Chromatin structure is regulated through posttranslational modifications of histone variants that modulate transcription. Although highly homologous, histone variants display unique amino acid ...sequences associated with specific functions. Abnormal incorporation of histone variants contributes to cancer initiation, therapy resistance, and metastasis. This study reports that, among its biologic functions, histone H3.1 serves as a chromatin redox sensor that is engaged by mitochondrial H2O2. In breast cancer cells, the oxidation of H3.1Cys96 promotes its eviction and replacement by H3.3 in specific promoters. We also report that this process facilitates the opening of silenced chromatin domains and transcriptional activation of epithelial-to-mesenchymal genes associated with cell plasticity. Scavenging nuclear H2O2 or amino acid substitution of H3.1(C96S) suppresses plasticity, restores sensitivity to chemotherapy, and induces remission of metastatic lesions. Hence, it appears that increased levels of H2O2 produced by mitochondria of breast cancer cells directly promote redox-regulated H3.1-dependent chromatin remodeling involved in chemoresistance and metastasis.
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•Cysteine oxidation is a functional modification of the H3.1 histone variant•H3.1Cys96 oxidation promotes its exchange by H3.3•H3.1Cys96 oxidation promotes multidrug resistance in breast cancer•H3.1Cys96 modification by ROS promotes metastasis
Palma et al. report that H3.1Cys96 oxidation is a functional posttranslational modification involved in the regulation of gene expression. In breast cancer, H3.1Cys96 oxidation promotes resistance to first-line chemotherapeutic drugs and stimulates metastasis. They also show that suppressing H3.1Cys96 oxidation inhibits metastasis while resensitizing cancer cells to chemotherapy.
Accumulating mutations may drive cells into the acquisition of abnormal phenotypes that are characteristic of cancer cells. Cancer cells feature profound alterations in proliferation programs that ...result in a new population of cells that overrides normal tissue construction and maintenance programs. To achieve this goal, cancer cells are endowed with up regulated survival signaling pathways. They also must counteract the cytotoxic effects of high levels of nitric oxide (NO) and of reactive oxygen species (ROS), which are by products of cancer cell growth. Accumulating experimental evidence associates cancer cell survival with their capacity to up-regulate antioxidant systems. Elevated expression of the antioxidant protein thioredoxin-1 (Trx1) has been correlated with cancer development. Trx1 has been characterized as a multifunctional protein, playing different roles in different cell compartments. Trx1 migrates to the nucleus in cells exposed to nitrosative/oxidative stress conditions. Trx1 nuclear migration has been related to the activation of transcription factors associated with cell survival and cell proliferation. There is a direct association between the p21Ras-ERK1/2 MAP Kinases survival signaling pathway and Trx1 nuclear migration under nitrosative stress. The expression of the cytoplasmic protein, the thioredoxin-interacting protein (Txnip), determines the change in Trx1 cellular compartmentalization. The anti-apoptotic actions of Trx1 and its denitrosylase activity occur in the cytoplasm and serve as important regulators of cell survival. Within this context, this review focuses on the participation of Trx1 in cells under nitrosative/oxidative stress in survival signaling pathways associated with cancer development.
ABSTRACT
Ethylene response factors (ERFs) comprise one of the largest transcription factor families in many plant species. Tobacco (Nicotiana tabacum) ERF3 (NtERF3) and other ERF‐associated ...amphiphilic repression (EAR) motif‐containing ERFs are known to function as transcriptional repressors. NtERF3 and several repressor‐type ERFs induce cell death in tobacco leaves and are also associated with a defence response against tobacco mosaic virus (TMV).
We investigated whether transcriptional activator‐type NtERFs function together with NtERF3 in the defence response against TMV infection by performing transient ectopic expression, together with gene expression, chromatin immunoprecipitation (ChIP) and promoter analyses.
Transient overexpression of NtERF2 and NtERF4 induced cell death in tobacco leaves, albeit later than that induced by NtERF3. Fusion of the EAR motif to the C‐terminal end of NtERF2 and NtERF4 abolished their cell death‐inducing ability. The expression of NtERF2 and NtERF4 was upregulated at the early phase of N gene‐triggered hypersensitive response (HR) against TMV infection. The cell death phenotype induced by overexpression of wild‐type NtERF2 and NtERF4 was suppressed by co‐expression of an EAR motif‐deficient form of NtERF3. Furthermore, ChIP and promoter analyses suggested that NtERF2, NtERF3 and NtERF4 positively or negatively regulate the expression of NtERF3 by binding to its promoter region.
Overall, our results revealed the cell death‐inducing abilities of genes encoding activator‐type NtERFs, including NtERF2 and NtERF4, suggesting that the HR‐cell death signalling via the repressor‐type NtERF3 is competitively but coordinately regulated by these NtERFs.
Hypersensitive response‐associated cell death signaling via the repressor‐type ethylene response factor NtERF3 in tobacco is competitively but coordinately regulated by repressor‐type and activator‐type ERFs.
A pilot cross-sectional study of patients with acute cervical spinal cord injury (SCI).
The precise evaluation of the severity of SCI is important for developing novel therapies. Although several ...biomarkers in cerebrospinal fluid have been tested, few analyses of blood samples have been reported. A novel biomarker for axonal injury, phosphorylated form of the high-molecular-weight neurofilament subunit NF-H (pNF-H), has been reported to be elevated in blood from rodent SCI model. The aim of this study is to investigate whether pNF-H values in blood can serve as a biomarker to evaluate the severity of patients with SCI.
Tokyo Metropolitan Bokutoh Hospital and National Rehabilitation Center, Japan.
This study enrolled 14 patients with acute cervical SCI. Sequential plasma samples were obtained from 6 h to 21 days after injury. Patients were classified according to American Spinal Injury Association impairment scale (AIS) at the end of the follow-up (average, 229.1 days). Plasma pNF-H values were compared between different AIS grades.
In patients with complete SCI, pNF-H became detectable at 12 h after injury and remained elevated at 21 days after injury. There was a statistically significant difference between AIS A (complete paralysis) patients and AIS C (incomplete paralysis) patients.
Plasma pNF-H was elevated in accordance with the severity of SCI and reflected a greater magnitude of axonal damage. Therefore, pNF-H is a potential biomarker to independently distinguish AIS A patients (complete SCI) from AIS C-E patients (incomplete SCI). However, further studies are required to evaluate its utility in predicting prognosis of patients in the incomplete category.
Background
Guidelines recommend treating patients with an internal carotid artery near occlusion (ICANO) with best medical therapy (BMT) based on weak evidence. Consequently, patients with ICANO were ...excluded from randomized trials. The aim of this individual‐patient data (IPD) meta‐analysis was to determine the optimal treatment approach.
Methods
A systematic search was performed in MEDLINE, EMBASE and the Cochrane Library databases in January 2018. The primary outcome was the occurrence of any stroke or death within the first 30 days of treatment, analysed by multivariable mixed‐effect logistic regression. The secondary outcome was the occurrence of any stroke or death beyond 30 days up to 1 year after treatment, evaluated by Kaplan–Meier survival analysis.
Results
The search yielded 1526 articles, of which 61 were retrieved for full‐text review. Some 32 studies met the inclusion criteria and pooled IPD were available from 11 studies, including some 703 patients with ICANO. Within 30 days, any stroke or death was reported in six patients (1·8 per cent) in the carotid endarterectomy (CEA) group, five (2·2 per cent) in the carotid artery stenting (CAS) group and seven (4·9 per cent) in the BMT group. This resulted in a higher 30‐day stroke or death rate after BMT than after CEA (odds ratio 5·63, 95 per cent c.i. 1·30 to 24·45; P = 0·021). No differences were found between CEA and CAS. The 1‐year any stroke‐ or death‐free survival rate was 96·1 per cent for CEA, 94·4 per cent for CAS and 81·2 per cent for BMT.
Conclusion
These data suggest that BMT alone is not superior to CEA or CAS with respect to 30‐day or 1‐year stroke or death prevention in patients with ICANO. These patients do not appear to constitute a high‐risk group for surgery, and consideration should made to including them in future RCTs of internal carotid artery interventions.
Best medical therapy is not superior to carotid endartectomy or carotid artery stenting with respect to 30‐day or 1‐year stroke/death prevention in patients with an internal carotid artery near occlusion. These patients do not constitute a high‐risk subgroup for surgery and should not be excluded from future RCTs.
Surgery and stenting less risky than previously thought
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