Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC), ...a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL) response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight) once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8(+), but not CD4(+) T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy.
The identification of indicators for severe HFMD is critical for early prevention and control of the disease. With this goal in mind, 185 severe and 345 mild HFMD cases were assessed. Patient ...demographics, clinical features, MRI findings, and laboratory test results were collected. Gradient boosting tree (GBT) was then used to determine the relative importance (RI) and interaction effects of the variables. Results indicated that elevated white blood cell (WBC) count > 15 × 10
/L (RI: 4
.47, p < 0.001) was the top predictor of severe HFMD, followed by spinal cord involvement (RI: 26.62, p < 0.001), spinal nerve roots involvement (RI: 10.34, p < 0.001), hyperglycemia (RI: 3.40, p < 0.001), and brain or spinal meninges involvement (RI: 2.45, p = 0.003). Interactions between elevated WBC count and hyperglycemia (H statistic: 0.231, 95% CI: 0-0.262, p = 0.031), between spinal cord involvement and duration of fever ≥3 days (H statistic: 0.291, 95% CI: 0.035-0.326, p = 0.035), and between brainstem involvement and body temperature (H statistic: 0.313, 95% CI: 0-0.273, p = 0.017) were observed. Therefore, GBT is capable to identify the predictors for severe HFMD and their interaction effects, outperforming conventional regression methods.
To investigate the most important factors affecting the prognosis of the patients with squamous cell carcinoma (SCC) of the larynx.
Based on the clinical and follow-up data, 205 patients with SCC of ...the larynx receiving total laryngectomy, partial laryngectomy, or CO2 laser surgery in GuangDong General Hospital were retrospectively analyzed. A survival analysis was performed by the Kaplan-Meier method and a multivariable analysis of prognostic factors was carried out using the Cox proportional hazard model.
Subtypes of carcinoma included 69.8% glottic and 30.2% supraglottic. Most patients were in N0 stage (77.6%), and 22.4% patients were in N1∼N3 stage. Over half of the patients were in T1∼T2 stage (55.1%), 20.0% in T3, and 24.9% in T4. Mean follow-up duration was 49.2 months. The survival rates 1, 2, and 3 years after the surgery were 99.0%, 91.7%, and 81.5%, respectively. The survival rate for those patients with clinical stage IV was significantly lower than for those with clinical stage I and II (p<0.001 and p = 0.013, respectively). The disease-free progression rates 1, 2, and 3 years after the surgery were 83.9%, 74.6%, and 71.2%, respectively. Futhermore, those patients with a Charlson score of 1 to 2 and ≥3 had higher risk of mortality than those with a Charlson score of 0 (hazard ratios of 1.8 and 2.41 p = 0.042 and p = 0.008). Multivariable analysis revealed that clinical stage, surgical margin, and comorbidity were significantly associated with both mortality and disease-free progression.
The surgical resection margin, clinical stage, and comorbidity were independent factors affecting the laryngeal cancer prognosis. The survival rates were lower for patients with advanced laryngeal cancer, positive surgical margins, or severe comorbidity, suggesting the importance of early diagnosis, early treatment, negative surgical margins, and conditions of comorbidity.
Although the tumorigenic potential of glioma stem cells (GSCs) is associated with multiple molecular alterations, the gene amplification status of GSCs has not been elucidated. Overexpression of ...HomeoboxA5 (HOXA5) is associated with increased glioma malignancy. In this study, we identify the gene amplification and protein overexpression of HOXA5 in GSCs and its function in regulating GSC maintenance and the downstream transcriptional effector, to explore the significance of HOXA5 amplification/overexpression for GSC identification and prognostic determination. The HOXA5 gene is significantly amplified in glioblastoma (GBM) and is an independent prognostic factor for predicting worse patient outcomes. Specifically, HOXA5 gene amplification and the resultant protein overexpression are correlated with increased proportions of GSCs and enhanced self-renewal/invasiveness of these cells. Disruption of HOXA5 expression impairs GSC survival and GBM tumor propagation. Mechanistically, HOXA5 directly binds to the promoter region of protein tyrosine phosphatase receptor type Z1 (PTPRZ1), thereby upregulating this gene for GSC maintenance. Suppression of PTPRZ1 largely compromises the pro-tumoral effect of HOXA5 on GSCs. In summary, HOXA5 amplification serves as a genetic biomarker for predicting worse GBM outcome, by enhancing PTPRZ1-mediated GSC survival.
•HOXA5 is amplified in GBM and predicts poor patient prognosis.•HOXA5 transcriptionally activates PTPRZ1 to enhance GSC self-renewal and invasiveness.•HOXA5 gene amplification could help for personalized molecular diagnosis and targeted therapy.
A spiro ent-clerodane homodimer with a rare 6/6/6/6/6-fused pentacyclic scaffold, spiroarborin (1), together with four new monomeric analogues (2–5), were isolated from Callicarpa arborea. Their ...structures were elucidated by comprehensive spectroscopic data analysis, quantum-chemical calculations, and X-ray diffraction. A plausible biosynthetic pathway of 1 was proposed, and a biomimetic synthesis of its derivative was accomplished. Compound 1 showed a potent inhibitory effect by directly binding to the YEATS domain of the 11-19 leukemia (ENL) protein with an IC50 value of 7.3 μM. This gave a K D value of 5.0 μM, as recorded by a surface plasmon resonance binding assay.
This study describes a new species of the genus
,
from the Huoqiuba Nature Reserve, Suiyang County, Guizhou Province, China, based on morphological data and phylogenetic analyses (16S rRNA mtDNA). ...The new species can be distinguished from other congeners by the molecular divergence and by a combination of morphological characters, including body size, dorsal and ventral patterns, dorsal skin texture, size of the pectoral and femoral glands, degree of webbing and fringing on the toes and fingers, dorsum coloration, and iris coloration in life. Currently, the genus
contains 75 species, 21 of which are found in China, including seven species reported from Guizhou Province. The uncorrected sequence divergence percentage between
and all homologous DNA sequences available for the 16S rRNA gene was found to be >4.7%. The new record of the species and its relationships with others in the same genus imply that species distribution, habitat variation, environmental adaptation, and diversity of the genus
in southwest China need to be further investigated.
Neutrophil-lymphocyte ratio (NLR) has been shown to be associated with prognosis in various solid tumors. This study aimed to evaluate the prognostic role of NLR in patients with laryngeal squamous ...cell carcinoma (LSCC).
A total of 141 LSCC patients were retrospectively reviewed. Patients' demographics were analyzed along with clinical and pathologic data. The optimal cutoff value of NLR was determined using receiver operating characteristic (ROC) curve analysis. The impact of the NLR and other potential prognostic factors on disease-free survival (DFS) and overall survival (OS) was assessed using the Kaplan-Meier method and multivariate Cox regression analysis.
The optimal cutoff value of the NLR was 2.17. In the NLR ≤ 2.17 group, the 1-, 3-, and 5-year DFS rates were 88.2, 73.9 and 69.1 %, respectively, while in the NLR > 2.17 group, the DFS rates were 83.0, 54.6 and 49.2 %, respectively. Correspondingly, the 1-, 3-, and 5-year OS rates were 98.9, 85.1 and 77.4 % in the NLR ≤ 2.17 group and 97.9, 63.8 and 53.3 % in the NLR > 2.17 group, respectively. The multivariate Cox proportional hazard model analysis showed that NLR > 2.17 was a prognostic factor for both DFS hazard ratio (HR) = 1.869; 95 % confidence interval (CI) 1.078-3.243; P = 0.026 and OS (HR =2.177; 95 % CI 1.208-3.924; P = 0.010).
Our results showed that elevated preoperative NLR was an independent predictor of poor prognosis for patients with LSCC after surgical resection.
Glioma stem cells (GSCs) are self-renewing tumor cells with multi-lineage differentiation potential and the capacity of construct glioblastoma (GBM) heterogenicity. Mitochondrial morphology is ...associated with the metabolic plasticity of GBM cells. Previous studies have revealed distinct mitochondrial morphologies and metabolic phenotypes between GSCs and non-stem tumor cells (NSTCs), whereas the molecules regulating mitochondrial dynamics in GBM cells are largely unknown. Herein, we report that carnitine palmitoyltransferase 1A (CPT1A) is preferentially expressed in NSTCs, and governs mitochondrial dynamics and GSC differentiation. Expressions of CPT1A and GSC marker CD133 were mutually exclusive in human GBMs. Overexpression of CPT1A inhibited GSC self-renewal but promoted mitochondrial fusion. In contrast, disruption of CPT1A in NSTCs promoted mitochondrial fission and reprogrammed NSTCs toward GSC feature. Mechanistically, CPT1A overexpression increased the phosphorylation of dynamin-related protein 1 at Ser-637 to promote mitochondrial fusion. In vivo, CPT1A overexpression decreased the percentage of GSCs, impaired GSC-derived xenograft growth and prolonged tumor-bearing mice survival. Our work identified CPT1A as a critical regulator of mitochondrial dynamics and GSC differentiation, indicating that CPT1A could be developed as a molecular target for GBM cell-differentiation strategy.
Paeonia veitchii has been widely distributed in China under different ecological types. Its roots contain diverse phytochemical constituents, which possess very high bioactivities. However, the ...influence of ecological factors on activities and ingredients of P. veitchii roots still remains unknown. The purpose of this research was to analyze the variation in bioactivities and phytochemical composition of P. veitchii roots upon exposure to various ecological factors. Seven P. veitchii populations collected from different regions in China were evaluated. The results of correlation analysis suggested that four major ecological factors, including average annual temperature, elevation, total potassium, and organic matter, had a strong correlation with the bioactivities of P. veitchii roots. Further, the major ecological factors were also highly correlated with the contents of naringin, gallic acid, benzoylpaeoniflorin, and paeoniflorin. The principal component analysis results supported four major metabolites as the main contributing ingredients. All populations were classified into three groups, G1, G2, and G3, through hierarchical cluster analysis. G1 showed more significant advantages in the above‐mentioned four ecological factors, four active ingredients, and bioactivities compared to the other two groups. P. veitchii roots growing at lower average annual temperature, high elevation, rich total potassium and organic matter in the soils were presumed to have relatively higher bioactivities. These data expand the study on the bioactivities and phytochemical composition of P. veitchii roots and have a guiding significance for the ecological factor selection during the cultivation process of this herbaceous peony species.
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