bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adaptation of Iron Homeostasis Pathways by a Pseudomonas aeruginosa Pyoverdine Mutant in the Cystic Fibrosis Lung
Authors: Nguyen Angela T. , O'Neill Maura J. , Watts Annabelle M. , Robson Cynthia L. , Lamont Iain L. , Wilks Angela , Oglesby-Sherrouse Amanda G. 
Published: April 2014

ABSTRACT

Cystic fibrosis (CF) patients suffer from chronic bacterial lung infections, most notably by
Pseudomonas aeruginosa
, which persists for decades in the lungs and undergoes extensive evolution.
P. aeruginosa
requires iron for virulence and uses the fluorescent siderophore pyoverdine to scavenge and solubilize ferric iron during acute infections. Pyoverdine mutants accumulate in the lungs of some CF patients, however, suggesting that the heme and ferrous iron acquisition pathways of
P. aeruginosa
are more important in this environment. Here, we sought to determine how evolution of
P. aeruginosa
in the CF lung affects iron acquisition and regulatory pathways through the use of longitudinal CF isolates. These analyses demonstrated a significant reduction of siderophore production during the course of CF lung infection in nearly all strains tested. Mass spectrometry analysis of one of these strains showed that the later CF isolate has streamlined the metabolic flux of extracellular heme through the HemO heme oxygenase, resulting in more-efficient heme utilization. Moreover, gene expression analysis shows that iron regulation via the PrrF small RNAs (sRNAs) is enhanced in the later CF isolate. Finally, analysis of
P. aeruginosa
gene expression in the lungs of various CF patients demonstrates that both PrrF and HemO are consistently expressed in the CF lung environment. Combined, these results suggest that heme is a critical source of iron during prolonged infection of the CF lung and that changes in iron and heme regulatory pathways play a crucial role in adaptation of
P. aeruginosa
to this ever-changing host environment.
CugP Is a Novel Ubiquitous Non-GalU-Type Bacterial UDP-Glucose Pyrophosphorylase Found in Cyanobacteria
Authors: Maeda Kaisei , Narikawa Rei , Ikeuchi Masahiko 
Published: April 2014

ABSTRACT

UDP-glucose pyrophosphorylase synthesizes UDP-glucose from UTP and glucose 1-phosphate and exists in almost all species. Most bacteria possess a GalU-type UDP-glucose pyrophosphorylase, whereas many cyanobacteria species do not. In certain cyanobacteria, UDP-glucose is used as a substrate for synthesis of exopolysaccharide cellulose in spite of the absence of GalU-type UDP-glucose pyrophosphorylase. Therefore, there should be an uncharacterized UDP-glucose pyrophosphorylase in cyanobacteria. Here, we show that all cyanobacteria possess a non-GalU-type bacterial UDP-glucose pyrophosphorylase, i.e., CugP, a novel family in the nucleotide triphosphate transferase superfamily. The expressed recombinant
Synechocystis
sp. strain PCC 6803 CugP had pyrophosphorylase activity that was highly specific for UTP and glucose 1-phosphate. The fact that the CugP gene cannot be deleted completely in
Synechocystis
sp. PCC 6803 suggests its central role as the substrate supplier for galactolipid synthesis. Galactolipids are major constituents of the photosynthetic thylakoid membrane and important for photosynthetic activity. Based on phylogenetic analysis, this CugP-type UDP-glucose pyrophosphorylase may have recently been horizontally transferred to certain noncyanobacteria.
Understanding the role of embarrassment in gynaecological screening: a qualitative study from the ASPIRE cervical cancer screening project in Uganda
Authors: Teng Flora F , Mitchell Sheona M , Sekikubo Musa , Biryabarema Christine , Byamugisha Josaphat K , Steinberg Malcolm , Money Deborah M , Ogilvie Gina S 
Published: April 2014

ObjectiveTo define embarrassment and develop an understanding of the role of embarrassment in relation to cervical cancer screening and self-collected human papillomavirus (HPV) DNA testing in Uganda.DesignCross-sectional, qualitative study using semistructured one-to-one interviews and focus groups.Participants6 key-informant health workers and 16 local women, purposively sampled. Key informant inclusion criteria: Ugandan members of the project team. Focus group inclusion criteria: woman age 30–69 years, Luganda or Swahili speaking, living or working in the target Ugandan community. Exclusion criteria: unwillingness to sign informed consent.SettingPrimary and tertiary low-resource setting in Kampala, Uganda.ResultsIn Luganda, embarrassment relating to cervical cancer is described in two forms. ‘Community embarrassment’ describes discomfort based on how a person may be perceived by others. ‘Personal embarrassment’ relates to shyness or discomfort with her own genitalia. Community embarrassment was described in themes relating to place of study recruitment, amount of privacy in dwellings, personal relationship with health workers, handling of the vaginal swab and misunderstanding of HPV self-collection as HIV testing. Themes of personal embarrassment related to lack of knowledge, age and novelty of the self-collection swab. Overall, embarrassment was a barrier to screening at the outset and diminished over time through education and knowledge. Fatalism regarding cervical cancer diagnosis, worry about results and stigma associated with a cervical cancer diagnosis were other psychosocial barriers described. Overcoming psychosocial barriers to screening can include peer-to-peer education, drama and media campaigns.ConclusionsEmbarrassment and other psychosocial barriers may play a large role at the onset of a screening programme, but over time as education and knowledge increase, and the social norms around screening evolve, its role diminishes. The role of peer-to-peer education and community authorities on healthcare cannot be overlooked and can have a major impact in overcoming psychosocial and social barriers to screening.
Patient and public involvement in research and the Cancer Experiences Collaborative: benefits and challenges
Authors: Froggatt Katherine , Preston Nancy , Turner Mary , Kerr Chris 
Published: April 2014

Aims and objectivesThe involvement of patients in the design and conduct of research is increasingly promoted by policy and research bodies. The experiences of individuals who become involved in research in this way are not well understood. This study aims to describe the experiences of people's participation in patient and public involvement (PPI) in supportive and palliative care research, specifically with respect to the benefits and challenges of participation for the individuals and the broader research support structures.MethodsIn this qualitative exploratory study, semistructured interviews were undertaken with individuals who had a cancer diagnosis and were involved in a supportive and palliative care research collaborative over a period of 6 years. Recruitment was through the host university organisations involved in the research collaborative. A thematic analysis was undertaken to identify commonalities and differences across their experiences.FindingsThe eight participants in the study were highly motivated and undertook PPI in research alongside other voluntary activities. They identified a number of research and personal benefits: bringing a lay perspective into research, making a difference and personal gains. Personal gains concerned support, new knowledge and skills and greater confidence. The challenges to participation that were identified included the emotional and practical nature of the work, issues of language and identifying the difference made.ConclusionsInvolvement in supportive and palliative care research is valued by people with a cancer diagnosis, but there are ongoing issues of emotional support and good communication through the use of appropriate language in documentation.
Scaling laws for aggradation, denudation and progradation rates: the case for time-scale invariance at sediment sources and sinks
Authors: Sadler Peter M. , Jerolmack Douglas J. 
Published: April 2014

Abstract

Linear rates of sediment aggradation and fluvial incision are inverse functions of measurement interval, a generic consequence of unsteadiness in the underlying processes. This effect results from a one-dimensional approach–that is, vertical rates determined at a single location–and significantly complicates comparisons of rates at different timescales. Mass conservation imposes an important but underutilized constraint; sediment by-passing or eroded from one location must deposit somewhere else. Over the long term, sediment generation and deposition must balance. In principle, the effects of unsteadiness could be eliminated if the total volume of sediment eroded or deposited over different intervals could be measured. In practice, however, obtaining such three-dimensional data from an individual site is virtually impossible. Here, we advance from one- to two-dimensional rate data. We present two new global compilations of data: denudation rates of fluvial uplands; and lateral migration (progradation) rates of siliciclastic lowland and marine systems, from ripple to shelf-slope scale. Important new findings are: (1) upland denudation rates determined from specific sediment yield show little or no dependence of rate on time interval; (2) in the transfer zone between sediment source and sink, rates of erosion and deposition balance over all scales; and (3) progradation mirrors aggradation over all timescales. The product of progradation and aggradation is independent of timescale, implying that global sediment flux into the world’s oceans has been constant on the order of 10
0
m
2
/yr, from scales of months to tens of millions of years. Results show that global rates of denudation and accumulation are time invariant with appropriate spatial averaging; however, site-specific application remains a daunting challenge.
Accumulation of Memory Precursor CD8 T Cells in Regressing Tumors following Combination Therapy with Vaccine and Anti-PD-1 Antibody
Authors: Karyampudi Lavakumar , Lamichhane Purushottam , Scheid Adam D. , Kalli Kimberly R. , Shreeder Barath , Krempski James W. , Behrens Marshall D. , Knutson Keith L. 
Published: April 2014

Abstract
Immunosuppression in the tumor microenvironment blunts vaccine-induced immune effectors. PD-1/B7-H1 is an important inhibitory axis in the tumor microenvironment. Our goal in this study was to determine the effect of blocking this inhibitory axis during and following vaccination against breast cancer. We observed that using anti-PD-1 antibody and a multipeptide vaccine (consisting of immunogenic peptides derived from breast cancer antigens, neu, legumain, and β-catenin) as a combination therapy regimen for the treatment of breast cancer–bearing mice prolonged the vaccine-induced progression-free survival period. This prolonged survival was associated with increase in number of Tc1 and Tc2 CD8 T cells with memory precursor phenotype, CD27+IL-7RhiT-betlo, and decrease in number of PD-1+ dendritic cells (DC) in regressing tumors and enhanced antigen reactivity of tumor-infiltrating CD8 T cells. It was also observed that blockade of PD-1 on tumor DCs enhanced IL-7R expression on CD8 T cells. Taken together, our results suggest that PD-1 blockade enhances breast cancer vaccine efficacy by altering both CD8 T cell and DC components of the tumor microenvironment. Given the recent success of anti-PD-1 monotherapy, our results are encouraging for developing combination therapies for the treatment of patients with cancer in which anti-PD-1 monotherapy alone may be ineffective (i.e., PD-L1–negative tumors). Cancer Res; 74(11); 2974–85. ©2014 AACR.
P-Glycoprotein, CYP3A, and Plasma Carboxylesterase Determine Brain and Blood Disposition of the mTOR Inhibitor Everolimus (Afinitor) in Mice
Authors: Tang Seng Chuan , Sparidans Rolf W. , Cheung Ka Lei , Fukami Tatsuki , Durmus Selvi , Wagenaar Els , Yokoi Tsuyoshi , van Vlijmen Bart J.M. , Beijnen Jos H. , Schinkel Alfred H. 
Published: April 2014

Abstract
Purpose: To clarify the role of ABCB1, ABCG2, and CYP3A in blood and brain exposure of everolimus using knockout mouse models.
Experimental Design: We used wild-type, Abcb1a/1b−/−, Abcg2−/−, Abcb1a/1b;Abcg2−/−, and Cyp3a−/− mice to study everolimus oral bioavailability and brain accumulation.
Results: Following everolimus administration, brain concentrations and brain-to-liver ratios were substantially increased in Abcb1a/1b−/−and Abcb1a/1b;Abcg2−/−, but not Abcg2−/−mice. The fraction of everolimus located in the plasma compartment was highly increased in all knockout strains. In vitro, everolimus was rapidly degraded in wild-type but not knockout plasma. Carboxylesterase 1c (Ces1c), a plasma carboxylesterase gene, was highly upregulated (∼80-fold) in the liver of knockout mice relative to wild-type mice, and plasma Ces1c likely protected everolimus from degradation by binding and stabilizing it. This binding was prevented by preincubation with the carboxylesterase inhibitor BNPP. In vivo knockdown experiments confirmed the involvement of Ces1c in everolimus stabilization. Everolimus also markedly inhibited the hydrolysis of irinotecan and p-nitrophenyl acetate by mouse plasma carboxylesterase and recombinant human CES2, respectively. After correcting for carboxylesterase binding, Cyp3a−/−, but not Abcb1a/1b−/−, Abcg2−/−, or Abcb1a/1b;Abcg2−/−mice, displayed highly (&gt;5-fold) increased oral availability of everolimus.
Conclusions: Brain accumulation of everolimus was restricted by Abcb1, but not Abcg2, suggesting the use of coadministered ABCB1 inhibitors to improve brain tumor treatment. Cyp3a, but not Abcb1a/1b, restricted everolimus oral availability, underscoring drug–drug interaction risks via CYP3A. Upregulated Ces1c likely mediated the tight binding and stabilization of everolimus, causing higher plasma retention in knockout strains. This Ces upregulation might confound other pharmacologic studies. Clin Cancer Res; 20(12); 3133–45. ©2014 AACR.
CADM1 Expression and Stepwise Downregulation of CD7 Are Closely Associated with Clonal Expansion of HTLV-I–Infected Cells in Adult T-cell Leukemia/Lymphoma
Authors: Kobayashi Seiichiro , Nakano Kazumi , Watanabe Eri , Ishigaki Tomohiro , Ohno Nobuhiro , Yuji Koichiro , Oyaizu Naoki , Asanuma Satomi , Yamagishi Makoto , Yamochi Tadanori , Watanabe Nobukazu , Tojo Arinobu , Watanabe Toshiki , Uchimaru Kaoru 
Published: April 2014

AbstractPurpose: Cell adhesion molecule 1 (CADM1), initially identified as a tumor suppressor gene, has recently been reported to be ectopically expressed in primary adult T-cell leukemia–lymphoma (ATL) cells. We incorporated CADM1 into flow-cytometric analysis to reveal oncogenic mechanisms in human T-cell lymphotrophic virus type I (HTLV-I) infection by purifying cells from the intermediate stages of ATL development.Experimental Design: We isolated CADM1- and CD7-expressing peripheral blood mononuclear cells of asymptomatic carriers and ATLs using multicolor flow cytometry. Fluorescence-activated cell sorted (FACS) subpopulations were subjected to clonal expansion and gene expression analysis.Results: HTLV-I–infected cells were efficiently enriched in CADM1+ subpopulations (D, CADM1posCD7dim and N, CADM1posCD7neg). Clonally expanding cells were detected exclusively in these subpopulations in asymptomatic carriers with high proviral load, suggesting that the appearance of D and N could be a surrogate marker of progression from asymptomatic carrier to early ATL. Further disease progression was accompanied by an increase in N with a reciprocal decrease in D, indicating clonal evolution from D to N. The gene expression profiles of D and N in asymptomatic carriers showed similarities to those of indolent ATLs, suggesting that these subpopulations represent premalignant cells. This is further supported by the molecular hallmarks of ATL, that is, drastic downregulation of miR-31 and upregulation of abnormal Helios transcripts.Conclusion: The CADM1 versus CD7 plot accurately reflects disease progression in HTLV-I infection, and CADM1+ cells with downregulated CD7 in asymptomatic carriers have common properties with those in indolent ATLs. Clin Cancer Res; 20(11); 2851–61. ©2014 AACR.
Druggable Oncogene Fusions in Invasive Mucinous Lung Adenocarcinoma
Authors: Nakaoku Takashi , Tsuta Koji , Ichikawa Hitoshi , Shiraishi Kouya , Sakamoto Hiromi , Enari Masato , Furuta Koh , Shimada Yoko , Ogiwara Hideaki , Watanabe Shun-ichi , Nokihara Hiroshi , Yasuda Kazuki , Hiramoto Masaki , Nammo Takao , Ishigame Teruhide , Schetter Aaron J. , Okayama Hirokazu , Harris Curtis C. , Kim Young Hak , Mishima Michiaki , Yokota Jun , Yoshida Teruhiko , Kohno Takashi 
Published: April 2014

Abstract
Purpose: To identify druggable oncogenic fusions in invasive mucinous adenocarcinoma (IMA) of the lung, a malignant type of lung adenocarcinoma in which KRAS mutations frequently occur.
Experimental Design: From an IMA cohort of 90 cases, consisting of 56 cases (62%) with KRAS mutations and 34 cases without (38%), we conducted whole-transcriptome sequencing of 32 IMAs, including 27 cases without KRAS mutations. We used the sequencing data to identify gene fusions, and then performed functional analyses of the fusion gene products.
Results: We identified oncogenic fusions that occurred mutually exclusively with KRAS mutations: CD74-NRG1, SLC3A2-NRG1, EZR-ERBB4, TRIM24-BRAF, and KIAA1468-RET. NRG1 fusions were present in 17.6% (6/34) of KRAS-negative IMAs. The CD74-NRG1 fusion activated HER2:HER3 signaling, whereas the EZR-ERBB4 and TRIM24-BRAF fusions constitutively activated the ERBB4 and BRAF kinases, respectively. Signaling pathway activation and fusion-induced anchorage-independent growth/tumorigenicity of NIH3T3 cells expressing these fusions were suppressed by tyrosine kinase inhibitors approved for clinical use.
Conclusions: Oncogenic fusions act as driver mutations in IMAs without KRAS mutations, and thus represent promising therapeutic targets for the treatment of such IMAs. Clin Cancer Res; 20(12); 3087–93. ©2014 AACR.
TLR7 Ligand Augments GM-CSF–Initiated Antitumor Immunity through Activation of Plasmacytoid Dendritic Cells
Authors: Narusawa Megumi , Inoue Hiroyuki , Sakamoto Chika , Matsumura Yumiko , Takahashi Atsushi , Inoue Tomoko , Watanabe Ayumi , Miyamoto Shohei , Miura Yoshie , Hijikata Yasuki , Tanaka Yoshihiro , Inoue Makoto , Takayama Koichi , Okazaki Toshihiko , Hasegawa Mamoru , Nakanishi Yoichi , Tani Kenzaburo 
Published: April 2014

Abstract
Vaccination with irradiated granulocyte macrophage colony-stimulating factor (GM-CSF)–transduced autologous tumor cells (GVAX) has been shown to induce therapeutic antitumor immunity. However, its effectiveness is limited. We therefore attempted to improve the antitumor effect by identifying little-known key pathways in GM-CSF–sensitized dendritic cells (GM-DC) in tumor-draining lymph nodes (TDLN). We initially confirmed that syngeneic mice subcutaneously injected with poorly immunogenic Lewis lung carcinoma (LLC) cells transduced with Sendai virus encoding GM-CSF (LLC/SeV/GM) remarkably rejected the tumor growth. Using cDNA microarrays, we found that expression levels of type I interferon (IFN)–related genes, predominantly expressed in plasmacytoid DCs (pDC), were significantly upregulated in TDLN-derived GM-DCs and focused on pDCs. Indeed, mouse experiments demonstrated that the effective induction of GM-CSF–induced antitumor immunity observed in immunocompetent mice treated with LLC/SeV/GM cells was significantly attenuated when pDC-depleted or IFNα receptor knockout (IFNAR−/−) mice were used. Importantly, in both LLC and CT26 colon cancer–bearing mice, the combinational use of imiquimod with autologous GVAX therapy overcame the refractoriness to GVAX monotherapy accompanied by tolerability. Mechanistically, mice treated with the combined vaccination displayed increased expression levels of CD86, CD9, and Siglec-H, which correlate with an antitumor phenotype, in pDCs, but decreased the ratio of CD4+CD25+FoxP3+ regulatory T cells in TDLNs. Collectively, these findings indicate that the additional use of imiquimod to activate pDCs with type I IFN production, as a positive regulator of T-cell priming, could enhance the immunologic antitumor effects of GVAX therapy, shedding promising light on the understanding and treatment of GM-CSF–based cancer immunotherapy. Cancer Immunol Res; 2(6); 568–80. ©2014 AACR.
Early Results of Massachusetts Healthcare Reform on Racial, Ethnic, and Socioeconomic Disparities in Cardiovascular Care
Authors: Albert Michelle A. , Ayanian John Z. , Silbaugh Treacy S. , Lovett Ann , Resnic Fred , Jacobs Aryana , Normand Sharon-Lise T. 
Published: April 2014

Background—
Insured adults receive invasive cardiovascular procedures more frequently than uninsured adults. We examined the impact of healthcare reform in Massachusetts on use of coronary revascularization procedures and in-hospital and 1-year mortality by race/ethnicity, education, and sex.

Methods and Results—
Using hospital claims data, we compared differences in coronary revascularization rates (coronary artery bypass grafting or percutaneous coronary intervention) and in-hospital mortality by race/ethnicity, education, and sex among Massachusetts residents aged 21 to 64 years hospitalized with a principal discharge diagnosis of ischemic heart disease before (November 1, 2004, to July 31, 2006) and after (December 1, 2006, to September 30, 2008) reform; 1-year mortality was calculated for those undergoing revascularization. Adjusted logistic regression assessed 24 216 discharges before reform and 20 721 discharges after reform. Blacks had 30% lower odds of receiving coronary revascularization than whites in the prereform period. Compared with whites in the postreform period, blacks (odds ratio=0.73; 95% confidence interval, 0.63–0.84) and Hispanics (odds ratio= 0.84; 95% confidence interval, 0.74–0.97) were less likely and Asians (odds ratio=1.29; 95% confidence interval, 1.01–1.65) were more likely to receive coronary revascularization. Patients living in more educated communities, men, and persons with private insurance were more likely to receive coronary revascularization before and after reform. Compared with the prereform period, the adjusted odds of in-hospital mortality were higher in patients living in less-educated communities in the postreform period. No differences in 1-year mortality by race/ethnicity, education, or sex for revascularized patients were observed before or after reform.

Conclusions—
Reducing insurance barriers to receipt of coronary revascularization procedures has not yet eliminated preexisting demographic and educational disparities in access to these procedures.
Contact and Compromise
Authors: Pickett Justin T. , Baker Thomas , Metcalfe Christi , Gertz Marc , Bellandi Rose 
Published: April 2014

Objectives: Informed by intergroup contact theory, this study explores the relationships between intergroup contact, perceived out-group threat, and support for conciliatory solutions to the violent conflict between Israeli Jews and Palestinians in Israel and the Palestinian territories. Methods: Regression and structural equation models analyze public opinion data collected in Israel in 2011 and 2012. The analyses assess whether quantity and quality of Israeli Jews’ contact with Israeli Arabs in day-to-day encounters are associated with their support for conciliatory policies. Results: The quality, but not the quantity, of contact is associated with lower levels of perceived Palestinian threat and, in turn, with increased support for compromise. Conclusion: The current study provides initial evidence that everyday interactions with Israeli Arabs, when they occur under optimal conditions, may have the potential to reduce Israeli Jews’ perceptions of Palestinian threat and, in turn, increase their support for compromise.