bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protective Effect of Qnr on Agents Other than Quinolones That Target DNA Gyrase
Authors: Jacoby George A. , Corcoran Marian A. , Hooper David C. 
Published: August 2015

ABSTRACT
Qnr is a plasmid-encoded and chromosomally determined protein that protects DNA gyrase and topoisomerase IV from inhibition by quinolones. Despite its prevalence worldwide and existence prior to the discovery of quinolones, its native function is not known. Other synthetic compounds and natural products also target bacterial topoisomerases. A number were studied as molecular probes to gain insight into how Qnr acts. Qnr blocked inhibition by synthetic compounds with somewhat quinolone-like structure that target the GyrA subunit, such as the 2-pyridone ABT-719, the quinazoline-2,4-dione PD 0305970, and the spiropyrimidinetrione pyrazinyl-alkynyl-tetrahydroquinoline (PAT), indicating that Qnr is not strictly quinolone specific, but Qnr did not protect against GyrA-targeting simocyclinone D8 despite evidence that both simocyclinone D8 and Qnr affect DNA binding to gyrase. Qnr did not affect the activity of tricyclic pyrimidoindole or pyrazolopyridones, synthetic inhibitors of the GyrB subunit, or nonsynthetic GyrB inhibitors, such as coumermycin A1, novobiocin, gyramide A, or microcin B17.Thus, in this set of compounds the protective activity of Qnr was confined to those that, like quinolones, trap gyrase on DNA in cleaved complexes.
Toll-Like Receptor 9 Contributes to Defense against Acinetobacter baumannii Infection
Authors: Noto Michael J. , Boyd Kelli L. , Burns William J. , Varga Matthew G. , Peek Richard M. , Skaar Eric P. 
Published: August 2015

ABSTRACT

Acinetobacter baumannii
is a common nosocomial pathogen capable of causing severe diseases associated with significant morbidity and mortality in impaired hosts. Pattern recognition receptors, such as the Toll-like receptors (TLRs), play a key role in pathogen detection and function to alert the immune system to infection. Here, we examine the role for TLR9 signaling in response to
A. baumannii
infection. In a murine model of
A. baumannii
pneumonia, TLR9
−/−
mice exhibit significantly increased bacterial burdens in the lungs, increased extrapulmonary bacterial dissemination, and more severe lung pathology compared with those in wild-type mice. Following systemic
A. baumannii
infection, TLR9
−/−
mice have significantly increased bacterial burdens in the lungs, as well as decreased proinflammatory cytokine and chemokine production. These results demonstrate that TLR9-mediated pathogen detection is important for host defense against the opportunistic pathogen
Acinetobacter baumannii
.
Fibronectin Binding Proteins SpsD and SpsL Both Support Invasion of Canine Epithelial Cells by Staphylococcus pseudintermedius
Authors: Pietrocola Giampiero , Gianotti Valentina , Richards Amy , Nobile Giulia , Geoghegan Joan A. , Rindi Simonetta , Monk Ian R. , Bordt Andrea S. , Foster Timothy J. , Fitzgerald J. Ross , Speziale Pietro 
Published: August 2015

ABSTRACT

In this study, we investigated the cell wall-anchored fibronectin-binding proteins SpsD and SpsL from the canine commensal and pathogen
Staphylococcus pseudintermedius
for their role in promoting bacterial invasion of canine progenitor epidermal keratinocytes (CPEK). Invasion was examined by the gentamicin protection assay and fluorescence microscopy. An Δ
spsD ΔspsL
mutant of strain ED99 had a dramatically reduced capacity to invade CPEK monolayers, while no difference in the invasion level was observed with single mutants.
Lactococcus lactis
transformed with plasmids expressing SpsD and SpsL promoted invasion, showing that both proteins are important. Soluble fibronectin was required for invasion, and an RGD-containing peptide or antibodies recognizing the integrin α
5
β
1
markedly reduced invasion, suggesting an important role for the integrin in this process. Src kinase inhibitors effectively blocked internalization, suggesting a functional role for the kinase in invasion. In order to identify the minimal fibronectin-binding region of SpsD and SpsL involved in the internalization process, recombinant fragments of both proteins were produced. The SpsD
520–846
and SpsL
538–823
regions harboring the major fibronectin-binding sites inhibited
S. pseudintermedius
internalization. Finally, the effects of staphylococcal invasion on the integrity of different cell lines were examined. Because SpsD and SpsL are critical factors for adhesion and invasion, blocking these processes could provide a strategy for future approaches to treating infections.
Streptolysin S Promotes Programmed Cell Death and Enhances Inflammatory Signaling in Epithelial Keratinocytes during Group A Streptococcus Infection
Authors: Flaherty Rebecca A. , Puricelli Jessica M. , Higashi Dustin L. , Park Claudia J. , Lee Shaun W. 
Published: August 2015

ABSTRACTStreptococcus pyogenes, or group AStreptococcus(GAS), is a pathogen that causes a multitude of human diseases from pharyngitis to severe infections such as toxic shock syndrome and necrotizing fasciitis. One of the primary virulence factors produced by GAS is the peptide toxin streptolysin S (SLS). In addition to its well-recognized role as a cytolysin, recent evidence has indicated that SLS may influence host cell signaling pathways at sublytic concentrations during infection. We employed an antibody array-based approach to comprehensively identify global host cell changes in human epithelial keratinocytes in response to the SLS toxin. We identified key SLS-dependent host responses, including the initiation of specific programmed cell death and inflammatory cascades with concomitant downregulation of Akt-mediated cytoprotection. Significant signaling responses identified by our array analysis were confirmed using biochemical and protein identification methods. To further demonstrate that the observed SLS-dependent host signaling changes were mediated primarily by the secreted toxin, we designed a Transwell infection system in which direct bacterial attachment to host cells was prevented, while secreted factors were allowed access to host cells. The results using this approach were consistent with our direct infection studies and reveal that SLS is a bacterial toxin that does not require bacterial attachment to host cells for activity. In light of these findings, we propose that the production of SLS by GAS during skin infection promotes invasive outcomes by triggering programmed cell death and inflammatory cascades in host cells to breach the keratinocyte barrier for dissemination into deeper tissues.
Chitinase 3-Like 1 Promotes Candida albicans Killing and Preserves Corneal Structure and Function by Controlling Host Antifungal Responses
Authors: Gao Nan , Yu Fu-Shin X. 
Published: August 2015

ABSTRACT

Chitinase 3-like 1 (CHI3L1) has been shown to play a role in promoting antibacterial responses, decreasing tissue injury, and enhancing pulmonary repair. This study sought to elucidate the role of CHI3L1 in augmenting the corneal innate immune response to
Candida albicans
infection in an animal model of fungal keratitis. Flagellin applied topically 24 h prior to
C. albicans
inoculation significantly protected the corneal from
C. albicans
and induced CHI3L1 expression in C57BL/6 mouse corneas. CHI3L1, however, played a detectable but minor role in flagellin-induced protection. While
C. albicans
keratitis was more severe in the corneas treated with
Chi3l1
small interfering RNA (siRNA), corneas treated with recombinant CHI3L1 before
C. albicans
inoculation had markedly ameliorated keratitis, reduced fungal load, and decreased polymorphonucleocyte (PMN) infiltration in an interleukin 13 receptor α2 (IL-13Rα2)-dependent manner. CHI3L1 treatment resulted in the induction of the antimicrobial peptides β-defensin 3, CRAMP, and chemokine CXCL10 and its receptor CXCR3 in corneal epithelial cells. Importantly, CHI3L1 administered after
C. albicans
inoculation also had strong protection against fungal keratitis, suggesting a therapeutic window. This is the first report demonstrating that CHI3L1 is induced during fungal infection, where it acts as an immunomodulator to promote fungal clearance and to regulate antifungal innate immune responses in the cornea.
Even a low-dose of moderate-to-vigorous physical activity reduces mortality by 22% in adults aged ≥60 years: a systematic review and meta-analysis
Authors: Hupin David , Roche Frédéric , Gremeaux Vincent , Chatard Jean-Claude , Oriol Mathieu , Gaspoz Jean-Michel , Barthélémy Jean-Claude , Edouard Pascal 
Published: August 2015

BackgroundThe health benefits of 150 min a week of moderate-to-vigorous-intensity physical activity (MVPA) in older adults, as currently recommended, are well established, but the suggested dose in older adults is often not reached.ObjectivesWe aimed to determine whether a lower dose of MVPA was effective in reducing mortality, in participants older than 60 years.MethodsThe PubMed and Embase databases were searched from inception to February 2015. Only prospective cohorts were included. Risk ratios of death were established into four doses based on weekly Metabolic Equivalent of Task (MET)-minutes, defined as inactive (reference), low (1–499), medium (500–999) or high (≥1000). Data were pooled and analysed through a random effects model using comprehensive meta-analysis software.ResultsOf the 835 reports screened, nine cohort studies remained, totalling 122 417 participants, with a mean follow-up of 9.8±2.7 years and 18 122 reported deaths (14.8%). A low dose of MVPA resulted in a 22% reduction in mortality risk (RR=0.78 (95% CI 0.71 to 0.87) p<0.0001). MVPA beyond this threshold brought further benefits, reaching a 28% reduction in all-cause mortality in older adults who followed the current recommendations (RR=0.72 (95% CI 0.65 to 0.80) p<0.0001) and a 35% reduction beyond 1000 MET-min per week (RR=0.65 (95% CI 0.61 to 0.70) p<0.0001).ConclusionsA dose of MVPA below current recommendations reduced mortality by 22% in older adults. A further increase in physical activity dose improved these benefits in a linear fashion. Older adults should be encouraged to include even low doses of MVPA in their daily lives.
Impact of preoperative serum albumin on 30-day mortality following surgery for colorectal cancer: a population-based cohort study
Authors: Montomoli Jonathan , Erichsen Rune , Antonsen Sussie , Nilsson Tove , Sørensen Henrik Toft 
Published: August 2015

ObjectiveSurgery is the only potentially curable treatment for colorectal cancer (CRC), but it is hampered by high mortality. Human serum albumin (HSA) below 35 g/L is associated with poor overall prognosis in patients with CRC, but evidence regarding the impact on postoperative mortality is sparse.MethodsWe performed a population-based cohort study including patients undergoing CRC surgery in North and Central Denmark (1997–2011). We categorised patients according to HSA concentration measured 1–30 days prior to surgery date. We used the Kaplan-Meier method to compute 30-day mortality and Cox regression model to compute HRs as measures of the relative risk of death, controlling for potential confounders. We further stratified patients by preoperative conditions, including cancer stage, comorbidity level, and C reactive protein concentration.ResultsOf the 9339 patients undergoing first-time CRC surgery with preoperative HSA measurement, 26.4% (n=2464) had HSA below 35 g/L. 30-day mortality increased from 4.9% among patients with HSA 36–40 g/L to 26.9% among patients with HSA equal to or below 25 g/L, compared with 2.0% among patients with HSA above 40 g/L. The corresponding adjusted HRs increased from 1.75 (95% CI 1.25 to 2.45) among patients with HSA 36–40 g/L to 7.59 (95% CI 4.95 to 11.64) among patients with HSA equal to or below 25 g/L, compared with patients with HSA above 40 g/L. The negative impact associated with a decrement of HSA was found in all subgroups.ConclusionsA decrement in preoperative HSA concentration was associated with substantial concentration-dependent increased 30-day mortality following CRC surgery.
Natriuretic peptides for the detection of paroxysmal atrial fibrillation
Authors: Seegers Joachim , Zabel Markus , Grüter Timo , Ammermann Antje , Weber-Krüger Mark , Edelmann Frank , Gelbrich Götz , Binder Lutz , Herrmann-Lingen Christoph , Gröschel Klaus , Hasenfuß Gerd , Feltgen Nicolas , Pieske Burkert , Wachter Rolf 
Published: August 2015

Background and purposeSilent atrial fibrillation (AF) and tachycardia (AT) are considered precursors of ischaemic stroke. Therefore, detection of paroxysmal atrial rhythm disorders is highly relevant, but is clinically challenging. We aimed to evaluate the diagnostic value of natriuretic peptide levels in the detection of paroxysmal AT/AF in a pilot study.MethodsNatriuretic peptide levels were analysed in two independent patient cohorts (162 patients with arterial hypertension or other cardiovascular risk factors and 82 patients with retinal vessel disease). N-terminal-pro-brain natriuretic peptide (NT-proBNP) and BNP were measured before the start of a 7-day Holter monitoring period carefully screened for AT/AF.Results244 patients were included; 16 had paroxysmal AT/AF. After excluding patients with a history of AT/AF (n=5), 14 patients had newly diagnosed AT/AF (5.8%) NT-proBNP and BNP levels were higher in patients with paroxysmal AT/AF in both cohorts: (1) 154.4 (IQR 41.7; 303.6) versus 52.8 (30.4; 178.0) pg/mL and 70.0 (31.9; 142.4) versus 43.9 (16.3; 95.2) and (2) 216.9 (201.4; 277.1) versus 90.8 (42.3–141.7) and 96.0 (54.7; 108.2) versus 29.1 (12.0; 58.1). For the detection of AT/AF episodes, NT-proBNP and BNP had an area under the curve in receiver operating characteristic analysis of 0.76 (95% CI, 0.64 to 0.88; p=0.002) and 0.75 (0.61 to 0.89; p=0.004), respectively.ConclusionsNT-proBNP and BNP levels are elevated in patients with silent AT/AF as compared with sinus rhythm. Thus, screening for undiagnosed paroxysmal AF using natriuretic peptide level initiated Holter monitoring may be a useful strategy in prevention of stroke or systemic embolism.
AVHotRR: near-real time routine for volcano monitoring using IR satellite data
Authors: Lombardo Valerio 
Published: August 2015

Abstract
The AVHotRR routine has been in operation since 2006 to process satellite data for monitoring active volcanoes in the Mediterranean area. Although originally developed to work with advanced very high-resolution radiometer (AVHRR) data, AVHotRR has been developed over the years to adapt to other sensors. In this work we present an improved version of the algorithm for hot-spot detection and effusion rate estimate. The underlying principles upon which the algorithm is based are discussed, focusing on the enhancements. The currently implemented version makes it possible to integrate results from different datasets in order to better constrain the detection of volcanic hot spots. In particular, the high temporal resolution of the SEVIRI instrument aboard MSG is key to reducing false positives in AVHRR and moderate resolution imaging spectroradiometer MODIS images. We propose here a new detection method based on the wavelet transform of SEVIRI data. Results from the application of AVHotRR to a dataset of AVHRR and SEVIRI images from Mt Etna, Italy, are presented and discussed with reference to the advantages and limitations of the algorithm.
mNoC
Authors: Pang Jun , Dwyer Christopher , Lebeck Alvin R. 
Published: August 2015

Moore's law and the continuity of device scaling have led to an increasing number of cores/nodes on a chip, creating a need for new mechanisms to achieve high-performance and power-efficient Network-on-Chip (NoC). Nanophotonics based NoCs provide for higher bandwidth and more power efficient designs than electronic networks. Present approaches often use an external laser source, ring resonators, and waveguides. However, they still suffer from important limitations: large static power consumption, and limited network scalability.
In this article, we explore the use of emerging molecular scale devices to construct nanophotonic networks: Molecular-scale Network-on-Chip (mNoC). We leverage on-chip emitters such as quantum dot LEDs, which provide electrical to optical signal modulation, and chromophores, which provide optical signal filtering for receivers. These devices replace the ring resonators and the external laser source used in contemporary nanophotonic NoCs. They reduce energy consumption or enable scaling to larger crossbars for a reduced energy budget. We present a Single Writer Multiple Reader (SWMR) bus based crossbar mNoC. Our evaluation shows that an mNoC can achieve more than 88% reduction in energy for a 64×64 crossbar compared to similar ring resonator based designs. Additionally, an mNoC can scale to a 256×256 crossbar with an average 10% performance improvement and 54% energy reduction.
Ceacam1L Modulates STAT3 Signaling to Control the Proliferation of Glioblastoma-Initiating Cells
Authors: Kaneko Sadahiro , Nakatani Yuka , Takezaki Tatsuya , Hide Takuichiro , Yamashita Daisuke , Ohtsu Naoki , Ohnishi Takanori , Terasaka Shunsuke , Houkin Kiyohiro , Kondo Toru 
Published: August 2015

Abstract
Glioblastoma-initiating cells (GIC) are a tumorigenic cell subpopulation resistant to radiotherapy and chemotherapy, and are a likely source of recurrence. However, the basis through which GICs are maintained has yet to be elucidated in detail. We herein demonstrated that the carcinoembryonic antigen–related cell adhesion molecule Ceacam1L acts as a crucial factor in GIC maintenance and tumorigenesis by activating c-Src/STAT3 signaling. Furthermore, we showed that monomers of the cytoplasmic domain of Ceacam1L bound to c-Src and STAT3 and induced their phosphorylation, whereas oligomerization of this domain ablated this function. Our results suggest that Ceacam1L-dependent adhesion between GIC and surrounding cells play an essential role in GIC maintenance and proliferation, as mediated by signals transmitted by monomeric forms of the Ceacam1L cytoplasmic domain. Cancer Res; 75(19); 4224–34. ©2015 AACR.
The Distinctive Mutational Spectra of Polyomavirus-Negative Merkel Cell Carcinoma
Authors: Harms Paul William , Vats Pankaj , Verhaegen Monique Elise , Robinson Dan R. , Wu Yi-Mi , Dhanasekaran Saravana Mohan , Palanisamy Nallasivam , Siddiqui Javed , Cao Xuhong , Su Fengyun , Wang Rui , Xiao Hong , Kunju Lakshmi P. , Mehra Rohit , Tomlins Scott A. , Fullen Douglas Randall , Bichakjian Christopher Keram , Johnson Timothy M. , Dlugosz Andrzej Antoni , Chinnaiyan Arul M. 
Published: August 2015

Abstract
Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine tumor. Merkel cell polyomavirus (MCPyV) may contribute to tumorigenesis in a subset of tumors via inhibition of tumor suppressors such as retinoblastoma (RB1) by mutated viral T antigens, but the molecular pathogenesis of MCPyV-negative MCC is largely unexplored. Through our MI-ONCOSEQ precision oncology study, we performed integrative sequencing on two cases of MCPyV-negative MCC, as well as a validation cohort of 14 additional MCC cases (n = 16). In addition to previously identified mutations in TP53, RB1, and PIK3CA, we discovered activating mutations of oncogenes, including HRAS and loss-of-function mutations in PRUNE2 and NOTCH family genes in MCPyV-negative MCC. MCPyV-negative tumors also displayed high overall mutation burden (10.09 ± 2.32 mutations/Mb) and were characterized by a prominent UV-signature pattern with C &gt; T transitions comprising 85% of mutations. In contrast, mutation burden was low in MCPyV-positive tumors (0.40 ± 0.09 mutations/Mb) and lacked a UV signature. These findings suggest a potential ontologic dichotomy in MCC, characterized by either viral-dependent or UV-dependent tumorigenic pathways. Cancer Res; 75(18); 3720–7. ©2015 AACR.
Colon Cancer Growth and Dissemination Relies upon Thrombin, Stromal PAR-1, and Fibrinogen
Authors: Adams Gregory N. , Rosenfeldt Leah , Frederick Malinda , Miller Whitney , Waltz Dusty , Kombrinck Keith , McElhinney Kathryn E. , Flick Matthew J. , Monia Brett P. , Revenko Alexey S. , Palumbo Joseph S. 
Published: August 2015

Abstract
Thrombin-mediated proteolysis is a major determinant of metastasis, but is not universally important for primary tumor growth. Here, we report that colorectal adenocarcinoma represents one important exception whereby thrombin-mediated functions support both primary tumor growth and metastasis. In contrast with studies of multiple nongastrointestinal cancers, we found that the growth of primary tumors formed by murine and human colon cancer cells was reduced in mice by genetic or pharmacologic reduction of circulating prothrombin. Reduced prothrombin expression was associated with lower mitotic indices and invasion of surrounding tissue. Mechanistic investigations revealed that thrombin-driven colonic adenocarcinoma growth relied upon at least two targets of thrombin-mediated proteolysis, protease-activated receptor-1 (PAR-1) expressed by stromal cells and the extracellular matrix protein, fibrinogen. Colonic adenocarcinoma growth was reduced in PAR-1–deficient mice, implicating stromal cell-associated PAR-1 as one thrombin target important for tumor outgrowth. Furthermore, tumor growth was dramatically impeded in fibrinogen-deficient mice, offering the first direct evidence of a critical functional role for fibrinogen in malignant tumor growth. Tumors harvested from fibrinogen-deficient mice displayed a relative reduction in cell proliferative indices, as well as increased tumor necrosis and decreased tumor vascular density. Collectively, our findings established a functional role for thrombin and its targets PAR-1 and fibrinogen in the pathogenesis of colonic adenocarcinoma, supporting tumor growth as well as local invasion and metastasis. Cancer Res; 75(19); 4235–43. ©2015 AACR.
HER2 Activating Mutations Are Targets for Colorectal Cancer Treatment
Authors: Kavuri Shyam M. , Jain Naveen , Galimi Francesco , Cottino Francesca , Leto Simonetta M. , Migliardi Giorgia , Searleman Adam C. , Shen Wei , Monsey John , Trusolino Livio , Jacobs Samuel A. , Bertotti Andrea , Bose Ron 
Published: August 2015

Abstract
The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of patients with colorectal cancer. Introduction of the HER2 mutations S310F, L755S, V777L, V842I, and L866M into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation. HER2 mutants are potently inhibited by low nanomolar doses of the irreversible tyrosine kinase inhibitors neratinib and afatinib. HER2 gene sequencing of 48 cetuximab-resistant, quadruple (KRAS, NRAS, BRAF, and PIK3CA) wild-type (WT) colorectal cancer patient-derived xenografts (PDX) identified 4 PDXs with HER2 mutations. HER2-targeted therapies were tested on two PDXs. Treatment with a single HER2-targeted drug (trastuzumab, neratinib, or lapatinib) delayed tumor growth, but dual HER2-targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2-mutated PDXs.
Significance: HER2 activating mutations cause EGFR antibody resistance in colorectal cell lines, and PDXs with HER2 mutations show durable tumor regression when treated with dual HER2-targeted therapy. These data provide a strong preclinical rationale for clinical trials targeting HER2 activating mutations in metastatic colorectal cancer. Cancer Discov; 5(8); 832–41. ©2015 AACR.
See related commentary by Pectasides and Bass, p. 799.
This article is highlighted in the In This Issue feature, p. 783