Liver Injury Induced by Anticancer Chemotherapy and Radiation Therapy

Cytotoxic chemotherapy prolongs survival of patients with advanced and metastatic tumors. This is, however, a double-edged sword with many adverse effects. Since the liver has a rich blood supply and plays an active role in the metabolism of medications, it is not surprising that there can be hepatic injury related to chemotherapy. In addition, radioembolization may affect the parenchyma of normal and cirrhotic livers. We review chemotherapy-associated liver injury in patients with colorectal liver metastases, including downsizing chemotherapy and neoadjuvant chemotherapy. We discuss the mechanism of the hepatic injury, secondary to reactive oxygen species, and the spectrum of hepatic injury including, steatosis, steatohepatitis, hepatic sinusoidal injury and highlight the pharmacogenomics of such liver insults. Methods for reducing and treating the hepatotoxicity are discussed for specific agents including tamxifen and the newly introduced targeted antibodies

Evolution of density perturbations in double exponential quintessence models

In this work we investigate the evolution of matter density perturbations for quintessence models with a self-interaction potential that is a combination of exponentials. One of the models is based on the Einstein theory of gravity, while the other is based on the Brans-Dicke scalar tensor theory. We constrain the parameter space of the models using the determinations for the growth rate of perturbations derived from data of the 2-degree Field Galaxy Redshift Survey.Comment: 5 pages, 3 eps figure

RNA-editing-mediated exon evolution

BACKGROUND: Alu retroelements are specific to primates and abundant in the human genome. Through mutations that create functional splice sites within intronic Alus, these elements can become new exons in a process denoted exonization. It was recently shown that Alu elements are also heavily changed by RNA editing in the human genome. RESULTS: Here we show that the human nuclear prelamin A recognition factor contains a primate-specific Alu-exon that exclusively depends on RNA editing for its exonization. We demonstrate that RNA editing regulates the exonization in a tissue-dependent manner, through both the creation of a functional AG 3' splice site, and alteration of functional exonic splicing enhancers within the exon. Furthermore, a premature stop codon within the Alu-exon is eliminated by an exceptionally efficient RNA editing event. The sequence surrounding this editing site is important not only for editing of that site but also for editing in other neighboring sites as well. CONCLUSION: Our results show that the abundant RNA editing of Alu sequences can be recruited as a mechanism supporting the birth of new exons in the human genome

On virialization with dark energy

We review the inclusion of dark energy into the formalism of spherical collapse, and the virialization of a two-component system, made of matter and dark energy. We compare two approaches in previous studies. The first assumes that only the matter component virializes, e.g. as in the case of a classic cosmological constant. The second approach allows the full system to virialize as a whole. We show that the two approaches give fundamentally different results for the final state of the system. This might be a signature discriminating between the classic cosmological constant which cannot virialize and a dynamical dark energy mimicking a cosmological constant. This signature is independent of the measured value of the equation of state. An additional issue which we address is energy non-conservation of the system, which originates from the homogeneity assumption for the dark energy. We propose a way to take this energy loss into account.Comment: 15 pages, 5 figures. Accepted for publication in JCA

Characterization of heterogeneous vancomycin-intermediate resistance, MIC and accessory gene regulator (agr) dysfunction among clinical bloodstream isolates of staphyloccocus aureus

<p>Abstract</p> <p>Background</p> <p>The development of hVISA has been associated with vancomycin clinical failures and is commonly misidentified in clinical microbiology laboratories. Therefore, the objectives of this present study was to improve the reliability of methodologies and criteria for identifying hVISA, evaluate the prevalence of hVISA among clinical bloodstream isolates of <it>S. aureus </it>and determine if there exists a relationship between accessory gene regulator (<it>agr) </it>dysfunction and the hVISA phenotype.</p> <p>Methods</p> <p>The presence of hVISA in 220 clinical <it>S. aureus </it>isolates (121 MSSA, 99 MRSA) from bloodstream infections was examined by CLSI broth microdilution, Macro & Standard Etest. Isolates which were classified as hVISA by Macro Etest, were additionally evaluated using a modified PAP-AUC method using a modified starting inoculum of 10¹⁰CFU/mL, and growth on brain heart infusion agar with 4 mg/L vancomycin (BHIV4) at 10⁸and 10¹⁰CFU/mL, and <it>agr </it>function was assessed by delta-hemolysin production.</p> <p>Results</p> <p>Broth microdilution MIC_50/90of <it>S.aureus </it>and hVISA was 1.0/2.0 and 1.5/2.0 mg/L (<it>p</it>= 0.02), respectively. Macro Etest identified 12 (5.5%) hVISA isolates; higher among MRSA (9.1%) versus MSSA (2.5%) (<it>p </it>= 0.03). The mean modified PAP-AUC ratios (> 0.8) of 7 MRSA strains and 3 MSSA strains were significantly different (<it>p </it>= 0.001). 58% of hVISA strains were found to be <it>agr </it>dysfunctional when 21% of MRSA strains were <it>agr </it>dysfunctional. hVISA was detected among <it>S. aureus </it>bloodstream isolates, which were classified as susceptible among clinical microbiology laboratories.</p> <p>Conclusions</p> <p>Evaluating the correlation between Etest MICs and modified PAP-AUC ratio values will add further improvement of discriminating hVISA, and <it>agr </it>dysfunction may be predictive of strains which display a greater predilection to display the hVISA phenotype.</p

Constraining dark energy with Sunyaev-Zel'dovich cluster surveys

We discuss the prospects of constraining the properties of a dark energy component, with particular reference to a time varying equation of state, using future cluster surveys selected by their Sunyaev-Zel'dovich effect. We compute the number of clusters expected for a given set of cosmological parameters and propogate the errors expected from a variety of surveys. In the short term they will constrain dark energy in conjunction with future observations of type Ia supernovae, but may in time do so in their own right.Comment: 5 pages, 3 figures, 1 table, version accepted for publication in PR

Blimp1(+) cells generate functional mouse sebaceous gland organoids in vitro

Most studies on the skin focus primarily on the hair follicle and interfollicular epidermis, whereas little is known regarding the homeostasis of the sebaceous gland (SG). The SG has been proposed to be replenished by different pools of hair follicle stem cells and cells that resides in the SG base, marked by Blimp1. Here, we demonstrate that single Blimp1(+) cells isolated from mice have the potential to generate SG organoids in vitro. Mimicking SG homeostasis, the outer layer of these organoids is composed of proliferating cells that migrate inward, undergo terminal differentiation and generating lipid-filled sebocytes. Performing confocal microscopy and mass-spectrometry, we report that these organoids exhibit known markers and a lipidomic profile similar to SGs in vivo. Furthermore, we identify a role for c-Myc in sebocyte proliferation and differentiation, and determine that SG organoids can serve as a platform for studying initial stages of acne vulgaris, making this a useful platform to identify potential therapeutic targets

Structure formation in the presence of dark energy perturbations

We study non-linear structure formation in the presence of dark energy. The influence of dark energy on the growth of large-scale cosmological structures is exerted both through its background effect on the expansion rate, and through its perturbations as well. In order to compute the rate of formation of massive objects we employ the Spherical Collapse formalism, which we generalize to include fluids with pressure. We show that the resulting non-linear evolution equations are identical to the ones obtained in the Pseudo-Newtonian approach to cosmological perturbations, in the regime where an equation of state serves to describe both the background pressure relative to density, and the pressure perturbations relative to the density perturbations as well. We then consider a wide range of constant and time-dependent equations of state (including phantom models) parametrized in a standard way, and study their impact on the non-linear growth of structure. The main effect is the formation of dark energy structure associated with the dark matter halo: non-phantom equations of state induce the formation of a dark energy halo, damping the growth of structures; phantom models, on the other hand, generate dark energy voids, enhancing structure growth. Finally, we employ the Press-Schechter formalism to compute how dark energy affects the number of massive objects as a function of redshift.Comment: 21 pages, 8 figures. Matches published version, with caption of Fig. 6 correcte

Quinstant Dark Energy Predictions for Structure Formation

We explore the predictions of a class of dark energy models, quinstant dark energy, concerning the structure formation in the Universe, both in the linear and non-linear regimes. Quinstant dark energy is considered to be formed by quintessence and a negative cosmological constant. We conclude that these models give good predictions for structure formation in the linear regime, but fail to do so in the non-linear one, for redshifts larger than one.Comment: 9 pages, 14 figures, "Accepted for publication in Astrophysics & Space Science