DNA methylation plays important biological roles in plants and animals. To examine the rice genomic methylation landscape and assess its functional significance, we generated single-base resolution DNA methylome maps for Asian cultivated rice Oryza sativa ssp. japonica, indica and their wild relatives, Oryza rufipogon and Oryza nivara.The overall methylation level of rice genomes is four times higher than that of Arabidopsis. Consistent with the results reported for Arabidopsis, methylation in promoters represses gene expression while gene-body methylation generally appears to be positively associated with gene expression. Interestingly, we discovered that methylation in gene transcriptional termination regions (TTRs) can significantly repress gene expression, and the effect is even stronger than that of promoter methylation. Through integrated analysis of genomic, DNA methylomic and transcriptomic differences between cultivated and wild rice, we found that primary DNA sequence divergence is the major determinant of methylational differences at the whole genome level, but DNA methylational difference alone can only account for limited gene expression variation between the cultivated and wild rice. Furthermore, we identified a number of genes with significant difference in methylation level between the wild and cultivated rice.The single-base resolution methylomes of rice obtained in this study have not only broadened our understanding of the mechanism and function of DNA methylation in plant genomes, but also provided valuable data for future studies of rice epigenetics and the epigenetic differentiation between wild and cultivated rice.
Abstract Caspase-3 is the best known executioner caspase in apoptosis. We generated caspase-3 knockout (C3KO) and knockdown human colorectal cancer cells, and found that they are unexpectedly sensitized to DNA-damaging agents including 5-fluorouracil (5-FU), etoposide, and camptothecin. C3KO xenograft tumors also displayed enhanced therapeutic response and cell death to 5-FU. C3KO cells showed intact apoptosis and activation of caspase-7 and -9, impaired processing of caspase-8, and induction of necrosis in response to DNA-damaging agents. This form of necrosis is associated with HMGB1 release and ROS production, and suppressed by genetic or pharmacological inhibition of RIP1, MLKL1, or caspase-8, but not inhibitors of pan-caspases or RIP3. 5-FU treatment led to the formation of a z-VAD-resistant pro-caspase-8/RIP1/FADD complex, which was strongly stabilized by caspase-3 KO. These data demonstrate a key role of caspase-3 in caspase-8 processing and suppression of DNA damage-induced necrosis, and provide a potentially novel way to chemosensitize cancer cells.
Abstract We show that ATM kinase inhibition using AZ31 prior to 9 or 9.25 Gy total body irradiation (TBI) reduced median time to moribund in mice to 8 days. ATR kinase inhibition using AZD6738 prior to TBI did not reduce median time to moribund. The striking finding associated with ATM inhibition prior to TBI was increased crypt loss within the intestine epithelium. ATM inhibition reduced upregulation of p21, an inhibitor of cyclin-dependent kinases, and blocked G1 arrest after TBI thereby increasing the number of S phase cells in crypts in wild-type but not Cdkn1a(p21 CIP/WAF1 ) −/− mice. In contrast, ATR inhibition increased upregulation of p21 after TBI. Thus, ATM activity is essential for p21-dependent arrest while ATR inhibition may potentiate arrest in crypt cells after TBI. Nevertheless, ATM inhibition reduced median time to moribund in Cdkn1a(p21 CIP/WAF1 ) −/− mice after TBI. ATM inhibition also increased cell death in crypts at 4 h in Cdkn1a(p21 CIP/WAF1 ) −/− , earlier than at 24 h in wild-type mice after TBI. In contrast, ATR inhibition decreased cell death in crypts in Cdkn1a(p21 CIP/WAF1 ) −/− mice at 4 h after TBI. We conclude that ATM activity is essential for p21-dependent and p21-independent mechanisms that radioprotect intestinal crypts and that ATM inhibition promotes GI syndrome after TBI.
This study aims to observe whether the renal fascias could be effectively shown by dual-source CT (DSCT) and to explore the superior communication of the perirenal space (PS) in vivo in adults.275 cases were included in the normal group and 124 cases in the acute pancreatitis group in this study; all images obtained by DSCT were observed; the superior adherence of the renal fascias and the pattern of superior communication of the PS were judged; and the consistency between the two groups was compared.The superior adherence of the renal fascias was reliably displayed in 57.8% of the normal group and 69.4% of the acute pancreatitis group, the anterior renal fascia (ARF) did not fuse with the posterior renal fascia superiorly. The left ARF fused with the posterior parietal peritoneum in 57.9% of the normal group and 45.3% of the pancreatitis group, where the left PS communicated with the subdiaphragmatic retroperitoneal space (SDRS). The left ARF fused with the peritoneum laterally and simultaneously with the inferior phrenic fascia medially in 42.1% and 54.7% of each group, respectively, where the left PS was open towards the SDRS laterally but sealed off from the SDRS medially. The right ARF fused with the peritoneum in all cases; and the right PS was open towards the bare area of the liver.To some extent, DSCT can display renal fascia and its superior adherence and reflect the superior communication of the PS.This study was conducted in vivo in adults by high-resolution DSCT, and more samples could be provided.
BACKGROUND:This meta-analysis investigates the associations of adiponectin (ADIPOQ) genetic polymorphisms with the susceptibility to colorectal cancer (CRC). MATERIAL AND METHODS:2 reviewers independently searched 6 databases – PubMed, Cochrane Library, Ovid, Embase, China National Knowledge Infrastructure (CNKI) and Wanfang databases – to identify published studies relevant to adiponectin gene polymorphisms and CRC. Studies retrieved from database searches were screened using our stringent inclusion and exclusion criteria. Full texts of the selected studies were accessed and related data was extracted using a standardized data extraction form. Comprehensive Meta-analysis 2.0 software was used for statistical analyses. RESULTS:A total of 188 studies were initially retrieved from database search, and 6 studies were eventually selected, through a rigorous screening process, for inclusion in this meta-analysis. The 6 studies contained a total of 1897 patients (Asians: 1190; white: 707) with CRC in case group and 2475 healthy controls (Asians: 1325; white: 1150) in the control group. Results of the current meta-analysis revealed that the rs2241766 T>G single-nucleotide polymorphisms (SNP) increase the risk of CRC; rs1501299 G>T under dominant model was associated with increased risk of CRC; and rs266729 C>G SNP under allele model conferred an increased risk of CRC. CONCLUSIONS:Our meta-analysis strongly suggests that the ADIPOQ rs2241766 T>G, rs1501299 G>T, and rs266729 C>G SNPs correlate with an increased risk of CRC.
Spontaneous regression of non-Hodgkin lymphoma (NHL) has been reported in low-grade tumors but is an extremely rare event in intermediate- and high-grade disease. Documentation of spontaneous regression by serial fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging has not been reported in the literature. We present 3 cases of spontaneous regression, 1 each of follicular lymphoma (FL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL), which showed spontaneous regression on serial FDG-PET imaging. All patients underwent serial whole-body FDG-PET scans 60 minutes after intravenous injection of 9-11 mCi of this radiotracer. None of them had any chemotherapy, radiotherapy, or surgery after the baseline PET scan. Spontaneous regression of disease in all 3 cases was correlated with conventional imaging and clinical course. All 3 patients had positive FDG-PET results on their baseline scan. There was complete disappearance of FDG uptake on a follow-up PET scan for the patient with follicular lymphoma. These results suggest complete regression. The patients with MCL and DLBCL both showed a significant reduction in FDG uptake on serial whole-body PET scans, suggesting partial regression in both cases. Although spontaneous regression of lymphoma is uncommon, this phenomenon can be successfully demonstrated by FDG-PET imaging. Therefore, serial PET imaging may play an important role in detecting this unusual event and may further enhance our understanding of the biologic behavior of this malignancy.
Abstract Purpose: This study aims to provide a better set of DNA methylation markers in urine sediments for sensitive and specific detection of bladder cancer. Experimental Design: Fifty-nine tumor-associated genes were profiled in three bladder cancer cell lines, a small cohort of cancer biopsies and urine sediments by methylation-specific PCR. Twenty-one candidate genes were then profiled in urine sediments from 132 bladder cancer patients (8 cases for stage 0a; 68 cases for stage I; 50 cases for stage II; 4 cases for stages III; and 2 cases for stage IV), 23 age-matched patients with noncancerous urinary lesions, 6 neurologic diseases, and 7 healthy volunteers. Results: Despite six incidences of four genes reported in 3 of 23 noncancerous urinary lesion patients analyzed, cancer-specific hypermethylation in urine sediments were reported for 15 genes (P < 0.05). Methylation assessment of an 11-gene set (SALL3, CFTR, ABCC6, HPR1, RASSF1A, MT1A, RUNX3, ITGA4, BCL2, ALX4, MYOD1, DRM, CDH13, BMP3B, CCNA1, RPRM, MINT1, and BRCA1) confirmed the existing diagnosis of 121 among 132 bladder cancer cases (sensitivity, 91.7%) with 87% accuracy. Significantly, more than 75% of stage 0a and 88% of stage I disease were detected, indicating its value in the early diagnosis of bladder cancer. Interestingly, the cluster of reported methylation markers used in the U.S. bladder cancers is distinctly different from that identified in this study, suggesting a possible epigenetic disparity between the American and Chinese cases. Conclusions: Methylation profiling of an 11-gene set in urine sediments provides a sensitive and specific detection of bladder cancer.
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