bluuebunny/crossref_metadata_2025_split huggingface dataset:
Innate immunity triggers IL-32 expression by fibroblast-like synoviocytes in rheumatoid arthritis
Authors: Alsaleh Ghada , Sparsa Laetitia , Chatelus Emmanuel , Ehlinger Mathieu , Gottenberg Jacques-Eric , Wachsmann Dominique , Sibilia Jean 
Published: July 2010

Abstract
Introduction
Interleukin-32 (IL-32) is a recently described cytokine that is a strong inducer of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, IL-1β, IL-6, and IL-8. The expression of this cytokine is highly increased in the rheumatoid synovium and correlated with the severity of joint inflammation. Little is known regarding the innate immune-related regulation of IL-32 by fibroblast-like synoviocytes (FLSs). We therefore investigated the effect of innate immune stimulation by ligands of Toll-like receptor (TLR)2, TLR3, and TLR4, and cytokines such as TNF-α and interferon (IFN)-γ, on IL-32 expression by FLSs.

Methods
FLSs were isolated from patients with rheumatoid arthritis (RA) according to the ACR criteria. Quantitative RT-PCR, confocal analysis, and ELISA were performed to evaluate IL-32 mRNA induction and IL-32 release by FLSs stimulated with TLR2 (BLP), TLR3 (poly I:C), and TLR4 (lipopolysaccharide) ligands, TNF-α and IFN-γ.

Results
TLR2, -3, and -4 ligands as well as IFN-γ and TNF-α induced IL-32 β, γ and δ mRNA expression by RA FLSs. Mature IL-32 was expressed intracellularly and released by cells stimulated with the various activators. The IL-32α isoform was expressed intracellularly in response to TNF-α and poly I:C and not released in culture supernatants. Stimulation of FLS with TNF-α, BLP, lipopolysaccharide, or poly I:C concomitant with IFN-γ increased IL-32 expression compared with stimulation with IFN-γ alone.

Conclusions
IL-32 synthesis by FLSs is tightly regulated by innate immunity in rheumatoid arthritis. Thus TNF-α, IFN-γ, double-strand RNA, hyaluronic acid, or other damage-associated molecular patterns (DAMPs), highly secreted in synovial tissues of RA patients, might trigger IL-32 secretion by FLSs. IL-32 might therefore represent a relevant therapeutic target in RA.
Mammostrat®as a tool to stratify breast cancer patients at risk of recurrence during endocrine therapy
Authors: Bartlett John MS , Thomas Jeremy , Ross Douglas T , Seitz Robert S , Ring Brian Z , Beck Rodney A , Pedersen Hans Christian , Munro Alison , Kunkler Ian H , Campbell Fiona M , Jack Wilma , Kerr Gillian R , Johnstone Laura , Cameron David A , Chetty Udi 
Published: July 2010

Abstract
Introduction
Patients with early-stage breast cancer, treated with endocrine therapy, have approximately 90% 5-year disease-free survival. However, for patients at higher risk of relapse despite endocrine therapy, additional adjuvant therapy, such as chemotherapy, may be indicated. The challenge is to prospectively identify such patients. The Mammostrat® test uses five immunohistochemical markers to stratify patients on tamoxifen therapy into risk groups to inform treatment decisions. We tested the efficacy of this panel in a mixed population of cases treated in a single center with breast-conserving surgery and long-term follow-up.

Methods
Tissue microarrays from a consecutive series (1981 to 1998) of 1,812 women managed by wide local excision and postoperative radiotherapy were collected following appropriate ethical review. Of 1,390 cases stained, 197 received no adjuvant hormonal or chemotherapy, 1,044 received tamoxifen only, and 149 received a combination of hormonal therapy and chemotherapy. Median age at diagnosis was 57, 71% were postmenopausal, 23.9% were node-positive and median tumor size was 1.5 cm. Samples were stained using triplicate 0.6 mm2 tissue microarray cores, and positivity for p53, HTF9C, CEACAM5, NDRG1 and SLC7A5 was assessed. Each case was assigned a Mammostrat® risk score, and distant recurrence-free survival (DRFS), relapse-free survival (RFS) and overall survival (OS) were analyzed by marker positivity and risk score.

Results
Increased Mammostrat® scores were significantly associated with reduced DRFS, RFS and OS in estrogen receptor (ER)-positive breast cancer (P < 0.00001). In multivariate analyses the risk score was independent of conventional risk factors for DRFS, RFS and OS (P < 0.05). In node-negative, tamoxifen-treated patients, 10-year recurrence rates were 7.6 ± 1.5% in the low-risk group versus 20.0 ± 4.4% in the high-risk group. Further, exploratory analyses revealed associations with outcome in both ER-negative and untreated patients.

Conclusions
This is the fifth independent study providing evidence that Mammostrat® can act as an independent prognostic tool for ER-positive, tamoxifen-treated breast cancer. In addition, this study revealed for the first time a possible association with outcome regardless of node status and ER-negative tumors. When viewed in the context of previous results, these data provide further support for this antibody panel as an aid to patient management in early-stage breast cancer.
Stimulation of human butyrophilin 3 molecules results in negative regulation of cellular immunity
Authors: Yamashiro Hiromichi , Yoshizaki Shinji , Tadaki Toshimasa , Egawa Kohji , Seo Naohiro 
Published: July 2010

Abstract
Stimulation of butyrophilin 3 molecules by specific agonistic mAbs results in down-regulation of proliferation and cytokine secretion in CD4 and CD8 T lymphocyte subsets.
The BTN molecule consists of three subfamilies, BTN1, BTN2. and BTN3, and possesses interesting properties for biological regulation. Although the biological significance of BTN1 and BTN2 has been progressively clarified, the receptor function of BTN3 remains to be elucidated as a result of the absence of appropriate agonists. To clarify the participation of BTN3 in immune regulation, BTN3-specific mAb, referred to as 34-7 and 232-5, were generated from BTN3 gene-immunized mice. The 232-5 mAb, specific to the extracellular domain of the BTN3 molecule, stained almost all populations of human PBMCs, including T, NK, NKT, and B cells. Notably, treatment with the 232-5 mAb resulted in phosphorylation of BTN3A3 molecules, leading to attenuated proliferation and cytokine secretion by CD4+ and CD8+ T cells in a CD4+ CD25+ Treg cell-independent manner, demonstrating the agonistic property of the 232-5 mAb in BTN3-mediated negative signal transduction. The magnitude of the cell surface expression of BTN3 molecules correlated inversely with lymphocyte activity, suggesting that BTN3 molecules contribute to the maintenance of the immune system. Taken together, our findings provide new insights for the role of BTN3 as an inhibitor of excessive cellular immune responses.
Bone marrow chimeric mice reveal a role for CX3CR1 in maintenance of the monocyte-derived cell population in the olfactory neuroepithelium
Authors: Vukovic Jana , Blomster Linda V , Chinnery Holly R , Weninger Wolfgang , Jung Steffen , McMenamin Paul G , Ruitenberg Marc J 
Published: July 2010

Abstract
Definition of the heterogeneity of monocyte-derived cells in the neurogenic olfactory neuroepithelium, their turnover, and the role of CX3CR1 in this process.
Macrophages in the olfactory neuroepithelium are thought to play major roles in tissue homeostasis and repair. However, little information is available at present about possible heterogeneity of these monocyte-derived cells, their turnover rates, and the role of chemokine receptors in this process. To start addressing these issues, this study used Cx3cr1gfp mice, in which the gene sequence for eGFP was knocked into the CX3CR1 gene locus in the mutant allele. Using neuroepithelial whole-mounts from Cx3cr1gfp/+ mice, we show that eGFP+ cells of monocytic origin are distributed in a loose network throughout this tissue and can be subdivided further into two immunophenotypically distinct subsets based on MHC-II glycoprotein expression. BM chimeric mice were created using Cx3cr1gfp/+ donors to investigate turnover of macrophages (and other monocyte-derived cells) in the olfactory neuroepithelium. Our data indicate that the monocyte-derived cell population in the olfactory neuroepithelium is actively replenished by circulating monocytes and under the experimental conditions, completely turned over within 6 months. Transplantation of Cx3cr1gfp/gfp (i.e., CX3CR1-deficient) BM partially impaired the replenishment process and resulted in an overall decline of the total monocyte-derived cell number in the olfactory epithelium. Interestingly, replenishment of the CD68lowMHC-II+ subset appeared minimally affected by CX3CR1 deficiency. Taken together, the established baseline data about heterogeneity of monocyte-derived cells, their replenishment rates, and the role of CX3CR1 provide a solid basis to further examine the importance of different monocyte subsets for neuroregeneration at this unique frontier with the external environment.
Inflammatory mediators promote production of shed LRP1/CD91, which regulates cell signaling and cytokine expression by macrophages
Authors: Gorovoy Matvey , Gaultier Alban , Campana W Marie , Firestein Gary S , Gonias Steven L 
Published: July 2010

Abstract
The shed form of LRP1/CD91, which is generated at increased levels in inflammation, regulates cell-signaling and cytokine expression by macrophages.
LRP1 is a type-1 transmembrane receptor that mediates the endocytosis of diverse ligands. LRP1 β-chain proteolysis results in release of sLRP1 that is present in human plasma. In this study, we show that LPS and IFN-γ induce shedding of LRP1 from RAW 264.7 cells and BMMs in vitro. ADAM17 was principally responsible for the increase in LRP1 shedding. sLRP1 was also increased in vivo in mouse plasma following injection of LPS and in plasma from human patients with RA or SLE. sLRP1, which was purified from human plasma, and full-length LRP1, purified from mouse liver, activated cell signaling when added to cultures of RAW 264.7 cells and BMMs. Robust activation of p38 MAPK and JNK was observed. The IKK-NF-κB pathway was transiently activated. Proteins that bind to the ligand-binding clusters in LRP1 failed to inhibit sLRP1-initiated cell signaling, however an antibody that targets the sLRP1 N terminus was effective. sLRP1 induced expression of regulatory cytokines by RAW 264.7 cells, including TNF-α, MCP-1/CCL2, and IL-10. These results demonstrate that sLRP1 is generated in inflammation and may regulate inflammation by its effects on macrophage physiology.
More than a sidekick: the IL-6 family cytokine IL-11 links inflammation to cancer
Authors: Putoczki Tracy , Ernst Matthias 
Published: July 2010

Abstract
Review discusses newly emerging role for IL-11 in inflammation-associated cancers of the gastrointestinal tract.
IL-11, a member of the IL-6 family of cytokines, exerts pleiotropic activities by stimulating hemopoiesis and thrombopoiesis, regulating macrophage differentiation, and conferring mucosal protection in the intestine. These effects are mediated by a multimeric complex comprising the ligand-binding IL-11Rα and the ubiquitously expressed gp130R β-subunit, which together, trigger intracellular signaling and engagement of Stat3. In turn, activated Stat3 promotes cell survival and proliferation as well as immune responses associated with inflammatory diseases and tumor progression. IL-6 and IL-11 compete for interaction with gp130, resulting in tissue-specific functions depending on the expression patterns of their respective α-subunit receptors. Although traditionally, IL-6 has been associated with aberrant Stat3 activation and associated pathologies, here, we discuss newly emerging roles for IL-11 in linking inflammation to cancer progression. We propose that in light of the recurrence of persistent STAT3 activation and elevated IL-11 expression in inflammation-associated gastrointestinal cancers in humans, inhibition of Stat3 or pharmacologically, more amenable upstream molecules such as IL-11 may represent novel, therapeutic targets.
Genetic redirection of T cells for cancer therapy
Authors: McCaffrey Ramona L , Schwartz Justin T , Lindemann Stephen R , Moreland Jessica G , Buchan Blake W , Jones Bradley D , Allen Lee-Ann H 
Published: July 2010

Abstract
Francisella tularensis uses both pre- and post-assembly mechanisms to inhibit NADPH oxidase activity at its own phagosome and throughout infected human neutrophils.
Ft is a facultative intracellular pathogen that infects many cell types, including neutrophils. In previous work, we demonstrated that the type B Ft strain LVS disrupts NADPH oxidase activity throughout human neutrophils, but how this is achieved is incompletely defined. Here, we used several type A and type B strains to demonstrate that Ft-mediated NADPH oxidase inhibition is more complex than appreciated previously. We confirm that phagosomes containing Ft opsonized with AS exclude flavocytochrome b558 and extend previous results to show that soluble phox proteins were also affected, as indicated by diminished phosphorylation of p47phox and other PKC substrates. However, a different mechanism accounts for the ability of Ft to inhibit neutrophil activation by formyl peptides, Staphylococcus aureus, OpZ, and phorbol esters. In this case, enzyme targeting and assembly were normal, and impaired superoxide production was characterized by sustained membrane accumulation of dysfunctional NADPH oxidase complexes. A similar post-assembly inhibition mechanism also diminished the ability of anti-Ft IS to confer neutrophil activation and bacterial killing, consistent with the limited role for antibodies in host defense during tularemia. Studies of mutants that we generated in the type A Ft strain Schu S4 demonstrate that the regulatory factor fevR is essential for NADPH oxidase inhibition, whereas iglI and iglJ, candidate secretion system effectors, and the acid phosphatase acpA are not. As Ft uses multiple mechanisms to block neutrophil NADPH oxidase activity, our data strongly suggest that this is a central aspect of virulence.
Serum Cathepsin S Is Associated with Serum C-Reactive Protein and Interleukin-6 Independently of Obesity in Elderly Men
Authors: Jobs E. , Risérus U. , Ingelsson E. , Helmersson J. , Nerpin E. , Jobs M. , Sundström J. , Lind L. , Larsson A. , Basu S. , Ärnlöv J. 
Published: July 2010

Objective: Cathepsin S has been suggested provide a mechanistic link between obesity and atherosclerosis, possibly mediated via adipose tissue-derived inflammation. Previous data have shown an association between circulating cathepsin S and inflammatory markers in the obese, but to date, community-based reports are lacking. Accordingly, we aimed to investigate the association between serum levels of cathepsin S and markers of cytokine-mediated inflammation in a community-based sample, with prespecified subgroup analyses in nonobese participants.
Methods: Serum cathepsin S, C-reactive protein (CRP), and IL-6 were measured in a community-based cohort of elderly men (Uppsala Longitudinal Study of Adult Men; mean age 71 years, n = 991). CRP and IL-6 were also measured at a reexamination after 7 yr.
Results: After adjustment for age, body mass index, fasting plasma glucose, diabetes treatment, systolic blood pressure, diastolic blood pressure, hypertension treatment, serum cholesterol, serum high-density lipoprotein cholesterol, prior cardiovascular disease, smoking, and leisure time physical activity, higher cathepsin S was associated with higher CRP (regression coefficient for 1 sd increase, 0.13; 95% confidence interval 0.07–0.19; P &lt; 0.001) and higher serum IL-6 (regression coefficient for 1 sd increase, 0.08; 95% confidence interval 0.01–0.14; P = 0.02). These associations remained similar in normal-weight participants (body mass index &lt;25 kg/m2, n = 375). In longitudinal analyses, higher cathepsin S at baseline was associated with higher serum CRP and IL-6 after 7 yr.
Conclusions: These results provide additional evidence for the interplay between cathepsin S and inflammatory activity and suggest that this association is present also in normal-weight individuals in the community.
The Effect of a High-Fat Meal on Postprandial Arterial Stiffness in Men with Obesity and Type 2 Diabetes
Authors: Phillips L. K. , Peake J. M. , Zhang X. , Hickman I. J. , Kolade O. , Sacre J. W. , Huang B. E. , Simpson P. , Li S. H. , Whitehead J. P. , Sharman J. E. , Martin J. H. , Prins J. B. 
Published: July 2010

Context: Postprandial dysmetabolism is emerging as an important cardiovascular risk factor. Augmentation index (AIx) is a measure of systemic arterial stiffness and independently predicts cardiovascular outcome.
Objective: The objective of this study was to assess the effect of a standardized high-fat meal on metabolic parameters and AIx in 1) lean, 2) obese nondiabetic, and 3) subjects with type 2 diabetes mellitus (T2DM).
Design and Setting: Male subjects (lean, n = 8; obese, n = 10; and T2DM, n = 10) were studied for 6 h after a high-fat meal and water control. Glucose, insulin, triglycerides, and AIx (radial applanation tonometry) were measured serially to determine the incremental area under the curve (iAUC).
Results: AIx decreased in all three groups after a high-fat meal. A greater overall postprandial reduction in AIx was seen in lean and T2DM compared with obese subjects (iAUC, 2251 ± 1204, 2764 ± 1102, and 1187 ± 429% · min, respectively; P &lt; 0.05). The time to return to baseline AIx was significantly delayed in subjects with T2DM (297 ± 68 min) compared with lean subjects (161 ± 88 min; P &lt; 0.05). There was a significant correlation between iAUC AIx and iAUC triglycerides (r = 0.50; P &lt; 0.05).
Conclusions: Obesity is associated with an attenuated overall postprandial decrease in AIx. Subjects with T2DM have a preserved, but significantly prolonged, reduction in AIx after a high-fat meal. The correlation between AIx and triglycerides suggests that postprandial dysmetabolism may impact on vascular dynamics. The markedly different response observed in the obese subjects compared with those with T2DM was unexpected and warrants additional evaluation.
β-Catenin (CTNNB1) Promotes Preovulatory Follicular Development but Represses LH-Mediated Ovulation and Luteinization
Authors: Fan Heng-Yu , O'Connor Annalouise , Shitanaka Manami , Shimada Masayuki , Liu Zhilin , Richards JoAnne S. 
Published: July 2010

AbstractWingless-type mouse mammary tumor virus integration site family (WNT)/β-catenin (CTNNB1) pathway components are expressed in ovarian granulosa cells, direct female gonad development, and are regulated by the pituitary gonadotropins. However, the in vivo functions of CTNNB1 during preovulatory follicular development, ovulation, and luteinization remain unclear. Using a mouse model Ctnnb1(Ex3)fl/fl;Cyp19-Cre (Ctnnb1(Ex3)gc−/−), expressing dominant stable CTNNB1 in granulosa cells of small antral and preovulatory follicles, we show that CTNNB1 facilitates FSH-induced follicular growth and decreases the follicle atresia (granulosa cell apoptosis). At the molecular level, WNT signaling and FSH synergistically promote the expression of genes required for cell proliferation and estrogen biosynthesis, but decrease FOXO1, which negatively regulates proliferation and steroidogenesis. Conversely, dominant stable CTNNB1 represses LH-induced oocyte maturation, ovulation, luteinization, and progesterone biosynthesis. Specifically, granulosa cells in the Ctnnb1(Ex3)gc−/− mice showed compromised responses to the LH surge and decreased levels of the epidermal growth factor-like factors (Areg and Ereg) that in vivo and in vitro mediate LH action. One underlying mechanism by which CTNNB1 prevents LH responses is by reducing phosphorylation of cAMP-responsive element-binding protein, which is essential for the expression of Areg and Ereg. By contrast, depletion of Ctnnb1 using the Ctnnb1fl/fl;Cyp19-Cre mice did not alter FSH regulation of preovulatory follicular development or female fertility but dramatically enhanced LH induction of genes in granulosa cells in culture. Thus, CTNNB1 can enhance FSH and LH actions in antral follicles but overactivation of CTNNB1 negatively effects LH-induced ovulation and luteinization, highlighting the cell context-dependent and developmental stage-specific interactions of WNT/CTNNB1 pathway and G protein-coupled gonadotropin receptors in female fertility.
Small maximal partial spreads in classical finite polar spaces
Authors: Klein Andreas , Metsch Klaus , Storme Leo 
Published: July 2010

Abstract
We prove lower bounds on the size of small maximal partial spreads in Q
+(4n + 1, q), W(2n + 1, q), and H(2n + 1, q
2). This research on the size of smallest maximal partial spreads in classical finite polar spaces is part of a detailed study on small and large maximal partial ovoids and spreads in classical finite polar spaces, performed in [De Beule, Klein, Metsch, Storme, Des. Codes Cryptogr 47: 21–34, 2008, De Beule, Klein, Metsch, Storme, European J. Combin 29: 1280–1297, 2008].
Generalized polygons with non-discrete valuation defined by two-dimensional affine ℝ-buildings
Authors: Struyve Koen , Van Maldeghem Hendrik 
Published: July 2010

Abstract
In this paper, we show that the building at infinity of a two-dimensional affine ℝ-building is a generalized polygon endowed with a valuation satisfying some specific axioms. Specializing to the discrete case of affine buildings, this solves part of a long standing conjecture about affine buildings of type , and it reproves the results obtained mainly by the second author for types and . The techniques are completely different from the ones employed in the discrete case, but they are considerably shorter, and general (i.e., independent of the type of the two-dimensional ℝ-building).
Tropical enumerative invariants of 𝔽0 and 𝔽2
Authors: Franz Marina , Markwig Hannah 
Published: July 2010

Abstract
There is an equation relating numbers of curves on satisfying incidence conditions and numbers of curves on 𝔽2 satisfying incidence conditions. The purpose of this paper is to give a tropical proof of this equation in the case of rational curves. We use induction on the degree and two Kontsevich-type formulas for curves on 𝔽0 and on 𝔽2. The formula for 𝔽2 was not known before and is proved using tropical geometry.
The Lerch zeta function II. Analytic continuation
Authors: Lagarias Jeffrey C. , Winnie Li Wen-Ching 
Published: July 2010

Abstract.
This is the second of four papers that study algebraic
and analytic structures associated with the Lerch zeta function.
The Lerch zeta function

(
s
,
a
,
c
)

:
=

n
=
0

e

2

i
n
a

(
n
+
c
)

s

$
\zeta (s,a,c) := \sum _{n=0}^\infty \frac{e^{2 \pi in a}}{ (n+c)^{s}}
$

was introduced by Lipschitz in 1857,
and is named after Lerch, who showed in 1887 that it satisfied
a functional equation. Here we analytically continue

(
s
,
a
,
c
)

$\zeta (s, a, c)$
as a function of three complex variables.
We show that it is well-defined as a multivalued function
on the manifold

:
=

(
s
,
a
,
c
)

(

)

(

)

,

${\mathcal {M}}:= \lbrace (s, a, c) \in {\mathbb {C}}\times ( {\mathbb {C}}\setminus {\mathbb {Z}}) \times ( {\mathbb {C}}\setminus {\mathbb {Z}}) \rbrace ,$
and that
this analytic continuation becomes single-valued on the maximal abelian cover of

${\mathcal {M}}$
.
We compute the monodromy functions describing the multivalued
nature of this function on

${\mathcal {M}}$
, and determine various of
its properties.
Manifolds associated with (2)n+1$(\mathbb {Z}_2)^{n+1}$-colored regular graphs
Authors: Bao Zhiqiang , Lü Zhi 
Published: July 2010

Abstract.
In this article we describe a canonical way to expand a certain kind
of

(

2

)

n
+
1

$(\mathbb {Z}_2)^{n+1}$
-colored regular graphs into closed

n

$n$
-manifolds by adding cells determined by the edge-colorings
inductively. We show that every closed combinatorial

n

$n$
-manifold
can be obtained in this way. When

n

3

$n\le 3$
, we give simple
equivalent conditions for a colored graph to admit an expansion. In
addition, we show that if a

(

2

)

n
+
1

$(\mathbb {Z}_2)^{n+1}$
-colored regular
graph admits an

n

$n$
-skeletal expansion, then it is realizable as the
induced graph of an

(
n
+
1
)

$(n+1)$
-dimensional closed

(

2

)

n
+
1

$(\mathbb {Z}_2)^{n+1}$
-manifold.