BACKGROUND: Serum antinuclear antibodies (ANAs) are positive in some patients with chronic lymphocytic leukemia (CLL), but the prognostic value of ANAs remains unknown. The aim of this study was to evaluate the role of ANAs as a prognostic factor in CLL. METHODS: This study retrospectively analyzed clinical data from 216 newly diagnosed CLL subjects with ANAs test from 2007 to 2017. Multivariate Cox regression analyses were used to screen the independent prognostic factors related to time to first treatment (TTFT), progression free survival (PFS) and overall survival (OS). Receiver operator characteristic curves and area under the curve (AUC) were utilized to assess the predictive accuracy of ANAs together with other independent factors for OS. RESULTS: The incidence of ANAs abnormality at diagnosis was 13.9%. ANAs positivity and TP53 disruption were independent prognostic indicators for OS. The AUC of positive ANAs together with TP53 disruption was 0.766 (95% confidence interval [CI]: 0.697-0.826), which was significantly larger than that of either TP53 disruption (AUC: 0.706, 95% CI: 0.634-0.772, P = 0.034) or positive ANAs (AUC: 0.595, 95% CI: 0.520-0.668, P < 0.001) in OS prediction. Besides, serum positive ANAs as one additional parameter to CLL-international prognostic index (IPI) obtained superior AUCs in predicting CLL OS than CLL-IPI alone. CONCLUSION This study identified ANAs as an independent prognostic factor for CLL, and further investigations are needed to validate this finding.
ADP-ribosyl Cyclase 1 ; blood ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antibodies, Antinuclear ; blood ; Autoimmunity ; physiology ; Female ; Humans ; Kaplan-Meier Estimate ; Leukemia, Lymphocytic, Chronic, B-Cell ; blood ; mortality ; Male ; Middle Aged ; Multivariate Analysis ; Mutation ; genetics ; Proportional Hazards Models ; Retrospective Studies ; Survival Analysis ; Tumor Suppressor Protein p53 ; blood ; Young Adult ; ZAP-70 Protein-Tyrosine Kinase ; blood

OBJECTIVE: To explore the correlation of genetic mutations and clinical features of myelodysplastic syndromes (MDS) with scores of Revised International Prognostic Scoring System (IPSS-R). METHODS: Eighty-seven patients with de novo MDS were enrolled. Mutations of MDS-related genes and clinical features were used to determine the incidence and subtype of mutations. Clinical features and IPSS-R scores of the patients with high frequency mutations involving TET2, TP53, ASXL1, RUNX1 and SF3B1 genes were compared. RESULTS: Fifty-four patients (62.1%) harbored at least one point mutation. The incidences of various mutations were significantly different, with the incidence of MDS-EB-2 being 100% and MDS-SLD being only 38.9%. Compared with the wild types, patients harboring mutations had higher lactate dehydrogenase, higher β2 microglobulin, higher percentage of bone marrow blast cells and lower hemoglobin levels (P=0.027, <0.01, <0.01, 0.046, respectively). The IPSS-R scores of MDS patients with mutations were significantly higher than the wild types (P<0.01). The IPSS-R scores of the TP53 mutation groups were 7.82±1.83, which was significantly higher than the control group (3.77±1.66, P<0.01). No difference was found between the IPSS-R between patients carrying TET2, ASXL1, RUNX1, and SF3B1 mutations or the wild types (P>0.05). CONCLUSION Genetic mutations are commonly found in MDS. MDS patients with mutations have unique clinical laboratory characteristics. Although the prognostic value of most genes is controversial, TP53 is an definite indicator of poor prognosis.
DNA Mutational Analysis ; Humans ; Incidence ; Mutation ; Myelodysplastic Syndromes ; genetics ; Prognosis ; Tumor Suppressor Protein p53 ; genetics

OBJECTIVE: To investigate the relationship between the precursors of high grade serous ovarian cancer (HGSOC) and the characteristics of patients with a low HGSOC risk in terms of the effects of pregnancy. METHODS: We prospectively examined consecutive cases in which the bilateral fallopian tubes were removed during benign gynecological or obstetric surgery and assessed the relationship between the patient characteristics, including parity and pregnancy, and the incidence of HGSOC precursors. All the fallopian tubes were examined by applying the Sectioning and Extensively Examining the Fimbriated End (SEE-FIM) Protocol. RESULTS: Of the 113 patients enrolled, 67 were gynecological and 46 were obstetric. The p53 signature was identified in 21 patients. No other precursors were identified. In a comparison of the p53 signature-positive and negative groups, parous women and pregnant women were significantly fewer in the p53 signature-positive group (53% vs. 86%, p=0.002, 10% vs. 47%, p=0.001, respectively). Current pregnancy was also associated with a significantly lower incidence of the p53 signature after multivariate adjustment (odds ratio [OR]=0.112; 95% confidence interval [95% CI]=0.017–0.731; p=0.022). Among gynecological patients, parous women were fewer in the p53 signature-positive group on univariate (47% vs. 73%, p=0.047) and multivariate analysis (OR=0.252; 95% CI=0.069–0.911; p=0.036). No other characteristics were associated with p53 signature positivity. CONCLUSIONS: The incidence of the p53 signature was significantly lower in parous women and pregnant women. This decreased incidence of early phase serous carcinogenesis may be one of the possible mechanisms underlying HGSOC risk reduction among parous women.
Carcinogenesis ; Cystadenocarcinoma, Serous ; Fallopian Tube Neoplasms ; Fallopian Tubes ; Female ; Humans ; Incidence ; Multivariate Analysis ; Obstetric Surgical Procedures ; Ovarian Neoplasms ; Parity ; Pregnancy ; Pregnant Women ; Prospective Studies ; Risk Reduction Behavior ; Tumor Suppressor Protein p53

Objective: To analyze the survival and first-line immune-chemotherapy (CIT) of chronic lymphocytic leukemia (CLL) with abnormal TP53 gene in the era of traditional CIT. Methods: The clinical data of 118 CLL patients diagnosed from January 2003 to August 2017 were collected. Survival was analyzed according to indicators including sex, age, Binet risk stratification, B symptoms, β(2)-microglobulin (β(2)-MG) , immunoglobulin heavy chain variable region gene (IGHV) mutation status, chromosome karyotype and TP53 gene deletion/mutation. The efficacy of first-line CIT of 101 CLL patients was further analyzed. Results: Among 118 patients, median progression-free survival (PFS) was 12 (95%CI 10.148-13.852) months and median overall survival (OS) was 53 (95%CI 41.822-64.178) months, only 30.5% patients survived over 5 years. Low β(2)-MG<3.5 mg/L indicated longer PFS (P=0.027) , female and Binet A patients had longer OS (P=0.011 and 0.013, respectively) . Of 118 patients, 17 (14.4%) didn't receive any therapy until follow-up time or the dead time. Among the 101 patients who received ≥1 CIT, median time to first treatment (TTFT) was 1 (0-62) months, patients in Binet A had longer TTFT (P<0.001) compared to the patients in Binet B/C. According to statistical needs, we divided those first-line CIT into four groups: there were 30 cases (29.7%) in mild chemotherapy group (mainly treated with nitrogen mustard phenylbutyrate or rituximab alone) , 32 cases (31.7%) in the fludarabine-containing group, 23 cases (22.8%) in high-dose methyprednisolone (HDMP) containing group and 16 cases (15.8%) in the other chemotherapy group. The first regimen contained HDMP can bring longer PFS (P<0.001) , however the OS between four groups had no statistical differences. Conclusion: CLL patients with abnormal TP53 gene had poor response to immunotherapy, rapid clinical progressing, first-line immunotherapy containing HDMP can prolong PFS and will create an opportunity for patients to participate in clinical trials of novel drugs.
Antineoplastic Combined Chemotherapy Protocols ; Female ; Genes, p53 ; Humans ; Immunotherapy ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics* ; Survival Analysis ; Tumor Suppressor Protein p53/genetics*

Objective: To explore the clinical and prognostic values of TP53 gene mutation in patients with acute myeloid leukemia (AML) . Methods: A retrospective analysis of 265 newly diagnosed AML patients with next-generation sequencing (NGS) data in the Hematology Department of Changhai Hospital from January 2010 to January 2019 was performed. Mutation analysis was carried out by targeted sequencing technology including 200 hematological malignancy related genes. The association of TP53 mutation with clinical features was analyzed. Results: Alterations in TP53 were found in 20 (7.5%) patients, including 17 case (6.4%) of missense mutations, 2 cases (0.7%) of frame-shift deletion mutations and 1 case (0.4%) of splicing sites mutation. A total of 23 kinds of TP53 mutations were detected, most of them (16, 69.6%) were located in the DNA binding domain of exon 5-8, 4 in the DNA binding domain of exon 3-4, 2 in exon 10 and 1 in splice site, respectively. The median age of patients with TP53 alterations was higher than those without [52 (26-72) years old vs 45 (14-75) years old, P= 0.008]. The frequency of complex karyotypes was higher in patients with TP53 alterations than those without [45.0% (9/20) vs 6.1% (15/245) , P<0.001]. Median overall survival (OS) of patients with TP53 alterations was shorter than those without[14.1 (95%CI 6.78-21.42) months vs 31.4 (95%CI 13.20-49.59) months, P=0.029]. The OS of patients treated with "Decitabine + CAG" was superior than that of patients treated with "3 + 7" regimen [30.0 (95%CI 27.35-38.84) months vs 12.5 (95%CI 5.80-19.19) months, P=0.018]. Multivariate analysis indicated that TP53, DNMT3A and USH2A alterations, WBC ≥ 12.45×10(9)/L had negative impacts on OS. Conclusion: The frequency of TP53 mutation was 7.5% in our cohort. Most mutations were located in the DNA binding domain. TP53 alterations were strongly associated with older age, complex karyotype and shorter OS. Decitabine-based induction chemotherapy and hematopoietic stem cell transplantation may improve OS, more cases and/or multicenter randomized studies are needed for further confirmation.
Adolescent ; Adult ; Aged ; DNA Mutational Analysis ; Humans ; Leukemia, Myeloid, Acute/genetics* ; Middle Aged ; Mutation ; Prognosis ; Retrospective Studies ; Tumor Suppressor Protein p53/genetics* ; Young Adult

Tumor-specific neoantigens have attracted much attention since they can be used as biomarkers to predict therapeutic effects of immune checkpoint blockade therapy and as potential targets for cancer immunotherapy. In this study, we developed a comprehensive tumor-specific neoantigen database (TSNAdb v1.0), based on pan-cancer immunogenomic analyses of somatic mutation data and human leukocyte antigen (HLA) allele information for 16 tumor types with 7748 tumor samples from The Cancer Genome Atlas (TCGA) and The Cancer Immunome Atlas (TCIA). We predicted binding affinities between mutant/wild-type peptides and HLA class I molecules by NetMHCpan v2.8/v4.0, and presented detailed information of 3,707,562/1,146,961 potential neoantigens generated by somatic mutations of all tumor samples. Moreover, we employed recurrent mutations in combination with highly frequent HLA alleles to predict potential shared neoantigens across tumor patients, which would facilitate the discovery of putative targets for neoantigen-based cancer immunotherapy. TSNAdb is freely available at http://biopharm.zju.edu.cn/tsnadb.
Antigens, Neoplasm ; metabolism ; Data Analysis ; Databases, Genetic ; Humans ; Immunotherapy ; Mutation ; genetics ; Neoplasms ; genetics ; immunology ; Tumor Suppressor Protein p53 ; genetics ; Urinary Bladder Neoplasms ; genetics

OBJECTIVE: This paper applied a transcriptomic approach to investigate the mechanisms of adriamycin (ADR) in treating proliferative vitreoretinopathy (PVR) using ARPE-19 cells. METHODS: The growth inhibitory effects of ADR on ARPE-19 cells were assessed by sulforhodamine B (SRB) assay and propidium iodide (PI) staining using flow cytometry. The differentially expressed genes between ADR-treated ARPE-19 cells and normal ARPE-19 cells and the signaling pathways involved were investigated by microarray analysis. Mitochondrial function was detected by JC-1 staining using flow cytometry and the Bcl-2/Bax protein family. The phosphorylated histone H2AX (γ-H2AX), phosphorylated checkpoint kinase 1 (p-CHK1), and phosphorylated checkpoint kinase 2 (p-CHK2) were assessed to detect DNA damage and repair. RESULTS: ADR could significantly inhibit ARPE-19 cell proliferation and induce caspase-dependent apoptosis in vitro. In total, 4479 differentially expressed genes were found, and gene ontology items and the p53 signaling pathway were enriched. A protein-protein interaction analysis indicated that the TP53 protein molecules regulated by ADR were related to DNA damage and oxidative stress. ADR reduced mitochondrial membrane potential and the Bcl-2/Bax ratio. p53-knockdown restored the activation of c-caspase-3 activity induced by ADR by regulating Bax expression, and it inhibited ADR-induced ARPE-19 cell apoptosis. Finally, the levels of the γ-H2AX, p-CHK1, and p-CHK2 proteins were up-regulated after ADR exposure. CONCLUSIONS The mechanism of ARPE-19 cell death induced by ADR may be caspase-dependent apoptosis, and it may be regulated by the p53-dependent mitochondrial dysfunction, activating the p53 signaling pathway through DNA damage.
Apoptosis ; Caspases/metabolism* ; Cell Proliferation ; Cell Survival/drug effects* ; Doxorubicin/pharmacology* ; Flow Cytometry ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; Membrane Potential, Mitochondrial ; Oligonucleotide Array Sequence Analysis ; Oxidative Stress/drug effects* ; Phosphorylation ; Propidium/chemistry* ; RNA, Small Interfering/metabolism* ; Retinal Pigment Epithelium/metabolism* ; Rhodamines/chemistry* ; Signal Transduction/drug effects* ; Transcriptome ; Tumor Suppressor Protein p53/metabolism* ; Vitreoretinopathy, Proliferative/drug therapy*

Royal jelly (RJ) from honeybee has been widely used as a health promotion supplement. The major royal jelly proteins (MRJPs) have been identified as the functional component of RJ. However, the question of whether MRJPs have anti-senescence activity for human cells remains. Human embryonic lung fibroblast (HFL-I) cells were cultured in media containing no MRJPs (A), MRJPs at 0.1 mg/ml (B), 0.2 mg/ml (C), or 0.3 mg/ml (D), or bovine serum albumin (BSA) at 0.2 mg/ml (E). The mean population doubling levels of cells in media B, C, D, and E were increased by 12.4%, 31.2%, 24.0%, and 10.4%, respectively, compared with that in medium A. The cells in medium C also exhibited the highest relative proliferation activity, the lowest senescence, and the longest telomeres. Moreover, MRJPs up-regulated the expression of superoxide dismutase-1 (SOD1) and down-regulated the expression of mammalian target of rapamycin (MTOR), catenin beta like-1 (CTNNB1), and tumor protein p53 (TP53). Raman spectra analysis showed that there were two unique bands related to DNA synthesis materials, amide carbonyl group vibrations and aromatic hydrogens. These results suggest that MRJPs possess anti-senescence activity for the HFL-I cell line, and provide new knowledge illustrating the molecular mechanism of MRJPs as anti-senescence factors.
Animals ; Bees ; Cattle ; Cell Line ; Cell Proliferation ; Cellular Senescence/drug effects* ; Culture Media ; Dose-Response Relationship, Drug ; Fatty Acids/chemistry* ; Fibroblasts/drug effects* ; Humans ; Insect Proteins/chemistry* ; Lung/drug effects* ; Serum Albumin/metabolism* ; Spectrum Analysis, Raman ; Superoxide Dismutase-1/metabolism* ; TOR Serine-Threonine Kinases/metabolism* ; Tumor Suppressor Protein p53/metabolism* ; beta Catenin/metabolism*

OBJECTIVETo investigate the effect of oridonin on the human acute lymphocytic leukemia cell line Jurkat and its mechanism.

METHODSJurkat cells were cultured in vitro and treated with various concentrations (0, 1.25, 2.5, 5, and 10 μmol/L) of oridonin for different lengths of time (24, 48, and 72 hours). The proliferation of Jurkat cells was analyzed by MTT assay. The changes in nuclear morphology were evaluated by fluorescence microscopy at 12 hours after treatment with various concentrations of oridonin. The expression levels of Brg1, P53, and C-myc were determined by semi-quantitative Western blot in Jurkat cells treated with various concentrations of oridonin for 24 hours or 5 μmol/L oridonin for various lengths of time (0, 2, 6, 12, and 24 hours). The expression levels of P53 and C-myc and proliferation of Jurkat cells were evaluated after Brg1 expression was knocked down by Brg1-specific siRNA.

RESULTSCompared with the control group, the proliferation of oridonin-treated Jurkat cells was significantly inhibited in a concentration- and time-dependent manner (P<0.05). According to the florescence microscopic analysis, oridonin treatment led to nuclear pyknosis in Jurkat cells. Compared with the control group, Jurkat cells treated with 5 μmol/L oridonin had reduced expression of Brg1 and C-myc but elevated expression of P53. Brg1 knock-down led to a significant reduction in proliferation of Jurkat cells (P<0.05), up-regulated expression of P53, and down-regulated expression of C-myc.

CONCLUSIONSOridonin can inhibit the proliferation of Jurkat cells, probably via the Brg1 signaling pathway.

Antineoplastic Agents, Phytogenic ; pharmacology ; Cell Proliferation ; drug effects ; DNA Helicases ; analysis ; physiology ; Diterpenes, Kaurane ; pharmacology ; Dose-Response Relationship, Drug ; Down-Regulation ; Humans ; Jurkat Cells ; Nuclear Proteins ; analysis ; physiology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; Proto-Oncogene Proteins c-myc ; analysis ; Signal Transduction ; physiology ; Transcription Factors ; analysis ; physiology ; Tumor Suppressor Protein p53 ; analysis

This study assessed the expression of the p53 protein, beta-catenin, and HER2 and their prognostic implications in patients with EBV-associated gastric cancer (EBVaGC). After reviewing 1318 consecutive cases of surgically resected or endoscopic submucosal dissected gastric cancers, 117 patients were identified as EBV-positive using EBV-encoded RNA in-situ hybridization. The immunohistochemistry results were interpreted as follows: strong p53 nuclear expression in at least 50% of tumor nuclei was interpreted as a positive result, strong beta-catenin expression in at least 10% of cytoplasmic nuclei was interpreted as a positive result, and moderate or strong complete or basolateral membrane staining in 10% of tumor cells was interpreted as a positive result for HER2. Immunohistochemical staining for p53 was performed on tumor tissue from 105 patients, among whom 25 (23.8%) tested positive. Meanwhile, beta-catenin expression was positive in 10 patients (17.5%) and HER2 expression was positive in 8 patients (6.8%). The positive expression of p53 was significantly associated with a high T stage (p=0.006). More patients with lymph node metastasis were p53-positive (p=0.013). In the univariate analysis, the p53-positive patients showed significantly decreased disease-free survival (DFS) when compared with the p53-negative patients (p=0.022), although the p53 status was only marginally associated with overall survival (OS) (p=0.080). However, p53 expression showed no prognostic significance on DFS in the multivariate analysis. Moreover, beta-catenin and HER2 showed no association with DFS and OS in the survival analysis. The current study found a significant correlation between p53 expression and tumor progression and lymph node metastases in patients with EBVaGC.
beta Catenin ; Cytoplasm ; Disease-Free Survival ; Epstein-Barr Virus Infections ; Humans ; Immunohistochemistry ; Lymph Nodes ; Membranes ; Multivariate Analysis ; Neoplasm Metastasis ; RNA ; Stomach Neoplasms ; Tumor Suppressor Protein p53