Separate and Combined Effects of DNMT and HDAC Inhibitors in Treating Human Multi-Drug Resistant Osteosarcoma HosDXR150 Cell Line

Understanding the molecular mechanisms underlying multi-drug resistance (MDR) is one of the major challenges in current cancer research. A phenomenon which is common to both intrinsic and acquired resistance, is the aberrant alteration of gene expression in drug-resistant cancers. Although such dysregulation depends on many possible causes, an epigenetic characterization is considered a main driver. Recent studies have suggested a direct role for epigenetic inactivation of genes in determining tumor chemo-sensitivity. We investigated the effects of the inhibition of DNA methyltransferase (DNMT) and hystone deacethylase (HDAC), considered to reverse the epigenetic aberrations and lead to the re-expression of de novo methylated genes in MDR osteosarcoma (OS) cells. Based on our analysis of the HosDXR150 cell line, we found that in order to reduce cell proliferation, co-treatment of MDR OS cells with DNMT (5-Aza-dC, DAC) and HDAC (Trichostatin A, TSA) inhibitors is more effective than relying on each treatment alone. In re-expressing epigenetically silenced genes induced by treatments, a very specific regulation takes place which suggests that methylation and de-acetylation have occurred either separately or simultaneously to determine MDR OS phenotype. In particular, functional relationships have been reported after measuring differential gene expression, indicating that MDR OS cells acquired growth and survival advantage by simultaneous epigenetic inactivation of both multiple p53-independent apoptotic signals and osteoblast differentiation pathways. Furthermore, co-treatment results more efficient in inducing the re-expression of some main pathways according to the computed enrichment, thus emphasizing its potential towards representing an effective therapeutic option for MDR OS.     

A Combined Transcriptomics and Lipidomics Analysis of Subcutaneous,Epididymal and Mesenteric Adipose Tissue Reveals Marked Functional Differences

Depot-dependent differences in adipose tissue physiology may reflect specialized functions and local interactions between adipocytes and surrounding tissues. We combined time-resolved microarray analyses of mesenteric- (MWAT), subcutaneous- (SWAT) and epididymal adipose tissue (EWAT) during high-fat feeding of male transgenic ApoE3Leiden mice with histology, targeted lipidomics and biochemical analyses of metabolic pathways to identify differentially regulated processes and site-specific functions. EWAT was found to exhibit physiological zonation. De novo lipogenesis in fat proximal to epididymis was stably low, whereas de novo lipogenesis distal to epididymis and at other locations was down-regulated in response to high-fat diet. The contents of linoleic acid and α-linolenic acid in EWAT were increased compared to other depots. Expression of the androgen receptor (Ar) was higher in EWAT than in MWAT and SWAT. We suggest that Ar may mediate depot-dependent differences in de novo lipogenesis rate and propose that accumulation of linoleic acid and α-linolenic acid in EWAT is favored by testosterone-mediated inhibition of de novo lipogenesis and may promote further elongation and desaturation of these polyunsaturated fatty acids during spermatogenesis.     

Predators and competitors of the mountain pine beetle Dendroctonus ponderosae (Coleoptera: Curculionidae) in stands of changing forest composition associated with elevation

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Interaction of pre-attack and induced monoterpene concentrations in host conifer defense against bark beetle-fungal complexes

Two pine species (Pinus resinosa, P. banksiana) responded to inoculation with fungi carried by bark beetles by rapidly increasing monoterpene concentrations at the entry site. Changes in total monoterpenes were more pronounced than changes in proportionate compositions. The extent and rate of host response was affected by fungal species, the viability of the inoculum, and host tree species. In general, host responses were highest to fungi that are phytopathogenic and consistently associated with the major bark beetles in the study region. Simple mechanical wounding cannot account for the observed allelochemical changes, as aseptic inoculations elicited only minor reactions. Similarly, inoculation with autoclaved inviable fungi generally elicited intermediate responses, suggesting that both structural and metabolic fungal properties are important. Responses by jack pine, P. banksiana, were generally more rapid and variable than those of red pine, P. resinosa. Dose-toxicity experiments with synthetic compounds demonstrated that monoterpene concentrations present in vivo only a few days after simulated attack are lethal to most beetles. Constitutive (pre-attack) monoterpene levels can also exert some toxicity. Because bark beetles engage in pheromone-mediated mass attacks that can deplete host defenses, constitutive monoterpene levels, while a necessary early phase of successful plant defense, appear insufficient by themselves. Such interactions between constitutive and induced defense chemistry may be important considerations when evaluating general theories of plant defense.     

Differential growth and recovery rates following defoliation in related deciduous and evergreen trees

 Deciduous larches, Larix spp., and evergreen pines, Pinus spp., are sympatric Pinaceae conifers. Adjacent monocultures of 10-year-old Larix decidua Mill. and Pinus resinosa Ait. were subjected to single-season artificial defoliation by clipping from 0% to 99% of each needle. Survival, above-ground productivity, and architecture were measured for 36 months. P. resinosa and L. decidua exhibited differential relationships with defoliation intensity and recovery time. Two months after treatment, defoliation reduced larch height growth but had no effect on radial growth. By contrast, P. resinosa stem radial growth was reduced immediately, but height growth was not decreased until the following year. Pine leader growth and above-ground biomass following 66% defoliation never recovered to control values or 33% defoliated pines. Conversely, defoliated larch quickly recovered from an initial growth loss to eliminate all treatment effects on biomass. The plasticity in architectural response found in larch, but not pine, might partially account for defoliation tolerance. Both P. resinosa and L. decidua exhibited non-linear responses to defoliation. These patterns may be caused partially by the uneven distribution of nutrients within needles, rather than a simple function of leaf area lost to defoliators. Concentrations of 13 nutrients in P. resinosa were highest either in the mid- (Ca, Mg, S, Zn, B, Mn, Fe, Al and Na) or basal- (N, P, K, and Cu) section. The relatively low nutrient content in needle tips may contribute to similar biomass productivity between trees defoliated 33% and controls. Removal of needle mid-sections significantly reduced whole-plant productivity. In contrast, L. decidua nutrients are concentrated in the distal sections. Nutrient concentrations were generally highest in larch. Our results agree with an emergent prediction of the carbon/nutrient balance theory that defoliation more severely reduces growth of evergreen than deciduous species. These results are discussed within the physiological, ecological and evolutionary context of allocation theory, with implications for natural resource management and plant-insect interaction theory. Received: 6 April 1995 / Accepted: 29 August 1995     

Visualization of DNA G-quadruplexes in herpes simplex virus 1-infected cells

We have previously shown that clusters of guanine quadruplex (G4) structures can form in the human herpes simplex-1 (HSV-1) genome. Here we used immunofluorescence and immune-electron microscopy with a G4-specific monoclonal antibody to visualize G4 structures in HSV-1 infected cells. We found that G4 formation and localization within the cells was virus cycle dependent: viral G4s peaked at the time of viral DNA replication in the cell nucleus, moved to the nuclear membrane at the time of virus nuclear egress and were later found in HSV-1 immature virions released from the cell nucleus. Colocalization of G4s with ICP8, a viral DNA processing protein, was observed in viral replication compartments. G4s were lost upon treatment with DNAse and inhibitors of HSV-1 DNA replication. The notable increase in G4s upon HSV-1 infection suggests a key role of these structures in the HSV-1 biology and indicates new targets to control both the lytic and latent infection.     

Power and Effective Study Size in Heritability Studies

Correlation between study units in quantitative genetics studies often makes it difficult to compare important inferential aspects of studies. Describing the relatedness between study units is critical to capture features of pedigree studies involving heritability, including power and precision of heritability estimates. Blangero et al. (Adv Genet 81:1–31, 2012) showed that in pedigree studies the power to detect heritability is a function of the true heritability and the eigenvalues of the kinship matrix. We extend this to a more general setting which allows statements about expected precision of heritability estimates. Using two different Taylor series approximations, we summarize the relatedness in a study design by one or two parameters. These relatedness summary parameters (RSPs) are functions of the eigenvalues or log-eigenvalues of the kinship matrix. Using the RSPs based on the log-eigenvalues, we accurately approximate the expectation of the likelihood ratio test and expected confidence interval widths. We define an effective sample size of a target study as one which has the equivalent power and precision to a reference design. Using unrelated sibpairs as the reference design provides very accurate assessments of power. RSPs and effective sample sizes provide new tools for comparing studies and communicating information about relatedness in heritability studies.     

The three dimensional analysis of the Sforzesco brace correction

Background

Scoliosis is a three dimensional deformity, and brace correction should be 3D too. There is a lack of knowledge of the effect of braces, particularly in the sagittal and transverse plane. The aim of this study is to analyse the Sforzesco Brace correction, through all the parameters provided by Eos 3D imaging system.

Method

Design: This is a cross sectional study from a prospective database started in March 2003.Participants: 16 AIS girls (mean age 14.01) in Sforzesco brace treatment, with EOS x-rays, at start, in brace after 1 month and out of brace after the first 4 months of treatment. Outcome measures: All the parameters and the Torsio-Index obtained from 3D Eos System, in and out of brace, in the three planes. Statistical analysis: the variability of the parameters and the mean differences were analyzed and compared using paired T test. ANOVA was used for multiple comparisons. Critical P value was set at 0.05.

Results

In the comparison of in-brace vs start of treatment, the mean Cobb angle changed significantly from 36.44 +/? 4 to 28.99?+??3.9° (p?=?0.01). Significant changes in all the sagittal parameters were found (p?=?0.02). In the axial plane, the Torsio Index changed significantly in-brace for thoracolumbar and lumbar curves (P?<?0.05). The analysis of the single vertebral tilt demonstrated that the effect of the brace is mostly concentrated at specific segments: T4-T5, T10-T12, L1 and L5 in the axial plane and T3-T6 and T10-L1 in the frontal plane.

Conclusion

The Sforzesco brace mostly modifies the middle of the spine and preserves the sagittal balance. The single vertebral orientation in each plane should be considered together with the typically used values to assess brace effect.