim of this study is to prospectively determine if discrimination of true-P16M from P16H is necessary for prediction of cancer development from OEDs.Methods: Patients (n = 265) with mild or moderate OED were recruited into the double blind two-center cohort. Total-P16M and P16H were analyzed using the 115-bp MethyLight, TET-assisted bisulfite (TAB) methylation-specific PCR (MSP), and TAB-sequencing. Total-P16M-positive and P16H-negative samples were defined as true-P16M-positive. Progression of OEDs was monitored for a minimum 24 months follow-up period.Results: P16H was detected in 23 of 73 (31.5%) total-P16M-positive OEDs. Follow-up information was obtained from 247 patients with an ultimate compliance rate of 93.2%. OED-derived squamous cell carcinomas were observed in 13.0% (32/247) patients during follow-up (median, 41.0 months). The cancer progression rate for total-P16M-positive patients was significantly increased when compared to total-P16M-negative patients [23.3% vs 8.6%; adjusted odds ratio = 2.67 (95% CI: 1.19-5.99)]. However, the cancer progression rates were similar between P16H- and true-P16M-positive OEDs [26.1% (6/23) vs 22.0% (11/50); odds ratio = 0.80 (95% CI: 0.22-2.92)]. The cancer-free survival was also similar for these patients.Conclusion: P16H and true-P16M are similar biomarkers for determining malignant potential of OEDs. Discrimination of P16H from true-P16M, at least in OED, may be not necessary in clinical applications.Trial Registration: This study is registered prospectively in the U.S. National Institutes of Health Clinical Trials Protocol Registration System (trial number NCT02967120, available at https://ClinicalTrials.gov/ct2/show/NCT02967120 ). [ABSTRACT FROM AUTHOR]