bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered Innate Defenses in the Neonatal Gastrointestinal Tract in Response to Colonization by Neuropathogenic Escherichia coli
Authors: Birchenough George M. H. , Johansson Malin E. V. , Stabler Richard A. , Dalgakiran Fatma , Hansson Gunnar C. , Wren Brendan W. , Luzio J. Paul , Taylor Peter W. 
Published: June 2013

ABSTRACT

Two-day-old (P2), but not 9-day-old (P9), rat pups are susceptible to systemic infection following gastrointestinal colonization by
Escherichia coli
K1. Age dependency reflects the capacity of colonizing K1 to translocate from gastrointestinal (GI) tract to blood. A complex GI microbiota developed by P2, showed little variation over P2 to P9, and did not prevent stable K1 colonization. Substantial developmental expression was observed over P2 to P9, including upregulation of genes encoding components of the small intestinal (α-defensins Defa24 and Defa-rs1) and colonic (trefoil factor Tff2) mucus barrier. K1 colonization modulated expression of these peptides: developmental expression of Tff2 was dysregulated in P2 tissues and was accompanied by a decrease in mucin Muc2. Conversely, α-defensin genes were upregulated in P9 tissues. We propose that incomplete development of the mucus barrier during early neonatal life and the capacity of colonizing K1 to interfere with mucus barrier maturation provide opportunities for neuropathogen translocation into the bloodstream.
Staphopains Modulate Staphylococcus aureus Biofilm Integrity
Authors: Mootz Joe M. , Malone Cheryl L. , Shaw Lindsey N. , Horswill Alexander R. 
Published: June 2013

ABSTRACT

Staphylococcus aureus
is a known cause of chronic biofilm infections that can reside on medical implants or host tissue. Recent studies have demonstrated an important role for proteinaceous material in the biofilm structure. The
S. aureus
genome encodes many secreted proteases, and there is growing evidence that these enzymes have self-cleavage properties that alter biofilm integrity. However, the specific contribution of each protease and mechanism of biofilm modulation is not clear. To address this issue, we utilized a sigma factor B (Δ
sigB
) mutant where protease activity results in a biofilm-negative phenotype, thereby creating a condition where the protease(s) responsible for the phenotype could be identified. Using a plasma-coated microtiter assay, biofilm formation was restored to the Δ
sigB
mutant through the addition of the cysteine protease inhibitor E-64 or by using Staphostatin inhibitors that specifically target the extracellular cysteine proteases SspB and ScpA (called Staphopains). Through construction of gene deletion mutants, we determined that an
sspB scpA
double mutant restored Δ
sigB
biofilm formation, and this recovery could be replicated in plasma-coated flow cell biofilms. Staphopain levels were also found to be decreased under biofilm-forming conditions, possibly allowing biofilm establishment. The treatment of
S. aureus
biofilms with purified SspB or ScpA enzyme inhibited their formation, and ScpA was also able to disperse an established biofilm. The antibiofilm properties of ScpA were conserved across
S. aureus
strain lineages. These findings suggest an underappreciated role of the SspB and ScpA cysteine proteases in modulating
S. aureus
biofilm architecture.
Promotion of Colonization and Virulence by Cholera Toxin Is Dependent on Neutrophils
Authors: Queen Jessica , Satchell Karla J. F. 
Published: June 2013

ABSTRACTThe innate immune response toVibrio choleraeinfection is poorly understood, but this knowledge is critical for the design of safe, effective vaccines. Using an adult mouse intestinal infection model, this study examines the contribution of neutrophils to host immunity, as well as the effect of cholera toxin and other secreted factors on this response. Depletion of neutrophils from mice with anti-Ly6G IA8 monoclonal antibody led to similar survival rates of mice infected with low or moderate doses of toxigenicV. choleraeEl Tor O1. At a high dose, neutropenic mice showed increased rates of survival compared to neutrophil-replete animals. Expression of cholera toxin was found to be protective to the neutropenic host, and this phenotype can be replicated by the administration of purified toxin. Neutrophils do not effectively clear colonizing bacteria from the small intestine, nor do they alter induction of early immune-modulating signals. In both neutropenic and neutrophil-replete animals, the local response to infection is characterized by expression of interleukin 6 (IL-6), IL-10, and macrophage inflammatory protein 2 alpha (MIP-2). Overall, these data indicate that the innate immune response to toxigenicV. choleraeinfection differs dramatically from the host response to nontoxigenic infection or vaccination, where neutrophils are protective to the host. In the absence of neutrophils, cholera toxin induces immunomodulatory effects that increase host survival. In cholera toxin-producing strains, similar to nontoxigenic infection, accessory toxins are critical to virulence, indicating that cholera toxin and the other secreted toxins modulate the host response by different mechanisms, with both contributing to bacterial persistence and virulence.
Immunization with the Yersiniabactin Receptor, FyuA, Protects against Pyelonephritis in a Murine Model of Urinary Tract Infection
Authors: Brumbaugh Ariel R. , Smith Sara N. , Mobley Harry L. T. 
Published: June 2013

ABSTRACT

Urinary tract infections (UTI) are common and represent a substantial economic and public health burden. Roughly 80% of these infections are caused by a heterogeneous group of uropathogenic
Escherichia coli
(UPEC) strains. Antibiotics are standard therapy for UTI, but a rise in antibiotic resistance has complicated treatment, making the development of a UTI vaccine more urgent. Iron receptors are a promising new class of vaccine targets for UTI, as UPEC require iron to colonize the iron-limited host urinary tract and genes encoding iron acquisition systems are highly expressed during infection. Previously, three of six UPEC siderophore and heme receptors were identified as vaccine candidates by intranasal immunization in a murine model of ascending UTI. To complete the assessment of iron receptors as vaccine candidates, an additional six UPEC iron receptors were evaluated. Of the six vaccine candidates tested in this study (FyuA, FitA, IroN, the gene product of the CFT073 locus
c0294
, and two truncated derivatives of ChuA), only FyuA provided significant protection (
P
= 0.0018) against UPEC colonization. Intranasal immunization induced a robust and long-lived humoral immune response. In addition, the levels of FyuA-specific serum IgG correlated with bacterial loads in the kidneys [Spearman's rank correlation coefficient ρ(14) = −0.72,
P
= 0.0018], providing a surrogate of protection. FyuA is the fourth UPEC iron receptor to be identified from our screens, in addition to IutA, Hma, and IreA, which were previously demonstrated to elicit protection against UPEC challenge. Together, these iron receptor antigens will facilitate the development of a broadly protective, multivalent UTI vaccine to effectively target diverse strains of UPEC.
Adjuvant Activity of Naturally Occurring Monophosphoryl Lipopolysaccharide Preparations from Mucosa-Associated Bacteria
Authors: Chilton Paula M. , Hadel Diana M. , To Thao T. , Mitchell Thomas C. , Darveau Richard P. 
Published: June 2013

ABSTRACTNatural heterogeneity in the structure of the lipid A portion of lipopolysaccharide (LPS) produces differential effects on the innate immune response. Gram-negative bacterial species produce LPS structures that differ from the classic endotoxic LPS structures. These differences include hypoacylation and hypophosphorylation of the diglucosamine backbone, both differences known to decrease LPS toxicity. The effect of decreased toxicity on the adjuvant properties of many of these LPS structures has not been fully explored. Here we demonstrate that two naturally produced forms of monophosphorylated LPS, from the mucosa-associated bacteriaBacteroides thetaiotaomicronandPrevotella intermedia, function as immunological adjuvants for antigen-specific immune responses. Each form of mucosal LPS increased vaccination-initiated antigen-specific antibody titers in both quantity and quality when given simultaneously with vaccine antigen preparations. Interestingly, adjuvant effects on initial T cell clonal expansion were selective for CD4 T cells. No significant increase in CD8 T cell expansion was detected. MyD88/Toll-like receptor 4 (TLR4) and TRIF/TLR4 signaling pathways showed equally decreased signaling with the LPS forms studied here as with endotoxic LPS or detoxified monophosphorylated lipid A (MPLA). Natural monophosphorylated LPS from mucosa-associated bacteria functions as a weak but effective adjuvant for specific immune responses, with preferential effects on antibody and CD4 T cell responses over CD8 T cell responses.
Gender inequalities in the promptness of diagnosis of bladder and renal cancer after symptomatic presentation: evidence from secondary analysis of an English primary care audit survey
Authors: Lyratzopoulos Georgios , Abel Gary A , McPhail Sean , Neal Richard D , Rubin Gregory P 
Published: June 2013

ObjectivesTo explore whether women experience greater delays in the diagnosis of bladder and renal cancer when first presenting to a general practitioner with symptoms caused by those cancers and potential reasons for such gender inequalities.DesignProspective national audit survey of cancer diagnosis.SettingEnglish primary care (2009–2010).Participants920 patients with bladder and 398 patients with renal cancer (252 (27%) and 165 (42%), respectively, were women).Primary and secondary outcome measuresProportion of patients with three or more pre-referral consultations; number of days from first presentation to referral; proportion of patients who presented with haematuria and proportion of patients investigated in primary care.ResultsWomen required three or more prereferral consultations more often than men (27% (95% CI 21% to 33%) vs 11% (9% to 14%) for bladder (p<0.001); and 30% (22% to 39%) vs 18% (13% to 25%) for renal cancer (p=0.025)) and had a greater number of days from presentation to referral. In multivariable analysis (adjusting for age, haematuria status and use of primary care-led investigations), being a woman was independently associated with higher odds of three or more pre-referral consultations (OR=3.29 (2.06 to 5.25, p<0.001) for bladder cancer; and OR=1.90 (1.06 to 3.42, p=0.031) for renal cancer). Although presentation with haematuria was associated with more timely diagnosis of bladder cancer, gender inequalities did not vary by haematuria status for either cancer (p=0.18 for bladder and p=0.27 for renal). Each year in the UK, approximately 700 women with either bladder or renal cancer experience a delayed diagnosis because of their gender, of whom more than a quarter (197, or 28%) present with haematuria.ConclusionsThere are notable gender inequalities in the timeliness of diagnosis of urological cancers. There is a need to both reinforce existing guidelines on haematuria investigation and develop new diagnostic decision aids and tests for patients who present without haematuria.
Sparse Euclidean Spanners with Tiny Diameter
Authors: Solomon Shay 
Published: June 2013

In STOC’95, Arya et al. [1995] showed that for any set of
n
points in R
d
, a (1 +
ε
)-spanner with diameter at most 2 (respectively, 3) and
O
(
n
log
n
) edges (respectively,
O
(
n
log log
n
) edges) can be built in
O
(
n
log
n
) time. Moreover, it was shown in Arya et al. [1995] and Narasimhan and Smid [2007] that for any
k
≥ 4, one can build in
O
(
n
(log
n
)2
k
α
k
(
n
)) time a (1 +
ε
)-spanner with diameter at most 2
k
and
O
(
n
2
k
α
k
(
n
)) edges. The function
α
k
is the inverse of a certain function at the
k
/2 th level of the primitive recursive hierarchy, where
α
0
(
n
) =
n
/2 ,
α
1
(
n
) = √
n
,
α
2
(
n
) = log
n
,
α
3
(
n
) = log log
n
,
α
4
(
n
) = log*
n
,
α
5
(
n
) = 12 log*
n
, ..., etc. It is also known [Narasimhan and Smid 2007] that if one allows quadratic time, then these bounds can be improved. Specifically, for any
k
≥ 4, a (1 +
ε
)-spanner with diameter at most
k
and
O
(
nkα
k
(
n
)) edges can be constructed in
O
(
n
2
) time [Narasimhan and Smid 2007].

A major open question in this area is whether one can construct within time
O
(
n
log
n
+
nkα
k
(
n
)) a (1 +
ε
)-spanner with diameter at most
k
and
O
(
nkα
k
(
n
)) edges. In this article, we answer this question in the affirmative. Moreover, in fact, we provide a stronger result. Specifically, we show that for any
k
≥ 4, a (1 +
ε
)-spanner with diameter at most
k
and
O
(
nα
k
(
n
)) edges can be built in optimal time
O
(
n
log
n
).
A Sequence Polymorphism in miR-608 Predicts Recurrence after Radiotherapy for Nasopharyngeal Carcinoma
Authors: Zheng Jian , Deng Jieqiong , Xiao Mang , Yang Lei , Zhang Liyuan , You Yonghe , Hu Min , Li Na , Wu Hongchun , Li Wei , Lu Jiachun , Zhou Yifeng 
Published: June 2013

Abstract
Nasopharyngeal carcinoma is treated with radiotherapy and other modalities, but there is little information on individual genetic factors to help predict and improve patient outcomes. Single-nucleotide polymorphisms (SNP) in mature microRNA (miRNA) sequences have the potential to exert broad impact as miRNAs target many mRNAs. The aim of this study was to evaluate the effects of SNPs in mature miRNA sequences on clinical outcome in patients with nasopharyngeal carcinoma receiving radiotherapy. In particular, we analyzed associations between seven SNPs and nasopharyngeal carcinoma locoregional recurrence (LRR) in 837 patients from eastern China, validating the findings in an additional 828 patients from southern China. We found that miR-608 rs4919510C&gt;G exhibited a consistent association with LRR in the discovery set [HR, 2.05; 95% confidence interval (CI), 1.35–3.21], the validation set (HR, 2.24; 95% CI, 1.45–3.38), and the combined dataset (HR, 2.08; 95% CI, 1.41–3.26). Biochemical investigations showed that rs4919510C&gt;G affects expression of miR-608 target genes along with nasopharyngeal carcinoma cell growth after irradiation in vivo and in vitro. Notably, X-ray radiation induced more chromatid breaks in lymphocyte cells from rs4919510CC carriers than in those from subjects with other genotypes (P = 0.0024). Our findings reveal rs4919510C&gt;G in miR-608 as a simple marker to predict LRR in patients with radiotherapy-treated nasopharyngeal carcinoma. Cancer Res; 73(16); 5151–62. ©2013 AACR.
Colorectal Cancer Screening with Blood-Based Biomarkers: Cost-Effectiveness of Methylated Septin 9 DNA versus Current Strategies
Authors: Ladabaum Uri , Allen John , Wandell Michael , Ramsey Scott 
Published: June 2013

Abstract
Background: Screening reduces colorectal cancer mortality, but many persons remain unscreened. Screening with a blood test could improve screening rates. We estimated the comparative effectiveness and cost-effectiveness of colorectal cancer screening with emerging biomarkers, illustrated by a methylated Septin 9 DNA plasma assay (mSEPT9), versus established strategies.
Methods: We conducted a cost-utility analysis using a validated decision analytic model comparing mSEPT9, fecal occult blood testing (FOBT), fecal immunochemical testing (FIT), sigmoidoscopy, and colonoscopy, projecting lifetime benefits and costs.
Results: In the base case, mSEPT9 decreased colorectal cancer incidence by 35% to 41% and colorectal cancer mortality by 53% to 61% at costs of $8,400 to $11,500/quality-adjusted life year gained versus no screening. All established screening strategies were more effective than mSEPT9. FIT was cost saving, dominated mSEPT9, and was preferred among all the alternatives. Screening uptake and longitudinal adherence rates over time strongly influenced the comparisons between strategies. At the population level, mSEPT9 yielded incremental benefit at acceptable costs when it increased the fraction of the population screened more than it was substituted for other strategies.
Conclusions: m SEPT9 seems to be effective and cost-effective compared with no screening. To be cost-effective compared with established strategies, mSEPT9 or blood-based biomarkers with similar test performance characteristics would need to achieve substantially higher uptake and adherence rates than the alternatives. It remains to be proven whether colorectal cancer screening with a blood test can improve screening uptake or long-term adherence compared with established strategies.
Impact: Our study offers insights into the potential role of colorectal cancer screening with blood-based biomarkers. Cancer Epidemiol Biomarkers Prev; 22(9); 1567–76. ©2013 AACR.
Molecular Pathways: YAP and TAZ Take Center Stage in Organ Growth and Tumorigenesis
Authors: Piccolo Stefano , Cordenonsi Michelangelo , Dupont Sirio 
Published: June 2013

Abstract
The evolution of a solid tumor is fueled by genetic aberrations. Yet, the tumor environment often dominates over the effects of genetics: normal tissues have powerful tumor-suppressive properties that constantly tame or eliminate cells carrying transforming mutations. Critical elements of such a suppressive microenvironment are structural characteristics of normal cells and tissues, such as cell polarity, attachment to the extracellular matrix (ECM), and epithelial organization. Once these tissue-level checkpoints have been overcome, tumor growth is enhanced by recruitment of stromal cells and remodeling of the ECM. Genetic inactivation in mouse models indicates the Hippo pathway as a fundamental inhibitor of organ growth during development and as a critical tumor suppressor in epithelial tissues, such as the liver, skin, and ovaries, and soft tissues. At the centerpiece of this pathway lie two related transcriptional coactivators, YAP and TAZ, that promote tissue proliferation and the self-renewal of normal and cancer stem cells, and incite metastasis. Strikingly, YAP and TAZ are controlled by the same architectural features that first inhibit and then foster cancer growth, such as ECM elasticity, cell shape, and epithelial-to-mesenchymal transition. These findings open unexpected opportunities for the development of new cancer therapeutics targeting key YAP/TAZ regulatory inputs such as Wnt signaling, cytoskeletal contractility, G-protein–coupled receptors, or YAP/TAZ-regulated transcription. Clin Cancer Res; 19(18); 4925–30. ©2013 AACR.
Identification of Circulating MicroRNA Signatures for Breast Cancer Detection
Authors: Chan Maurice , Liaw Chiew Suan , Ji Shen Mo , Tan Hwee Huang , Wong Chow Yin , Thike Aye Aye , Tan Puay Hoon , Ho Gay Hui , Lee Ann Siew-Gek 
Published: June 2013

Abstract
Purpose: There is a quest for novel noninvasive diagnostic markers for the detection of breast cancer. The goal of this study is to identify circulating microRNA (miRNA) signatures using a cohort of Asian Chinese patients with breast cancer, and to compare miRNA profiles between tumor and serum samples.
Experimental Design: miRNA from paired breast cancer tumors, normal tissue, and serum samples derived from 32 patients were comprehensively profiled using microarrays or locked nucleic acid real-time PCR panels. Serum samples from healthy individuals (n = 22) were also used as normal controls. Significant serum miRNAs, identified by logistic regression, were validated in an independent set of serum samples from patients (n = 132) and healthy controls (n = 101).
Results: The 20 most significant miRNAs differentially expressed in breast cancer tumors included miRNA (miR)-21, miR-10b, and miR-145, previously shown to be dysregulated in breast cancer. Only 7 miRNAs were overexpressed in both tumors and serum, suggesting that miRNAs may be released into the serum selectively. Interestingly, 16 of the 20 most significant miRNAs differentially expressed in serum samples were novel. MiR-1, miR-92a, miR-133a, and miR-133b were identified as the most important diagnostic markers, and were successfully validated; receiver operating characteristic curves derived from combinations of these miRNAs exhibited areas under the curves of 0.90 to 0.91.
Conclusion: The clinical use of miRNA signatures as a noninvasive diagnostic strategy is promising, but should be further validated for different subtypes of breast cancers. Clin Cancer Res; 19(16); 4477–87. ©2013 AACR.
Oncogenic Isocitrate Dehydrogenase Mutations: Mechanisms, Models, and Clinical Opportunities
Authors: Cairns Rob A. , Mak Tak W. 
Published: June 2013

Abstract
Heterozygous mutations in catalytic arginine residues of isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are common in glioma, acute myeloid leukemia, chondrosarcoma, cholangiocarcinoma, and angioimmunoblastic T-cell lymphoma. The mutant enzymes acquire a neomorphic activity that converts α-ketoglutarate (α-KG) to D-2-hydroxyglutarate (D2HG), a rare metabolite. In cells and tissues expressing mutant IDH, D2HG concentrations are highly elevated. D2HG may act as an “oncometabolite” by inhibiting a class of α-KG–dependent enzymes involved in epigenetic regulation, collagen synthesis, and cell signaling. Knock-in mouse models of IDH1 mutations have shed light on these mechanisms and will provide valuable animal models for further investigation.
Significance: Mutations in IDH1 and IDH2 promote the development of a number of malignancies. These active site mutations cause a gain-of-function leading to the accumulation of the rare metabolite D2HG. Mouse models of these mutations should provide insights into the mechanisms driving tumorigenesis and facilitate evaluation of new treatments. Cancer Discov; 3(7); 730–41. ©2013 AACR.
Right Ventricular Dysfunction in Systemic Sclerosis–Associated Pulmonary Arterial Hypertension
Authors: Tedford Ryan J. , Mudd James O. , Girgis Reda E. , Mathai Stephen C. , Zaiman Ari L. , Housten-Harris Traci , Boyce Danielle , Kelemen Benjamin W. , Bacher Anita C. , Shah Ami A. , Hummers Laura K. , Wigley Fredrick M. , Russell Stuart D. , Saggar Rajeev , Saggar Rajan , Maughan W. Lowell , Hassoun Paul M. , Kass David A. 
Published: June 2013

Background—
Systemic sclerosis–associated pulmonary artery hypertension (SScPAH) has a worse prognosis compared with idiopathic pulmonary arterial hypertension (IPAH), with a median survival of 3 years after diagnosis often caused by right ventricular (RV) failure. We tested whether SScPAH or systemic sclerosis–related pulmonary hypertension with interstitial lung disease imposes a greater pulmonary vascular load than IPAH and leads to worse RV contractile function.

Methods and Results—

We analyzed pulmonary artery pressures and mean flow in 282 patients with pulmonary hypertension (166 SScPAH, 49 systemic sclerosis–related pulmonary hypertension with interstitial lung disease, and 67 IPAH). An inverse relation between pulmonary resistance and compliance was similar for all 3 groups, with a near constant resistance×compliance product. RV pressure–volume loops were measured in a subset, IPAH (n=5) and SScPAH (n=7), as well as SSc without PH (n=7) to derive contractile indexes (end-systolic elastance [E
es
] and preload recruitable stroke work [M
sw
]), measures of RV load (arterial elastance [E
a
]), and RV pulmonary artery coupling (E
es
/E
a
). RV afterload was similar in SScPAH and IPAH (pulmonary vascular resistance=7.0±4.5 versus 7.9±4.3 Wood units; E
a
=0.9±0.4 versus 1.2±0.5 mm Hg/mL; pulmonary arterial compliance=2.4±1.5 versus 1.7±1.1 mL/mm Hg;
P
>0.3 for each). Although SScPAH did not have greater vascular stiffening compared with IPAH, RV contractility was more depressed (E
es
=0.8±0.3 versus 2.3±1.1,
P
<0.01; M
sw
=21±11 versus 45±16,
P
=0.01), with differential RV-PA uncoupling (E
es
/E
a
=1.0±0.5 versus 2.1±1.0;
P
=0.03). This ratio was higher in SSc without PH (E
es
/E
a
=2.3±1.2;
P
=0.02 versus SScPAH).

Conclusions—
RV dysfunction is worse in SScPAH compared with IPAH at similar afterload, and may be because of intrinsic systolic function rather than enhanced pulmonary vascular resistive and pulsatile loading.