10 research outputs found
Splicing Modulation Results in Aberrant Isoforms and Protein Products of p53 Pathway Genes and the Sensitization of B Cells to Non-Genotoxic MDM2 Inhibition
Several molecular subtypes of cancer are highly dependent on splicing for cell survival. There is a general interest in the therapeutic targeting of splicing by small molecules. E7107, a first-in-class spliceosome inhibitor, showed strong growth inhibitory activities against a large variety of human cancer xenografts. Chronic lymphocytic leukaemia (CLL) is a clinically heterogeneous hematologic malignancy, with approximately 90% of cases being TP53 wild-type at diagnosis. An increasing number of studies are evaluating alternative targeted agents in CLL, including MDM2âp53 binding antagonists. In this study, we report the effect of splicing modulation on key proteins in the p53 signalling pathway, an important cell death pathway in B cells. Splicing modulation by E7107 treatment reduced full-length MDM2 production due to exon skipping, generating a consequent reciprocal p53 increase in TP53WT cells. It was especially noteworthy that a novel p21WAF1 isoform with compromised cyclin-dependent kinase inhibitory activity was produced due to intron retention. E7107 synergized with the MDM2 inhibitor RG7388, via dual MDM2 inhibition; by E7107 at the transcript level and by RG7388 at the protein level, producing greater p53 stabilisation and apoptosis. This study provides evidence for a synergistic MDM2 and spliceosome inhibitor combination as a novel approach to treat CLL and potentially other haematological malignancies
Distances from Surface Brightness Fluctuations
The practice of measuring galaxy distances from their spatial fluctuations in
surface brightness is now a decade old. While several past articles have
included some review material, this is the first intended as a comprehensive
review of the surface brightness fluctuation (SBF) method. The method is
conceptually quite simple, the basic idea being that nearby (but unresolved)
star clusters and galaxies appear "bumpy", while more distant ones appear
smooth. This is quantified via a measurement of the amplitude of the Poisson
fluctuations in the number of unresolved stars encompassed by a CCD pixel
(usually in an image of an elliptical galaxy). Here, we describe the technical
details and difficulties involved in making SBF measurements, discuss
theoretical and empirical calibrations of the method, and review the numerous
applications of the method from the ground and space, in the optical and
near-infrared. We include discussions of stellar population effects and the
"universality" of the SBF standard candle. A final section considers the future
of the method.Comment: Invited review article to appear in: `Post-Hipparcos Cosmic Candles',
A. Heck & F. Caputo (Eds), Kluwer Academic Publ., Dordrecht, in press. 22
pages, including 3 postscript figures; uses Kluwer's crckapb.sty LaTex macro
file, enclose
Evolutionary and pulsational properties of white dwarf stars
Abridged. White dwarf stars are the final evolutionary stage of the vast
majority of stars, including our Sun. The study of white dwarfs has potential
applications to different fields of astrophysics. In particular, they can be
used as independent reliable cosmic clocks, and can also provide valuable
information about the fundamental parameters of a wide variety of stellar
populations, like our Galaxy and open and globular clusters. In addition, the
high densities and temperatures characterizing white dwarfs allow to use these
stars as cosmic laboratories for studying physical processes under extreme
conditions that cannot be achieved in terrestrial laboratories. They can be
used to constrain fundamental properties of elementary particles such as axions
and neutrinos, and to study problems related to the variation of fundamental
constants.
In this work, we review the essentials of the physics of white dwarf stars.
Special emphasis is placed on the physical processes that lead to the formation
of white dwarfs as well as on the different energy sources and processes
responsible for chemical abundance changes that occur along their evolution.
Moreover, in the course of their lives, white dwarfs cross different
pulsational instability strips. The existence of these instability strips
provides astronomers with an unique opportunity to peer into their internal
structure that would otherwise remain hidden from observers. We will show that
this allows to measure with unprecedented precision the stellar masses and to
infer their envelope thicknesses, to probe the core chemical stratification,
and to detect rotation rates and magnetic fields. Consequently, in this work,
we also review the pulsational properties of white dwarfs and the most recent
applications of white dwarf asteroseismology.Comment: 85 pages, 28 figures. To be published in The Astronomy and
Astrophysics Revie
The expansion field: The value of H_0
Any calibration of the present value of the Hubble constant requires
recession velocities and distances of galaxies. While the conversion of
observed velocities into true recession velocities has only a small effect on
the result, the derivation of unbiased distances which rest on a solid zero
point and cover a useful range of about 4-30 Mpc is crucial. A list of 279 such
galaxy distances within v<2000 km/s is given which are derived from the tip of
the red-giant branch (TRGB), from Cepheids, and from supernovae of type Ia (SNe
Ia). Their random errors are not more than 0.15 mag as shown by
intercomparison. They trace a linear expansion field within narrow margins from
v=250 to at least 2000 km/s. Additional 62 distant SNe Ia confirm the linearity
to at least 20,000 km/s. The dispersion about the Hubble line is dominated by
random peculiar velocities, amounting locally to <100 km/s but increasing
outwards. Due to the linearity of the expansion field the Hubble constant H_0
can be found at any distance >4.5 Mpc. RR Lyr star-calibrated TRGB distances of
78 galaxies above this limit give H_0=63.0+/-1.6 at an effective distance of 6
Mpc. They compensate the effect of peculiar motions by their large number.
Support for this result comes from 28 independently calibrated Cepheids that
give H_0=63.4+/-1.7 at 15 Mpc. This agrees also with the large-scale value of
H_0=61.2+/-0.5 from the distant, Cepheid-calibrated SNe Ia. A mean value of
H_0=62.3+/-1.3 is adopted. Because the value depends on two independent zero
points of the distance scale its systematic error is estimated to be 6%.
Typical errors of H_0 come from the use of a universal, yet unjustified P-L
relation of Cepheids, the neglect of selection bias in magnitude-limited
samples, or they are inherent to the adopted models.Comment: 44 pages, 4 figures, 6 tables, accepted for publication in the
Astronony and Astrophysics Review 15
Non-genotoxic MDM2 inhibition selectively induces pro-apoptotic p53 gene signature in chronic lymphocytic leukemia cells
The potential association between common comorbidities and severity and mortality of coronavirus disease 2019: A pooled analysis
Mercury accumulation, structural damages, and antioxidant and immune status changes in the gilthead seabream (Sparus aurata L.) exposed to methylmercury
In aquatic systems, mercury (Hg) is an environmental contaminant that causes acute and chronic damage to multiple organs. In fish, practically all of the organic Hg found is in the form of methylmercury (MeHg), which has been associated with animal and human health problems. This study evaluates the impact of waterborne- exposure to sublethal concentrations of MeHg (10 lgL-1) in gilthead seabream (Sparus aurata). Hg was seen to accumulate in liver and muscle, and histopathological damage to skin and liver was detected. Fish exposed to MeHg showed a decreased biological antioxidant potential and increased levels of the reactive oxygen molecules compared with the values found in control fish (non-exposed). Increased liver antioxidant enzyme activities (superoxide dismutase and catalase) were detected in 2 day- exposed fish with respect to the values of control fish. However, fish exposed to MeHg for 10 days showed liver antioxidant enzyme levels similar to those of the control fish but had increased hepato-somatic index and histopathological alterations in liver and skin. Serum complement levels were higher in fish exposed to MeHg for 30 days than in control fish. Moreover, headâkidney leukocyte activities increased, although only phagocytosis and peroxidase activities showed a significant increase after 10 and 30 days, respectively. The data show that 30 days of exposure to waterborne MeHg provokes more significant changes in fish than a short-term exposure of 2 or 10 days.VersiĂłn del editor1,927