331 research outputs found
Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer.
Renal cell carcinoma (RCC) is increasing in incidence, and a complete cure remains elusive. While immune-checkpoint antibodies are promising, interferon-based immunotherapy has been disappointing. Tryptophan metabolism, which produces immunosuppressive metabolites, is enhanced in RCC. Here we show indolamine-2,3-dioxygenase-1 (IDO1) expression, a kynurenine pathway enzyme, is increased not only in tumor cells but also in the microenvironment of human RCC compared to normal kidney tissues. Neither kynurenine metabolites nor IDO inhibitors affected the survival or proliferation of human RCC or murine renal cell adenocarcinoma (RENCA) cells in vitro. However, interferon-gamma (IFNγ) induced high levels of IDO1 in both RCC and RENCA cells, concomitant with enhanced kynurenine levels in conditioned media. Induction of IDO1 by IFNα was weaker than by IFNγ. Neither the IDO1 inhibitor methyl-thiohydantoin-DL-tryptophan (MTH-trp) nor IFNα alone inhibited RENCA tumor growth, however the combination of MTH-trp and IFNα reduced tumor growth compared to IFNα. Thus, the failure of IFNα therapy for human RCC is likely due to its inability to overcome the immunosuppressive environment created by increased IDO1. Based on our data, and given that IDO inhibitors are already in clinical trials for other malignancies, IFNα therapy with an IDO inhibitor should be revisited for RCC
Brown representability for space-valued functors
In this paper we prove two theorems which resemble the classical
cohomological and homological Brown representability theorems. The main
difference is that our results classify small contravariant functors from
spaces to spaces up to weak equivalence of functors.
In more detail, we show that every small contravariant functor from spaces to
spaces which takes coproducts to products up to homotopy and takes homotopy
pushouts to homotopy pullbacks is naturally weekly equivalent to a
representable functor.
The second representability theorem states: every contravariant continuous
functor from the category of finite simplicial sets to simplicial sets taking
homotopy pushouts to homotopy pullbacks is equivalent to the restriction of a
representable functor. This theorem may be considered as a contravariant analog
of Goodwillie's classification of linear functors.Comment: 19 pages, final version, accepted by the Israel Journal of
Mathematic
HARP/ACSIS: A submillimetre spectral imaging system on the James Clerk Maxwell Telescope
This paper describes a new Heterodyne Array Receiver Programme (HARP) and
Auto-Correlation Spectral Imaging System (ACSIS) that have recently been
installed and commissioned on the James Clerk Maxwell Telescope (JCMT). The
16-element focal-plane array receiver, operating in the submillimetre from 325
to 375 GHz, offers high (three-dimensional) mapping speeds, along with
significant improvements over single-detector counterparts in calibration and
image quality. Receiver temperatures are 120 K across the whole band and
system temperatures of 300K are reached routinely under good weather
conditions. The system includes a single-sideband filter so these are SSB
figures. Used in conjunction with ACSIS, the system can produce large-scale
maps rapidly, in one or more frequency settings, at high spatial and spectral
resolution. Fully-sampled maps of size 1 square degree can be observed in under
1 hour.
The scientific need for array receivers arises from the requirement for
programmes to study samples of objects of statistically significant size, in
large-scale unbiased surveys of galactic and extra-galactic regions. Along with
morphological information, the new spectral imaging system can be used to study
the physical and chemical properties of regions of interest. Its
three-dimensional imaging capabilities are critical for research into
turbulence and dynamics. In addition, HARP/ACSIS will provide highly
complementary science programmes to wide-field continuum studies, and produce
the essential preparatory work for submillimetre interferometers such as the
SMA and ALMA.Comment: MNRAS Accepted 2009 July 2. 18 pages, 25 figures and 6 table
Climate-driven regime shift of a temperate marine ecosystem.
Ecosystem reconfigurations arising from climate-driven changes in species distributions are expected to have profound ecological, social, and economic implications. Here we reveal a rapid climate-driven regime shift of Australian temperate reef communities, which lost their defining kelp forests and became dominated by persistent seaweed turfs. After decades of ocean warming, extreme marine heat waves forced a 100-kilometer range contraction of extensive kelp forests and saw temperate species replaced by seaweeds, invertebrates, corals, and fishes characteristic of subtropical and tropical waters. This community-wide tropicalization fundamentally altered key ecological processes, suppressing the recovery of kelp forests
On the Whitehead spectrum of the circle
The seminal work of Waldhausen, Farrell and Jones, Igusa, and Weiss and
Williams shows that the homotopy groups in low degrees of the space of
homeomorphisms of a closed Riemannian manifold of negative sectional curvature
can be expressed as a functor of the fundamental group of the manifold. To
determine this functor, however, it remains to determine the homotopy groups of
the topological Whitehead spectrum of the circle. The cyclotomic trace of B
okstedt, Hsiang, and Madsen and a theorem of Dundas, in turn, lead to an
expression for these homotopy groups in terms of the equivariant homotopy
groups of the homotopy fiber of the map from the topological Hochschild
T-spectrum of the sphere spectrum to that of the ring of integers induced by
the Hurewicz map. We evaluate the latter homotopy groups, and hence, the
homotopy groups of the topological Whitehead spectrum of the circle in low
degrees. The result extends earlier work by Anderson and Hsiang and by Igusa
and complements recent work by Grunewald, Klein, and Macko.Comment: 52 page
Understanding the small object argument
The small object argument is a transfinite construction which, starting from
a set of maps in a category, generates a weak factorisation system on that
category. As useful as it is, the small object argument has some problematic
aspects: it possesses no universal property; it does not converge; and it does
not seem to be related to other transfinite constructions occurring in
categorical algebra. In this paper, we give an "algebraic" refinement of the
small object argument, cast in terms of Grandis and Tholen's natural weak
factorisation systems, which rectifies each of these three deficiencies.Comment: 42 pages; supersedes the earlier arXiv preprint math/0702290; v2:
final journal version, minor corrections onl
Ethnic Inequalities in Mortality: The Case of Arab-Americans
BACKGROUND: Although nearly 112 million residents of the United States belong to a non-white ethnic group, the literature about differences in health indicators across ethnic groups is limited almost exclusively to Hispanics. Features of the social experience of many ethnic groups including immigration, discrimination, and acculturation may plausibly influence mortality risk. We explored life expectancy and age-adjusted mortality risk of Arab-Americans (AAs), relative to non-Arab and non-Hispanic Whites in Michigan, the state with the largest per capita population of AAs in the US. METHODOLOGY/PRINCIPAL FINDINGS: Data were collected about all deaths to AAs and non-Arab and non-Hispanic Whites in Michigan between 1990 and 2007, and year 2000 census data were collected for population denominators. We calculated life expectancy, age-adjusted all-cause, cause-specific, and age-specific mortality rates stratified by ethnicity and gender among AAs and non-Arab and non-Hispanic Whites. Among AAs, life expectancies among men and women were 2.0 and 1.4 years lower than among non-Arab and non-Hispanic White men and women, respectively. AA men had higher mortality than non-Arab and non-Hispanic White men due to infectious diseases, chronic diseases, and homicide. AA women had higher mortality than non-Arab and non-Hispanic White women due to chronic diseases. CONCLUSIONS/SIGNIFICANCE: Despite better education and higher income, AAs have higher age-adjusted mortality risk than non-Arab and non-Hispanic Whites, particularly due to chronic diseases. Features specific to AA culture may explain some of these findings
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