After decades of intense effort, therapeutics that leverage the immune system to fight cancer have now been conclusively demonstrated to be effective. Immuno-oncology has arrived and will play a key ...role in the treatment of cancer for the foreseeable future. However, the search for novel methods to improve immune responses to cancer continues unabated. Toward this end, small molecules that can either reduce immune suppression in the tumor milieu or enhance activation of cytotoxic lymphocyte responses to the tumor are actively being pursued. Such novel treatment strategies might be used as monotherapies or combined with other cancer therapies to increase and broaden their efficacy. In this article, we provide an overview of small molecule immunotherapeutic approaches for the treatment of cancer. Over the next decade and beyond, these approaches could further enhance our ability to harness the immune system to combat cancer and thus become additional weapons in the oncologist's armory.
Abstract
Galactic outflows are believed to play an important role in regulating star formation in galaxies, but estimates of the outflowing mass and momentum have historically been based on uncertain ...assumptions. Here, we measure the mass, momentum and energy outflow rates of seven nearby star-forming galaxies using ultraviolet absorption lines and observationally motivated estimates for the density, metallicity, and radius of the outflow. Low-mass galaxies generate outflows faster than their escape velocities with mass outflow rates up to twenty times larger than their star formation rates. These outflows from low-mass galaxies also have momenta larger than provided from supernovae alone, indicating that multiple momentum sources drive these outflows. Only 1–20 per cent of the supernovae energy is converted into kinetic energy, and this fraction decreases with increasing stellar mass, such that low-mass galaxies drive more efficient outflows. We find scaling relations between the outflows and the stellar mass of their host galaxies (M*) at the 2–3σ significance level. The mass-loading factor, or the mass outflow rate divided by the star formation rate, scales as M
$_\ast ^{-0.4}$
and with the circular velocity as v
$_\mathrm{circ}^{-1.6}$
. The scaling of the mass-loading factor is similar to recent simulations, but the observations are a factor of 5 smaller, possibly indicating that there is a substantial amount of unprobed gas in a different ionization phase. The outflow momenta are consistent with a model where star formation drives the outflow while gravity counteracts this acceleration.
THE MOLECULAR BARYON CYCLE OF M82 Chisholm, John; Matsushita, Satoki
The Astrophysical journal,
10/2016, Volume:
830, Issue:
2
Journal Article
Peer reviewed
Open access
ABSTRACT Baryons cycle into galaxies from the intergalactic medium and are converted into stars; a fraction of the baryons are ejected out of galaxies by stellar feedback. Here we present new ...high-resolution (3 9; 68 pc) 12CO(2-1) and 12CO(3-2) images that probe these three stages of the baryon cycle in the nearby starburst M82. We combine these new observations with previous 12CO(1-0) and Fe ii images to study the physical conditions within the molecular gas. Using a Bayesian analysis and the radiative transfer code RADEX, we model temperatures and densities of molecular hydrogen, as well as column densities of CO. Besides the disk, we concentrate on two regions within the galaxy: an expanding super-bubble and the base of a molecular streamer. Shock diagnostics, kinematics, and optical extinction suggest that the streamer is an inflowing filament, with a mass inflow rate of molecular gas of 3.5 yr−1. We measure the mass outflow rate of molecular gas of the expanding super-bubble to be 17 yr−1, five times higher than the inferred inflow rate and 1.3 times the star formation rate of the galaxy. The high mass outflow rate and large star formation rate will deplete the galaxy of molecular gas within eight million years, unless there are additional sources of molecular gas.
We study the ionization structure of galactic outflows in 37 nearby, star-forming galaxies with the Cosmic Origins Spectrograph on the Hubble Space Telescope. We use the O i, Si ii, Si iii, and Si iv ...ultraviolet absorption lines to characterize the different ionization states of outflowing gas. We measure the equivalent widths, line widths, and outflow velocities of the four transitions, and find shallow scaling relations between them and galactic stellar mass and star formation rate. Regardless of the ionization potential, lines of similar strength have similar velocities and line widths, indicating that the four transitions can be modelled as a comoving phase. The Si equivalent width ratios (e.g. Si iv/Si ii) have low dispersion, and little variation with stellar mass; while ratios with O i and Si vary by a factor of 2 for a given stellar mass. Photoionization models reproduce these equivalent width ratios, while shock models under predict the relative amount of high ionization gas. The photoionization models constrain the ionization parameter (U) between −2.25 < log (U) < −1.5, and require that the outflow metallicities are greater than 0.5 Z⊙. We derive ionization fractions for the transitions, and show that the range of ionization parameters and stellar metallicities leads to a factor of 1.15–10 variation in the ionization fractions. Historically, mass outflow rates are calculated by converting a column density measurement from a single metal ion into a total hydrogen column density using an ionization fraction, thus mass outflow rates are sensitive to the assumed ionization structure of the outflow.
Abstract
Stellar population models produce radiation fields that ionize oxygen up to O
+2
, defining the limit of standard H
ii
region models (<54.9 eV). Yet, some extreme emission-line galaxies, or ...EELGs, have surprisingly strong emission originating from much higher ionization potentials. We present UV HST/COS and optical LBT/MODS spectra of two nearby EELGs that have very high-ionization emission lines (e.g., He
ii
λλ
1640,4686 C
iv
λλ
1548,1550, Fe
v
λ
4227, Ar
iv
λλ
4711,4740). We define a four-zone ionization model that is augmented by a very high-ionization zone, as characterized by He
+2
(>54.4 eV). The four-zone model has little to no effect on the measured total nebular abundances, but does change the interpretation of other EELG properties: we measure steeper central ionization gradients; higher volume-averaged ionization parameters; and higher central
T
e
,
n
e
, and log
U
values. Traditional three-zone estimates of the ionization parameter can underestimate the average log
U
by up to 0.5 dex. Additionally, we find a model-independent dichotomy in the abundance patterns, where the
α
/H abundances are consistent but N/H, C/H, and Fe/H are relatively deficient, suggesting these EELGs are
α
/Fe-enriched by more than three times. However, there still is a high-energy ionizing photon production problem (HEIP
3
). Even for such
α
/Fe enrichment and very high log
U
s, photoionization models cannot reproduce the very high-ionization emission lines observed in EELGs.
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•Indoles may be alkylated by trichloroacetimidates with Lewis acids.•Benzylic and allylic imidates are most effective.•Electron poor imidates and/or indoles perform best as ...polyalkylation is lower.
Substituted indole scaffolds are often utilized in medicinal chemistry as they regularly possess significant pharmacological activity. Therefore the development of simple, inexpensive and efficient methods for alkylating the indole heterocycle continues to be an active research area. Reported are reactions of trichloroacetimidate electrophiles and indoles to address the challenges of accessing alkyl decorated indole structures. These alkylations perform best when either the indole or the imidate is functionalized with electron withdrawing groups to avoid polyalkylation.
Abstract
In the last few years, prominent high-ionization nebular emission lines (i.e., O
iii
, C
iii
, C
iv
, and He
ii
) have been observed in the deep UV spectra of
z
∼ 5–7 galaxies, indicating ...that extreme radiation fields characterize reionization-era systems. These lines have been linked to the leakage of Lyman continuum photons (necessary for reionization) both theoretically and observationally. Consequently, high-ionization UV emission lines present our best probe to detect and characterize the most distant galaxies that we will observe in the coming years, and are key to understanding the sources of reionization, yet the physics governing their production is poorly understood. Here we present recent high-resolution
Hubble Space Telescope
spectra of two nearby extreme UV emission-line galaxies, J104457 and J141851. We report the first observations of intense nebular He
ii
and double-peaked, resonantly scattered C
iv
emission, a combination that suggests these galaxies both produce and transmit a significant number of very high-energy ionizing photons (
E
> 47.89 eV) through relatively low column densities of high-ionization gas. This suggests that, in addition to photons at the H-ionizing edge, the very hard ionizing photons that escape from these galaxies may provide a secondary source of ionization that is currently unconstrained observationally. Simultaneous radiative transfer models of Ly
α
and C
iv
are needed to understand how ionizing radiation is transmitted through both low- and high-ionization gas. Future rest-frame far-UV observations of galaxies within the epoch of reionization using the
James Webb Space Telescope
or extremely large telescopes (ELTs) will allow us to constrain the escape of helium-ionizing photons and provide an estimate for their contribution to the reionization budget.
The pyrroloindoline core is found in many natural products. These structures often differ at the C3a position, which may be substituted with an oxygen, nitrogen, or sp(3)- or sp(2)-hybridized carbon. ...Utilizing a trichloroacetimidate leaving group, a diversity-oriented approach to these structures has been developed. The trichloroacetimidate intermediate allows for the rapid incorporation of anilines, alcohols, thiols, and carbon nucleophiles. This method was applied in the synthesis of arundinine and a formal synthesis of psychotriasine.
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•Pyrroloindolines can be formed by Lewis acid catalyzed alkylation using trichloroacetimidates.•Electron poor imidates and/or indoles perform best as polyalkylation is ...lower.•tert-Butyl trichloroacetimidate participates well leading to the formation of two contiguous quaternary centers.
Pyrroloindolines and related systems are present in a large number of complex natural products. These core structures have generated considerable synthetic interest, as many of the compounds possess challenging, elaborate structures and interesting biological properties. Recently we have focused on using trichloroacetimidates for the synthesis of these fascinating molecules. Trichloroacetimidates can be used as an electrophilic source of an alkyl group to form the pyrroloindoline directly from tryptamine derivatives. In this manner trichloroacetimidates provide a flexible solution to forming highly functionalized pyrroloindoline core structures, needing only a catalytic amount of a Lewis acid to effect the requisite transformations.
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