Glioblastoma (GBM) is a prevalent and highly lethal form of glioma, with rapid tumor progression and frequent recurrence. Excessive outgrowth of pericytes in GBM governs the ecology of the ...perivascular niche, but their function in mediating chemoresistance has not been fully explored. Herein, we uncovered that pericytes potentiate DNA damage repair (DDR) in GBM cells residing in the perivascular niche, which induces temozolomide (TMZ) chemoresistance. We found that increased pericyte proportion correlates with accelerated tumor recurrence and worse prognosis. Genetic depletion of pericytes in GBM xenografts enhances TMZ-induced cytotoxicity and prolongs survival of tumor-bearing mice. Mechanistically, C-C motif chemokine ligand 5 (CCL5) secreted by pericytes activates C-C motif chemokine receptor 5 (CCR5) on GBM cells to enable DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-mediated DDR upon TMZ treatment. Disrupting CCL5-CCR5 paracrine signaling through the brain-penetrable CCR5 antagonist maraviroc (MVC) potently inhibits pericyte-promoted DDR and effectively improves the chemotherapeutic efficacy of TMZ. GBM patient-derived xenografts with high CCL5 expression benefit from combined treatment with TMZ and MVC. Our study reveals the role of pericytes as an extrinsic stimulator potentiating DDR signaling in GBM cells and suggests that targeting CCL5-CCR5 signaling could be an effective therapeutic strategy to improve chemotherapeutic efficacy against GBM.
MicroRNAs (miRNAs) have been proven to play important roles at the post-transcriptional level in animals and plants. To investigate clustering patterns and specific sequence characteristics in the ...flanking regions of plant miRNA genes, we performed genome-wide analyses of Arabidopsis thaliana, Populus trichocarpa, Oryza sativa and Sorghum bicolor. Our results showed that miRNA pair distances were significantly higher than would have been expected to occur at random and that the number of miRNA gene pairs separated by very short distances of < 1 kb was higher than of protein-coding gene pairs. Analysis of the promoter architecture of different miRNA genes in plants revealed significant differences in the number and distribution of core promoters between intergenic miRNAs and intragenic miRNAs, and between highly conserved miRNAs and low conserved or nonconserved miRNAs. We applied two motif-finding algorithms to search for over-represented, statistically significant sequence motifs, and discovered six species-specific motifs across the four plant species studied. Moreover, we also identified, for the first time, several significantly over-represented motifs that were associated with conserved miRNAs, and these motifs may be useful for understanding the mechanism of origin of new plant miRNAs. The results presented provide a new insight into the transcriptional regulation and processing of plant miRNAs.
MicroRNAs (miRNAs) play important roles in post-transcriptional gene expression control. To gain new insight into human miRNAs, we performed comprehensive sequence-based homology search for known ...human miRNAs to study the evolutionary distribution of human miRNAs. Furthermore, we carried out a series of studies to compare various features for different lineage-specific human miRNAs. Our results showed that major expansions of human miRNA genes coincide with the advent of vertebrates, mammals and primates. Further system-level analysis revealed significant differences in human miRNAs that arose from different evolutionary time points for a number of characteristics, implicating genetic and functional diversification for different human miRNAs during evolution. Our finds provide more useful knowledge for further exploring origins and evolution of human miRNA genes.
► We perform an analysis of chromosomal organization of miRNA target genes. ► The particular gene organization is constrained by miRNA regulation. ► miRNAs tend to regulate genes within high-density ...regions in mammals. ► Chromosome bands where targets are enriched tend to be fragile sites.
The regulation of microRNAs (miRNAs) is a complicated process requiring a large number of molecular events to be coordinated in both space and time. It is not known whether this complicated regulation process constrains the organization of target genes on mammalian chromosomes. We performed a genome-wide analysis to provide a better picture of chromosomal organization of miRNA target genes. Our results showed clustering of the target genes (TGs) of miRNAs on mammalian chromosomes, and further revealed that the particular gene organization is constrained by miRNA regulation. The clustering pattern of TGs provides an insight into the complexity of miRNA regulation.
Microalgal oils, depending on their degree of unsaturation, can be utilized as either nutritional supplements or fuels; thus, a feedstock with genetically designed and tunable degree of unsaturation ...is desirable to maximize process efficiency and product versatility. Systematic profiling of ex vivo （in yeast）, in vitro, and in vivo activities of type-2 diacylglycerol acyltransferases in Nannochloropsis oceanica （NoDGAT2s or NoDGTTs）, via reverse genetics, revealed that NoDGAT2A prefers saturated fatty acids （SFAs）, NoDGAT2D prefers monounsaturated fatty acids （MUFAs）, and NoDGAT2C exhibits the strongest activity toward polyunsaturated fatty acids （PUFAs）. As NoDGAT2A, 2C, and 2D originated from the green alga, red alga, and eukaryotic host ancestral participants of secondary endosymbiosis, respectively, a mecha- nistic model of oleaginousness was unveiled, in which the indigenous and adopted NoDGAT2s formulated functional complementarity and specific transcript abundance ratio that underlie a rigid SFA：MUFA：PUFA hierarchy in triacylglycerol （TAG）. By rationally modulating the ratio of NoDGAT2A＇：2C~D transcripts, a bank of N. oceanica strains optimized for nutritional supplement or fuel production with a wide range of degree of unsaturation were created, in which proportion of SFAs, MUFAs, and PUFAs in TAG varied by 1.3-, 3.7-, and 11.2-fold, respectively. This established a novel strategy to simultaneously improve productivity and quality of oils from industrial microalgae.
Key Clinical Message
We report an extremely rare case of acute myelomonocytic leukemia (M4) with an MLL‐ELL fusion gene lacking the PML‐RARα rearrangement that transformed from hypergranular acute ...promyelocytic leukemia (APL) without showing any karyotypic evolution. The treatment was effective with chemotherapy for M4 and idarubicin plus a cytarabine‐based chemotherapy protocol without ATRA.
We report an extremely rare case of acute myelomonocytic leukemia (M4) with an MLL‐ELL fusion gene lacking the PML‐RARα rearrangement that transformed from hypergranular acute promyelocytic leukemia (APL) without showing any karyotypic evolution. The treatment was effective with chemotherapy for M4 and idarubicin plus a cytarabine‐based chemotherapy protocol without ATRA.
Cannabinoid receptor type 2 (CB
2
) activation is recently reported to promote proliferation of some types of resident stem cells (e.g., hematopoietic stem/progenitor cell or neural progenitor cell). ...Resident cardiac progenitor cell (CPC) activation and proliferation are crucial for endogenous cardiac regeneration and cardiac repair after myocardial infarction (MI). This study aims to explore the role and possible mechanisms of CB
2
receptor activation in enhancing myocardial repair. Our results revealed that CB2 receptor agonist AM1241 can significantly increase CPCs by c-kit and Runx1 staining in ischemic myocardium as well as improve cardiomyocyte proliferation. AM1241 also decreased serum levels of MDA, TNF-α and IL-6 after MI. In addition, AM1241 can ameliorate left ventricular ejection fraction and fractional shortening, and reduce fibrosis. Moreover, AM1241 treatment markedly increased p-Akt and HO-1 expression, and promoted Nrf-2 nuclear translocation. However, PI3K inhibitor wortmannin eliminated these cardioprotective roles of AM1241. In conclusion, AM1241 could induce myocardial regeneration and improve cardiac function, which might be associated with PI3K/Akt/Nrf2 signaling pathway activation. Our findings may provide a promising strategy for cardiac endogenous regeneration after MI.
AIM: To evaluate the change in spectrum of gastric polyps in the Chinese population in the past ten years.METHODS: A total of 157902 consecutive patients undergoing esophagogastroduodenoscopy(EGD) ...from 2004 to 2013 in a tertiary hospital were retrospectively reviewed using an EGD database.Endoscopic records of 4043 patients diagnosed with gastric polyps were recalled for analysis.Data including demographics,information on polyps such as location,pathological diagnosis,reflux esophagitis and Helicobacter pylori infection were obtained.We focused on epithelial polyps,especially hyperplastic polyps,fundic gland polyps and adenomas,and histological classification of specimens from biopsy and endoscopic polypectomy was performed by professional pathologists,based on the updated guidelines.To explore the age distribution of gastric polyps over time,we divided patients with polyps into four groups: A(aged < 30 years),B(aged 30-44 years),C(aged 45-59 years) and D(aged > 60 years).Differences in localization,age,and sex distribution of gastric polyps were analyzed by statistical software.RESULTS: A total of 157902 EGD procedures were performed in ten years at our digestive endoscopy center,of which 4043 cases were diagnosed with gastric polyps confirmed by pathology.There were 2574(63%) female and 1469(37%) male patients with an average age of 54.7 years.The overall prevalence of gastric polyps was 2.6%(4043/157902).Our database demonstrated a rising prevalence of gastric polyps over the decade,increasing from 1.0%(80/8025) to 4.70%(828/17787) between 2004 and 2013.There has been a change in the spectrum of gastric polyps with the frequencies of FGPs increasing from 19%(15/80) to 77%(638/828) and hyperplastic polyps decreasing from 65%(52/80) to 15%(123/828).Moreover,data on 1921 polyps in 828 patients diagnosed with gastric polyps in 2013 showed that FGP was the most common type in the current polyp spectrum,making up 81.3%(1562/1921).Location and age distribution of gastric polyps have also altered.The prevalence of polyps located in the antrum decreased from 37.5%(30/80) to 9.30%(77/828),with an increasing prevalence of polyps in the corpus,from 45%(36/80) to 64.25%(532/828).The constituent ratio of older patients(aged > 60 years) in the polyp population decreased from 62.5%(50/80) to 32.13%(266/828),while that of patients aged 45-60 years showed an increased trend.CONCLUSION: There was a shift change in the spectrum of gastric polyps in the Chinese population with altered location and age distribution in the past ten years.
The catechol-O-methyltransferase（COMT） gene is a schizophrenia susceptibility gene. A common functional polymorphism of this gene,Val158/158 Met,has been proposed to influence gray matter ...volume（GMV）. However,the effects of this polymorphism on cortical thickness/surface area in schizophrenic patients are less clear. In this study,we explored the relationship between the Val158 Met polymorphism of the COMT gene and the GMV/ cortical thickness/cortical surface area in 150 firstepisode treatment-nave patients with schizophrenia and 100 healthy controls. Main effects of diagnosis were found for GMV in the cerebellum and the visual,medial temporal,parietal,and middle frontal cortex. Patients with schizophrenia showed reduced GMVs in these regions. And main effects of genotype were detected for GMV in the left superior frontal gyrus. Moreover,a diagnosis × genotype interaction was found for the GMV of the left precuneus,and the effect of the COMT gene on GMV was due mainly to cortical thickness rather than cortical surface area. In addition,a pattern ofincreased GMV in the precuneus with increasing Met dose found in healthy controls was lost in patients with schizophrenia. These findings suggest that the COMTMet variant is associated with the disruption of dopaminergic influence on gray matter in schizophrenia,and the effect of the COMT gene on GMV in schizophrenia is mainly due to changes in cortical thickness rather than in cortical surface area.
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