Epidermal growth factor receptor (EGFR) and HER3 each form heterodimers with HER2 and have independently been implicated as key coreceptors that drive HER2-amplified breast cancer. Some studies ...suggest a dominant role for EGFR, a notion of renewed interest given the development of dual HER2/EGFR small-molecule inhibitors. Other studies point to HER3 as the primary coreceptor. To clarify the relative contributions of EGFR and HER3 to HER2 signaling, we studied receptor knockdown via small interfering RNA technology across a panel of six HER2-overexpressing cell lines. Interestingly, HER3 was as critical as HER2 for maintaining cell proliferation in most cell lines, whereas EGFR was dispensable. Induction of HER3 knockdown in the HER2-overexpressing BT474M1 cell line was found to inhibit growth in three-dimensional culture and induce rapid tumor regression of in vivo xenografts. Furthermore, preferential phosphorylation of HER3, but not EGFR, was observed in HER2-amplified breast cancer tissues. Given these data suggesting HER3 as an important therapeutic target, we examined the activity of pertuzumab, a HER2 antibody that inhibits HER3 signaling by blocking ligand-induced HER2/HER3 heterodimerization. Pertuzumab inhibited ligand-dependent morphogenesis in three-dimensional culture and induced tumor regression in the heregulin-dependent MDA-MB-175 xenograft model. Importantly, these activities of pertuzumab were distinct from those of trastuzumab, a monoclonal antibody currently used for treatment of HER2-amplified breast cancer patients. Our data suggest that inhibition of HER3 may be more clinically relevant than inhibition of EGFR in HER2-amplified breast cancer and also suggest that adding pertuzumab to trastuzumab may augment therapeutic benefit by blocking HER2/HER3 signaling.
We study the optical light curve (LC) relations of Type Ia supernovae (SNe Ia) for their use in cosmology using high-quality photometry published by the Carnegie Supernova Project (CSP-I). We revisit ...the classical luminosity decline rate (Δm15) relation and the Lira relation, as well as investigate the time evolution of the (B − V) color and B(B − V), which serves as the basis of the color-stretch relation and Color-MAgnitude Intercept Calibrations (CMAGIC). Our analysis is based on explosion and radiation transport simulations for spherically symmetric delayed-detonation models (DDT) producing normal-bright and subluminous SNe Ia. Empirical LC relations can be understood as having the same physical underpinnings, i.e., opacities, ionization balances in the photosphere, and radioactive energy deposition changing with time from below to above the photosphere. Some three to four weeks past maximum, the photosphere recedes to 56Ni-rich layers of similar density structure, leading to a similar color evolution. An important secondary parameter is the central density c of the WD because at higher densities, more electron-capture elements are produced at the expense of 56Ni production. This results in a Δm15 spread of 0.1 mag in normal-bright and 0.7 mag in subluminous SNe Ia and 0.2 mag in the Lira relation. We show why color-magnitude diagrams emphasize the transition between physical regimes and enable the construction of templates that depend mostly on Δm15 with little dispersion in both the CSP-I sample and our DDT models. This allows intrinsic SN Ia variations to be separated from the interstellar reddening characterized by E(B − V) and RB. Invoking different scenarios causes a wide spread in empirical relations, which may suggest one dominant scenario.
Abstract
Radiative transfer models of two transitional type Ia supernovae (SNe Ia) have been produced using the abundance stratification technique. These two objects – designated SN 2007on and SN ...2011iv – both exploded in the same galaxy, NGC 1404, which allows for a direct comparison. SN 2007on synthesized 0.25 $\rm M_{{\odot}}$ of 56Ni and was less luminous than SN 2011iv, which produced 0.31 $\rm M_{{\odot}}$ of 56Ni. SN 2007on had a lower central density (ρc) and higher explosion energy (Ekin ∼1.3 ± 0.3 × 1051erg) than SN 2011iv, and it produced less nuclear statistical equilibrium (NSE) elements (0.06 $\rm M_{{\odot}}$). Whereas, SN 2011iv had a larger ρc, which increased the electron capture rate in the lowest velocity regions, and produced 0.35 $\rm M_{{\odot}}$ of stable NSE elements. SN 2011iv had an explosion energy of ∼Ekin ∼0.9 ± 0.2 × 1051erg. Both objects had an ejecta mass consistent with the Chandrasekhar mass (Ch-mass), and their observational properties are well described by predictions from delayed-detonation explosion models. Within this framework, comparison to the sub-luminous SN 1986G indicates SN 2011iv and SN 1986G have different transition densities (ρtr) but similar ρc. Whereas SN 1986G and SN 2007on had a similar ρtr but different ρc. Finally, we examine the colour–stretch parameter sBV versus Lmax relation and determine that the bulk of SNe Ia (including the sub-luminous ones) are consistent with Ch-mass delayed-detonation explosions, where the main parameter driving the diversity is ρtr. We also find ρc to be driving the second-order scatter observed at the faint end of the luminosity–width relationship.
Recent structural studies on calmodulin complexes with anthrax adenylyl cyclase and rat Ca
2+-activated K
+ channel have uncovered unexpected ways by which calmodulin interacts with target proteins.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
We present a multiwavelength photometric and spectroscopic analysis of 13 super-Chandrasekhar-mass/2003fg-like Type Ia supernovae (SNe Ia). Nine of these objects were observed by the ...Carnegie Supernova Project. The 2003fg-like SNe have slowly declining light curves (Δ
m
15
(
B
) < 1.3 mag), and peak absolute
B
-band magnitudes of −19 <
M
B
< −21 mag. Many of the 2003fg-like SNe are located in the same part of the luminosity–width relation as normal SNe Ia. In the optical
B
and
V
bands, the 2003fg-like SNe look like normal SNe Ia, but at redder wavelengths they diverge. Unlike other luminous SNe Ia, the 2003fg-like SNe generally have only one
i
-band maximum, which peaks after the epoch of the
B
-band maximum, while their near-IR (NIR) light-curve rise times can be ≳40 days longer than those of normal SNe Ia. They are also at least 1 mag brighter in the NIR bands than normal SNe Ia, peaking above
M
H
= −19 mag, and generally have negative Hubble residuals, which may be the cause of some systematics in dark-energy experiments. Spectroscopically, the 2003fg-like SNe exhibit peculiarities such as unburnt carbon well past maximum light, a large spread (8000–12,000 km s
−1
) in Si
ii
λ
6355 velocities at maximum light with no rapid early velocity decline, and no clear
H
-band break at +10 days. We find that SNe with a larger pseudo-equivalent width of C
ii
at maximum light have lower Si
ii
λ
6355 velocities and more slowly declining light curves. There are also multiple factors that contribute to the peak luminosity of 2003fg-like SNe. The explosion of a C–O degenerate core inside a carbon-rich envelope is consistent with these observations. Such a configuration may come from the core-degenerate scenario.
Abstract
We present detailed ultraviolet, optical, and near-infrared light curves of the Type Ia supernova (SN) 2012fr, which exploded in the Fornax cluster member NGC 1365. These precise ...high-cadence light curves provide a dense coverage of the flux evolution from −12 to +140 days with respect to the epoch of
B
-band maximum (
t
B
max
). Supplementary imaging at the earliest epochs reveals an initial slow and nearly linear rise in luminosity with a duration of ∼2.5 days, followed by a faster rising phase that is well reproduced by an explosion model with a moderate amount of
56
Ni mixing in the ejecta. From our analysis of the light curves, we conclude that: (i) the explosion occurred <22 hr before the first detection of the supernova, (ii) the rise time to peak bolometric (
λ
> 1800 Å) luminosity was 16.5 ± 0.6 days, (iii) the supernova suffered little or no host-galaxy dust reddening, (iv) the peak luminosity in both the optical and near-infrared was consistent with the bright end of normal Type Ia diversity, and (v) 0.60 ± 0.15
M
⊙
of
56
Ni was synthesized in the explosion. Despite its normal luminosity, SN 2012fr displayed unusually prevalent high-velocity Ca
ii
and Si
ii
absorption features, and a nearly constant photospheric velocity of the Si
ii
λ
6355 line at ∼12,000
km
s
−
1
that began ∼5 days before
t
B
max
. We also highlight some of the other peculiarities in the early phase photometry and the spectral evolution. SN 2012fr also adds to a growing number of Type Ia supernovae that are hosted by galaxies with direct Cepheid distance measurements.
Abstract
We present near-IR (NIR) and optical observations of the Type Ic supernova (SN Ic) SN 2020oi in the galaxy M100 and the broad-lined SN Ic SN 2020bvc in UGC 9379, using Gemini, Las Cumbres ...Observatory, Southern Astrophysical Telescope, and other ground-based telescopes. The NIR spectrum of SN 2020oi at day 63 since the explosion shows strong CO emissions and a rising
K
-band continuum, which is the first unambiguous dust detection from an SN Ic. Non-LTE CO modeling shows that CO is still optically thick and that the lower limit to the CO mass is 10
−3
M
⊙
. The dust temperature is 810 K, and the dust mass is ∼10
−5
M
⊙
. We explore the possibilities that the dust is freshly formed in the ejecta, heated dust in the preexisting circumstellar medium, and an infrared echo. The light curves of SN 2020oi are consistent with a STELLA model with canonical explosion energy, 0.07
M
⊙
Ni mass, and 0.7
M
⊙
ejecta mass. A model of high explosion energy of 10
52
erg, 0.4
M
⊙
Ni mass, and 6.5
M
⊙
ejecta mass with the circumstellar matter reproduces the double-peaked light curves of SN 2020bvc. We observe temporal changes of absorption features of the IR Ca
ii
triplet, S
i
at 1.043
μ
m, and Fe
ii
at 5169 Å. The blueshifted lines indicate high velocities, up to 60,000 km s
−1
for SN 2020bvc and 20,000 km s
−1
for SN 2020oi, and the expansion velocity rapidly declines before the optical maximum. We present modeled spectral signatures and diagnostics of CO and SiO molecular bands between 1.4 and 10
μ
m.
Outcomes for patients with advanced hepatocellular carcinoma (HCC) remain poor despite recent progress in drug development. Emerging data implicate FGF19 as a potential HCC driver, suggesting its ...receptor, FGFR4, as a novel therapeutic target. We evaluated fisogatinib (BLU-554), a highly potent and selective oral FGFR4 inhibitor, in a phase I dose-escalation/dose-expansion study in advanced HCC using FGF19 expression measured by IHC as a biomarker for pathway activation. For dose escalation, 25 patients received 140 to 900 mg fisogatinib once daily; the maximum tolerated dose (600 mg once daily) was expanded in 81 patients. Fisogatinib was well tolerated; most adverse events were manageable, grade 1/2 gastrointestinal events, primarily diarrhea, nausea, and vomiting. Across doses, the overall response rate was 17% in FGF19-positive patients median duration of response: 5.3 months (95% CI, 3.7-not reached) and 0% in FGF19-negative patients. These results validate FGFR4 as a targetable driver in FGF19-positive advanced HCC. SIGNIFICANCE: Fisogatinib elicited clinical responses in patients with tumor FGF19 overexpression in advanced HCC. These results validate the oncogenic driver role of the FGFR4 pathway in HCC and the use of FGF19 as a biomarker for patient selection.
.
.
We present ultraviolet through near-infrared (NIR) broadband photometry, and visual-wavelength and NIR spectroscopy of the Type Iax supernova (SN) 2012Z. The data set consists of both early- and ...late-time observations, including the first late phase NIR spectrum obtained for a spectroscopically classified SN Iax. Simple model calculations of its bolometric light curve suggest SN 2012Z produced ~0.3 M⊙ of 56Ni, ejected about a Chandrasekhar mass of material, and had an explosion energy of ~1051 erg, making it one of the brightest (MB = −18.3 mag) and most energetic SN Iax yet observed. The late phase (+269d) NIRspectrum of SN 2012Z is found to broadly resemble similar epoch spectra of normal SNe Ia; however, like other SNe Iax, corresponding visual-wavelength spectra differ substantially from all supernova types. Constraints from the distribution of intermediate mass elements, e.g., silicon and magnesium, indicate that the outer ejecta did not experience significant mixing during or after burning, and the late phase NIR line profiles suggests most of the 56Ni is produced during high density burning. The various observational properties of SN 2012Z are found to be consistent with the theoretical expectations of a Chandrasekhar mass white dwarf progenitor that experiences a pulsational delayed detonation, which produced several tenths of a solar mass of 56Ni during the deflagration burning phase and little (or no) 56Ni during the detonation phase. Within this scenario only a moderate amount of Rayleigh-Taylor mixing occurs both during the deflagration and fallback phase of the pulsation, and the layered structure of the intermediate mass elements is a product of the subsequent denotation phase. The fact that the SNe Iax population does not follow a tight brightness-decline relation similar to SNe Ia can then be understood in the framework of variable amounts of mixing during pulsational rebound and variable amounts of 56Ni production during the early subsonic phase of expansion.
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FMFMET, NUK, UL, UM, UPUK
Activating mutations in KRAS and BRAF are found in more than 30% of all human tumours and 40% of melanoma, respectively, thus targeting this pathway could have broad therapeutic effects. Small ...molecule ATP-competitive RAF kinase inhibitors have potent antitumour effects on mutant BRAF(V600E) tumours but, in contrast to mitogen-activated protein kinase kinase (MEK) inhibitors, are not potent against RAS mutant tumour models, despite RAF functioning as a key effector downstream of RAS and upstream of MEK. Here we show that ATP-competitive RAF inhibitors have two opposing mechanisms of action depending on the cellular context. In BRAF(V600E) tumours, RAF inhibitors effectively block the mitogen-activated protein kinase (MAPK) signalling pathway and decrease tumour growth. Notably, in KRAS mutant and RAS/RAF wild-type tumours, RAF inhibitors activate the RAF-MEK-ERK pathway in a RAS-dependent manner, thus enhancing tumour growth in some xenograft models. Inhibitor binding activates wild-type RAF isoforms by inducing dimerization, membrane localization and interaction with RAS-GTP. These events occur independently of kinase inhibition and are, instead, linked to direct conformational effects of inhibitors on the RAF kinase domain. On the basis of these findings, we demonstrate that ATP-competitive kinase inhibitors can have opposing functions as inhibitors or activators of signalling pathways, depending on the cellular context. Furthermore, this work provides new insights into the therapeutic use of ATP-competitive RAF inhibitors.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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