Recent independent results from numerical simulations and observations have shown that brightest cluster galaxies (BCGs) have increased their stellar mass by a factor of almost 2 between z ∼ 0.9 and ...z ∼ 0.2. The numerical simulations further suggest that more than half this mass is accreted through major mergers. Using a sample of 18 distant galaxy clusters with over 600 spectroscopically confirmed cluster members between them, we search for observational evidence that major mergers do play a significant role. We find a major merger rate of 0.38 ± 0.14 mergers per Gyr at z ∼ 1. While the uncertainties, which stem from the small size of our sample, are relatively large, our rate is consistent with the results that are derived from numerical simulations. If we assume that this rate continues to the present day and that half of the mass of the companion is accreted on to the BCG during these mergers, then we find that this rate can explain the growth in the stellar mass of the BCGs that is observed and predicted by simulations. Major mergers therefore appear to be playing an important role, perhaps even the dominant one, in the build up of stellar mass in these extraordinary galaxies.
It has been reported that the miR-106b∼25 cluster, a paralog of the miR-17∼92 cluster, possesses oncogenic activities. However, the precise role of each microRNA (miRNA) in the miR-106b∼25 cluster is ...not yet known. In this study, we examined the function of miR-93, one of the microRNAs within the miR-106b∼25 cluster, in angiogenesis and tumor formation. We found that miR-93 enhanced cell survival, promoted sphere formation and augmented tumor growth. Most strikingly, when miR-93-overexpressing U87 cells were co-cultured with endothelial cells, they supported endothelial cell spreading, growth, migration and tube formation. In vivo studies revealed that miR-93-expressing cells induced blood vessel formation, allowing blood vessels to extend to tumor tissues in high densities. Angiogenesis promoted by miR-93 in return facilitated cell survival, resulting in enhanced tumor growth. We further showed that integrin-β8 is a target of miR-93. Higher levels of integrin-β8 are associated with cell death in tumor mass and in human glioblastoma. Silencing of integrin-β8 expression using small interfering RNA promoted cell proliferation, whereas ectopic expression of integrin-β8 decreased cell growth. These findings showed that miR-93 promotes tumor growth and angiogenesis by suppressing, at least in part, integrin-β8 expression. Our results suggest that inhibition of miR-93 function may be a feasible approach to suppress angiogenesis and tumor growth.
It has recently been shown that the upregulation of a pseudogene specific to a protein-coding gene could function as a sponge to bind multiple potential targeting microRNAs (miRNAs), resulting in ...increased gene expression. Similarly, it was recently demonstrated that circular RNAs can function as sponges for miRNAs, and could upregulate expression of mRNAs containing an identical sequence. Furthermore, some mRNAs are now known to not only translate protein, but also function to sponge miRNA binding, facilitating gene expression. Collectively, these appear to be effective mechanisms to ensure gene expression and protein activity. Here we show that expression of a member of the forkhead family of transcription factors, Foxo3, is regulated by the Foxo3 pseudogene (Foxo3P), and Foxo3 circular RNA, both of which bind to eight miRNAs. We found that the ectopic expression of the Foxo3P, Foxo3 circular RNA and Foxo3 mRNA could all suppress tumor growth and cancer cell proliferation and survival. Our results showed that at least three mechanisms are used to ensure protein translation of Foxo3, which reflects an essential role of Foxo3 and its corresponding non-coding RNAs.
Non-invasive gene delivery across the blood-spinal cord barrier (BSCB) remains a challenge for treatment of spinal cord injury and disease. Here, we demonstrate the use of magnetic resonance ...image-guided focused ultrasound (MRIgFUS) to mediate non-surgical gene delivery to the spinal cord using self-complementary adeno-associated virus serotype 9 (scAAV9). scAAV9 encoding green fluorescent protein (GFP) was injected intravenously in rats at three dosages: 4 × 10(8), 2 × 10(9) and 7 × 10(9) vector genomes per gram (VG g(-1)). MRIgFUS allowed for transient, targeted permeabilization of the BSCB through the interaction of focused ultrasound (FUS) with systemically injected Definity lipid-shelled microbubbles. Viral delivery at 2 × 10(9) and 7 × 10(9) VG g(-1) leads to robust GFP expression in FUS-targeted regions of the spinal cord. At a dose of 2 × 10(9) VG g(-1), GFP expression was found in 36% of oligodendrocytes, and in 87% of neurons in FUS-treated areas. FUS applications to the spinal cord could address a long-term goal of gene therapy: delivering vectors from the circulation to diseased areas in a non-invasive manner.
Inhibition of the bromodomain and extra-terminal (BET) proteins is a promising therapeutic strategy for various hematologic cancers. Previous studies suggest that BET inhibitors constrain tumor cell ...proliferation and survival mainly through the suppression of MYC transcription and activity. However, suppression of the transcription of additional genes also contributes to the antitumor activity of BET inhibitors but is less well understood. Here we examined the therapeutic potential of CPI-0610, a potent BET inhibitor currently undergoing phase I clinical testing, in multiple myeloma (MM). CPI-0610 displays potent cytotoxicity against MM cell lines and patient-derived MM cells through G
cell cycle arrest and caspase-dependent apoptosis. CPI-0610-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. We also confirmed the in vivo efficacy of CPI-0610 in a MM xenograft mouse model. Our study found IKZF1 and IRF4 to be among the primary targets of CPI-0610, along with MYC. Given that immunomodulatory drugs (IMiDs) stabilize cereblon and facilitate Ikaros degradation in MM cells, we combined it with CPI-0610. Combination studies of CPI-0610 with IMiDs show in vitro synergism, in part due to concomitant suppression of IKZF1, IRF4 and MYC, providing a rationale for clinical testing of this drug combination in MM patients.
Multidrug and toxin extrusion 2 (MATE2‐K (SLC47A2)), a polyspecific organic cation exporter, facilitates the renal elimination of the antidiabetes drug metformin. In this study, we characterized ...genetic variants of MATE2‐K, determined their association with metformin response, and elucidated their impact by means of a comparative protein structure model. Four nonsynonymous variants and four variants in the MATE2‐K basal promoter region were identified from ethnically diverse populations. Two nonsynonymous variants—c.485C>T and c.1177G>A—were shown to be associated with significantly lower metformin uptake and reduction in protein expression levels. MATE2‐K basal promoter haplotypes containing the most common variant, g.−130G>A (>26% allele frequency), were associated with a significant increase in luciferase activities and reduced binding to the transcriptional repressor myeloid zinc finger 1 (MZF‐1). Patients with diabetes who were homozygous for g.−130A had a significantly poorer response to metformin treatment, assessed as relative change in glycated hemoglobin (HbA1c) (−0.027 (−0.076, 0.033)), as compared with carriers of the reference allele, g.−130G (−0.15 (−0.17, −0.13)) (P = 0.002). Our study showed that MATE2‐K plays a role in the antidiabetes response to metformin.
Clinical Pharmacology & Therapeutics (2011); 90 5, 674–684. doi:10.1038/clpt.2011.165
A common bottleneck in any drug development process is finding sufficiently accurate models that capture key aspects of disease development and progression. Conventional drug screening models often ...rely on simple 2D culture systems that fail to recapitulate the complexity of the organ situation. In this study, we show the application of a robust high throughput 3D gut-on-a-chip model for investigating hallmarks of inflammatory bowel disease (IBD). Using the OrganoPlate platform, we subjected enterocyte-like cells to an immune-relevant inflammatory trigger in order to recapitulate key events of IBD and to further investigate the suitability of this model for compound discovery and target validation activities. The induction of inflammatory conditions caused a loss of barrier function of the intestinal epithelium and its activation by increased cytokine production, two events observed in IBD physiopathology. More importantly, anti-inflammatory compound exposure prevented the loss of barrier function and the increased cytokine release. Furthermore, knockdown of key inflammatory regulators
and
through on-chip adenoviral shRNA transduction alleviated IBD phenotype by decreasing cytokine production. In summary, we demonstrate the routine use of a gut-on-a-chip platform for disease-specific aspects modeling. The approach can be used for larger scale disease modeling, target validation and drug discovery purposes.
Untreated, obesity hypoventilation is associated with significant use of health care resources and high mortality. It remains unclear whether continuous positive airway pressure (CPAP) or bilevel ...ventilatory support (BVS) should be used as initial management. The aim of this study was to determine if one form of positive pressure is superior to the other in improving daytime respiratory failure.
A prospective randomised study was performed in patients with obesity hypoventilation referred with respiratory failure. After exclusion of patients with persisting severe nocturnal hypoxaemia (Spo(2) < 80% for > 10 min) or carbon dioxide retention (> 10 mm Hg) despite optimal CPAP, the remaining patients were randomly assigned to receive either CPAP or BVS over a 3-month period. The primary outcome was change in daytime carbon dioxide level. Secondary outcome measures included daytime sleepiness, quality of life, compliance with treatment and psychomotor vigilance testing.
Thirty-six patients were randomised to either home CPAP (n = 18) or BVS (n = 18). The two groups did not differ significantly at baseline with regard to physiological or clinical characteristics. Following 3 months of treatment, daytime carbon dioxide levels decreased in both groups (CPAP 6 (8) mm Hg; BVS 7 (7) mm Hg) with no between-group differences. There was no difference in compliance between the two treatment groups (5.8 (2.4) h/night CPAP vs 6.1 (2.1) h/night BVS). Although both groups reported an improvement in daytime sleepiness, subjective sleep quality and psychomotor vigilance performance were better with BVS.
Both CPAP and BVS appear to be equally effective in improving daytime hypercapnia in a subgroup of patients with obesity hypoventilation syndrome without severe nocturnal hypoxaemia.
Australian Clinical Trials Registry ACTRN01205000096651.
PTEN (Phosphatase and tensin homolog deleted on chromosome 10) expression in stromal fibroblasts suppresses epithelial mammary tumours, but the underlying molecular mechanisms remain unknown. Using ...proteomic and expression profiling, we show that Pten loss from mammary stromal fibroblasts activates an oncogenic secretome that orchestrates the transcriptional reprogramming of other cell types in the microenvironment. Downregulation of miR-320 and upregulation of one of its direct targets, ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2) are critical events in Pten-deleted stromal fibroblasts responsible for inducing this oncogenic secretome, which in turn promotes tumour angiogenesis and tumour-cell invasion. Expression of the Pten-miR-320-Ets2-regulated secretome distinguished human normal breast stroma from tumour stroma and robustly correlated with recurrence in breast cancer patients. This work reveals miR-320 as a critical component of the Pten tumour-suppressor axis that acts in stromal fibroblasts to reprogramme the tumour microenvironment and curtail tumour progression.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Based on high-resolution spectra obtained during gravitational microlensing events we present a detailed elemental abundance analysis of 32 dwarf and subgiant stars in the Galactic bulge. Combined ...with the sample of 26 stars from the previous papers in this series, we now have 58 microlensed bulge dwarfs and subgiants that have been homogeneously analysed. The results from the microlensed bulge dwarf stars in combination with other findings in the literature, in particular the evidence that the bulge has cylindrical rotation, indicate that the Milky Way could be an almost pure disk galaxy. The bulge would then just be a conglomerate of the other Galactic stellar populations, residing together in the central parts of the Galaxy, influenced by the Galactic bar.
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