bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two Novel Calcium-Dependent Protein Kinase 1 Inhibitors Interfere with Vertical Transmission in Mice Infected with Neospora caninum Tachyzoites
Authors: Müller Joachim , Aguado-Martínez Adriana , Balmer Vreni , Maly Dustin J. , Fan Erkang , Ortega-Mora Luis-Miguel , Ojo Kayode K. , Van Voorhis Wesley C. , Hemphill Andrew 
Published: January 2017

ABSTRACT

We present the effects of two novel bumped kinase inhibitors, BKI-1517 and BKI-1553, against
Neospora caninum
tachyzoites
in vitro
and in experimentally infected pregnant mice. These compounds inhibited tachyzoite proliferation of a transgenic beta-galactosidase reporter strain cultured in human foreskin fibroblasts with 50% inhibitory concentrations (IC
50
s) of 0.05 ± 0.03 and 0.18 ± 0.03 μM, respectively. As assessed by an alamarBlue assay, fibroblast IC
50
s were above 20 μM; however, morphological changes occurred in cultures treated with >5 μM BKI-1517 after prolonged exposure (>6 days). Treatment of intracellular tachyzoites with 5 μM BKI-1553 for 6 days inhibited endodyogeny by interfering with the separation of newly formed zoites from a larger multinucleated parasite mass. In contrast, parasites treated with 5 μM BKI-1517 did not form large complexes and showed much more evidence of cell death. However, after a treatment duration of 10 days
in vitro
, both compounds failed to completely prevent the regrowth of parasites from culture. BALB/c mice experimentally infected with
N. caninum
Spain7 (Nc-Spain7) and then treated during 6 days with BKI-1517 or BKI-1553 at different dosages showed a significant reduction of the cerebral parasite load. However, fertility was impaired by BKI-1517 when applied at 50 mg/kg of body weight/day. At 20 mg/kg/day, BKI-1517 significantly inhibited the vertical transmission of
N. caninum
to pups and increased the rate of survival of offspring. BKI-1553 was less detrimental to fertility and also provided significant but clearly less pronounced protection of dams and offspring. These results demonstrate that, when judiciously applied, this compound class protects offspring from vertical transmission and disease.
The Carbapenemase-Producing Klebsiella pneumoniae Population Is Distinct and More Clonal than the Carbapenem-Susceptible Population
Authors: Esteban-Cantos Andrés , Aracil Belén , Bautista Verónica , Ortega Adriana , Lara Noelia , Saez David , Fernández-Romero Sara , Pérez-Vázquez María , Navarro Ferran , Grundmann Hajo , Campos José , Oteo Jesús ,   the EuSCAPE-Spain Network
Published: January 2017

ABSTRACT

We studied in parallel the population structure of 90 carbapenemase-producing and 88 carbapenemase-susceptible
Klebsiella pneumoniae
isolates collected in 20 Spanish hospitals, in the context of the EuSCAPE project. Fourteen and 50 multilocus sequence types (MLSTs) were detected among the carbapenemase-producing and carbapenem-susceptible isolates, respectively. ST11 and ST15 clones were more frequent in the carbapenemase-producing group than in the carbapenemase-susceptible group (
P
< 0.0001). Among the members of the carbapenem-suceptible group, the cefotaxime-resistant population showed population parameters that differed between the populations of the wild-type strains and the carbapenemase producers.
Structure and Function of the PiuA and PirA Siderophore-Drug Receptors from Pseudomonas aeruginosa and Acinetobacter baumannii
Authors: Moynié Lucile , Luscher Alexandre , Rolo Dora , Pletzer Daniel , Tortajada Antoni , Weingart Helge , Braun Yvonne , Page Malcolm G. P. , Naismith James H. , Köhler Thilo 
Published: January 2017

ABSTRACT

The outer membrane of Gram-negative bacteria presents an efficient barrier to the permeation of antimicrobial molecules. One strategy pursued to circumvent this obstacle is to hijack transport systems for essential nutrients, such as iron. BAL30072 and MC-1 are two monobactams conjugated to a dihydroxypyridone siderophore that are active against
Pseudomonas aeruginosa
and
Acinetobacter baumannii
. Here, we investigated the mechanism of action of these molecules in
A. baumannii
. We identified two novel TonB-dependent receptors, termed
Ab
-PiuA and
Ab
-PirA, that are required for the antimicrobial activity of both agents. Deletion of either
piuA
or
pirA
in
A. baumannii
resulted in 4- to 8-fold-decreased susceptibility, while their overexpression in the heterologous host
P. aeruginosa
increased susceptibility to the two siderophore-drug conjugates by 4- to 32-fold. The crystal structures of PiuA and PirA from
A. baumannii
and their orthologues from
P. aeruginosa
were determined. The structures revealed similar architectures; however, structural differences between PirA and PiuA point to potential differences between their cognate siderophore ligands. Spontaneous mutants, selected upon exposure to BAL30072, harbored frameshift mutations in either the ExbD3 or the TonB3 protein of
A. baumannii
, forming the cytoplasmic-membrane complex providing the energy for the siderophore translocation process. The results of this study provide insight for the rational design of novel siderophore-drug conjugates against problematic Gram-negative pathogens.
The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages
Authors: Mallama Celeste A. , McCoy-Simandle Kessler , Cianciotto Nicholas P. 
Published: January 2017

ABSTRACT

Previously, we reported that mutants of
Legionella pneumophila
lacking a type II secretion (T2S) system elicit higher levels of cytokines (e.g., interleukin-6 [IL-6]) following infection of U937 cells, a human macrophage-like cell line. We now show that this effect of T2S is also manifest upon infection of human THP-1 macrophages and peripheral blood monocytes but does not occur during infection of murine macrophages. Supporting the hypothesis that T2S acts to dampen the triggering of an innate immune response, we observed that the mitogen-activated protein kinase (MAPK) and nuclear transcription factor kappa B (NF-κB) pathways are more highly stimulated upon infection with the T2S mutant than upon infection with the wild type. By using short hairpin RNA to deplete proteins involved in specific pathogen-associated molecular pattern (PAMP) recognition pathways, we determined that the dampening effect of the T2S system was not dependent on nucleotide binding oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible protein I (RIG-I)-like receptors (RLRs), double-stranded RNA (dsRNA)-dependent protein kinase receptor (PKR), or TIR domain-containing adaptor inducing interferon beta (TRIF) signaling or an apoptosis-associated speck-like protein containing a CARD (ASC)- or caspase-4-dependent inflammasome. However, the dampening effect of T2S on IL-6 production was significantly reduced upon gene knockdown of myeloid differentiation primary response 88 (MyD88), TANK binding kinase 1 (TBK1), or Toll-like receptor 2 (TLR2). These data indicate that the
L. pneumophila
T2S system dampens the signaling of the TLR2 pathway in infected human macrophages. We also document the importance of PKR, TRIF, and TBK1 in cytokine secretion during
L. pneumophila
infection of macrophages.
Distinct Roles of the Antiapoptotic Effectors NleB and NleF from Enteropathogenic Escherichia coli
Authors: Pollock Georgina L. , Oates Clare V. L. , Giogha Cristina , Wong Fok Lung Tania , Ong Sze Ying , Pearson Jaclyn S. , Hartland Elizabeth L. 
Published: January 2017

ABSTRACT

During infection, enteropathogenic
Escherichia coli
(EPEC) translocates effector proteins directly into the cytosol of infected enterocytes using a type III secretion system (T3SS). Once inside the host cell, these effector proteins subvert various immune signaling pathways, including death receptor-induced apoptosis. One such effector protein is the non-locus of enterocyte effacement (LEE)-encoded effector NleB1, which inhibits extrinsic apoptotic signaling via the FAS death receptor. NleB1 transfers a single
N
-acetylglucosamine (GlcNAc) residue to Arg
117
in the death domain of Fas-associated protein with death domain (FADD) and inhibits FAS ligand (FasL)-stimulated caspase-8 cleavage. Another effector secreted by the T3SS is NleF. Previous studies have shown that NleF binds to and inhibits the activity of caspase-4, -8, and -9
in vitro
. Here, we investigated a role for NleF in the inhibition of FAS signaling and apoptosis during EPEC infection. We show that NleF prevents the cleavage of caspase-8, caspase-3, and receptor-interacting serine/threonine protein kinase 1 (RIPK1) in response to FasL stimulation. When translocated into host cells by the T3SS or expressed ectopically, NleF also blocked FasL-induced cell death. Using the EPEC-like mouse pathogen
Citrobacter rodentium
, we found that NleB but not NleF contributed to colonization of mice in the intestine. Hence, despite their shared ability to block FasL/FAS signaling, NleB and NleF have distinct roles during infection.
General practitioner management related to skin cancer prevention and screening during standard medical encounters: a French cross-sectional study based on the International Classification of Primary Care
Authors: Rat Cédric , Houd Sara , Gaultier Aurélie , Grimault Charlotte , Quereux Gaelle , Mercier Alain , Letrilliart Laurent , Dreno Brigitte , Nguyen Jean Michel 
Published: January 2017

ObjectiveThe aim of this study was to assess general practitioner (GP) management practices related to skin cancer prevention and screening during standard medical encounters.SettingData on medical encounters addressing skin cancer issues were obtained from a French database containing information from 17 019 standard primary care consultations.ParticipantsData were collected between December 2011 and April 2012 by 54 trainees who reported the regular practice of 128 GPs using the International Classification of Primary Care.Outcome measuresReasons for encounters and the following care processes were recorded: counselling, clinical examinations and referral to a specialist. Medical encounters addressing skin cancer issues were compared with medical encounters that addressed other health problems using a multivariate analysis.ResultsOnly 0.7% of medical encounters addressed skin cancer issues. When patients did require management of a skin cancer-related issue, this was more likely initiated by the doctor than the patient (70.7% vs 29.3%; p<0.001). Compared with medical encounters addressing other health problems, encounters that addressed skin cancer problems required more tasks (3.7 vs 2.5; p<0.001) and lasted 1 min and 20 s longer (p=0.003). GPs were less involved in clinical examinations (67.5% vs 97.1%; p<0.001), both complete (7.3% vs 22.3%, p<0.001) and partial examinations (60.2% vs 74.9%), and were less involved in counselling (5.7% vs 16.9%; p<0.001). Patients presenting skin cancer issues were referred to a specialist more often than patients consulting for other health problems (39.0% vs 12.1%; p<0.001). GPs performed a biopsy in 6.7% of all skin cancer-related encounters.ConclusionsThis study demonstrates discrepancies between the high prevalence of skin cancer and the low rate of medical encounters addressing these issues in general practice. Our findings should be followed by qualitative interviews to better understand the observed practices in this field.
Dual Targeting of Epithelial Ovarian Cancer Via Folate Receptor α and the Proton-Coupled Folate Transporter with 6-Substituted Pyrrolo[2,3-d]pyrimidine Antifolates
Authors: Hou Zhanjun , Gattoc Leda , O'Connor Carrie , Yang Si , Wallace-Povirk Adrianne , George Christina , Orr Steve , Polin Lisa , White Kathryn , Kushner Juiwanna , Morris Robert T. , Gangjee Aleem , Matherly Larry H. 
Published: January 2017

Abstract
Folate uptake in epithelial ovarian cancer (EOC) involves the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT), both facilitative transporters and folate receptor (FR) α. Although in primary EOC specimens, FRα is widely expressed and increases with tumor stage, PCFT was expressed independent of tumor stage (by real-time RT-PCR and IHC). EOC cell line models, including cisplatin sensitive (IGROV1 and A2780) and resistant (SKOV3 and TOV112D) cells, expressed a 17-fold range of FRα and similar amounts (within ∼2-fold) of PCFT. Novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates AGF94 and AGF154 exhibited potent antiproliferative activities toward all of the EOC cell lines, reflecting selective cellular uptake by FRα and/or PCFT over RFC. When IGROV1 cells were pretreated with AGF94 at pH 6.8, clonogenicity was potently inhibited, confirming cell killing. FRα was knocked down in IGROV1 cells with lentiviral shRNAs. Two FRα knockdown clones (KD-4 and KD-10) showed markedly reduced binding and uptake of [3H]folic acid and [3H]AGF154 by FRα, but maintained high levels of [3H]AGF154 uptake by PCFT compared to nontargeted control cells. In proliferation assays, KD-4 and KD-10 cells preserved in vitro inhibition by AGF94 and AGF154, compared to a nontargeted control, attributable to residual FRα- and substantial PCFT-mediated uptake. KD-10 tumor xenografts in severe-compromised immune-deficient mice were likewise sensitive to AGF94. Collectively, our results demonstrate the substantial therapeutic potential of novel 6-substituted pyrrolo[2,3-d]pyrimidine antifolates with dual targeting of PCFT and FRα toward EOCs that express a range of FRα, along with PCFT, as well as cisplatin resistance. Mol Cancer Ther; 16(5); 819–30. ©2017 AACR.
Ras–MEK Signaling Mediates a Critical Chk1-Dependent DNA Damage Response in Cancer Cells
Authors: Lee Ho-June , Cao Yi , Pham Victoria , Blackwood Elizabeth , Wilson Catherine , Evangelista Marie , Klijn Christiaan , Stokoe David , Settleman Jeff 
Published: January 2017

Abstract
Cancer cell line profiling to identify previously unrecognized kinase dependencies revealed a novel nonmutational dependency on the DNA damage response checkpoint kinase Chk1. Although Chk1 is a promising therapeutic target in p53-deficient cancers, we found that Ras–MEK signaling engages Chk1 in a subset of osteosarcoma, ovarian, and breast cancer cells to enable their survival upon DNA damage, irrespective of p53 mutation status. Mechanistically, Ras–MEK signaling drives Chk1 expression and promotes cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DNA damage. Reciprocally, Chk1 engages a negative feedback loop to prevent hyperactivation of Ras–MEK signaling, thereby limiting DNA damage. Furthermore, exogenous DNA damage promotes Chk1 dependency, and pharmacologic Chk1 inhibition combined with genotoxic chemotherapy potentiates a DNA damage response and tumor cell killing. These findings reveal a mechanism-based diagnostic strategy to identify cancer patients that may benefit from Chk1-targeted therapy. Mol Cancer Ther; 16(4); 694–704. ©2017 AACR.
Preclinical Evaluation of Sequential Combination of Oncolytic Adenovirus Delta-24-RGD and Phosphatidylserine-Targeting Antibody in Pancreatic Ductal Adenocarcinoma
Authors: Dai Bingbing , Roife David , Kang Ya'an , Gumin Joy , Rios Perez Mayrim V. , Li Xinqun , Pratt Michael , Brekken Rolf A. , Fueyo-Margareto Juan , Lang Frederick F. , Fleming Jason B. 
Published: January 2017

Abstract
Delta-24-RGD (DNX-2401) is a conditional replication-competent oncolytic virus engineered to preferentially replicate in and lyse tumor cells with abnormality of p16/RB/E2F pathway. In a phase I clinical trial, Delta-24-RGD has shown favorable safety profile and promising clinical efficacy in brain tumor, which prompted us to evaluate its anticancer activity in pancreatic ductal adenocarcinoma (PDAC), which also has high frequency of homozygous deletion and promoter methylation of CDKN2A encoding the p16 protein. Our results demonstrate that Delta-24-RGD can induce dramatic cytotoxicity in a subset of PDAC cell lines with high cyclin D1 expression. Induction of autophagy and apoptosis by Delta-24-RGD in sensitive PDAC cells was confirmed with LC3B-GFP autophagy reporter and acridine orange staining as well as Western blotting analysis of LC3B-II expression. Notably, we found that Delta-24-RGD induced phosphatidylserine exposure in infected cells independent of cells' sensitivity to Delta-24-RGD, which renders a rationale for combination of Delta-24-RGD viral therapy and phosphatidylserine targeting antibody for PDAC. In a mouse PDAC model derived from a liver metastatic pancreatic cancer cell line, Delta-24-RGD significantly inhibited tumor growth compared with control (P &lt; 0.001), and combination of phosphatidylserine targeting antibody 1N11 further enhanced its anticancer activity (P &lt; 0.01) possibly through inducing synergistic anticancer immune responses. Given that these 2 agents are currently in clinical evaluation, our study warrants further clinical evaluation of this novel combination strategy in pancreatic cancer therapy. Mol Cancer Ther; 16(4); 662–70. ©2016 AACR.
Suppression of the Growth and Invasion of Human Head and Neck Squamous Cell Carcinomas via Regulating STAT3 Signaling and the miR-21/β-catenin Axis with HJC0152
Authors: Wang Yu , Wang Sinan , Wu Yansheng , Ren Yu , Li Zhaoqing , Yao Xiaofeng , Zhang Chao , Ye Na , Jing Chao , Dong Jiabin , Zhang Kailiang , Sun Shanshan , Zhao Minghui , Guo Wenyu , Qu Xin , Qiao Yu , Chen Haiying , Kong Lingping , Jin Rui , Wang Xudong , Zhang Lun , Zhou Jia , Shen Qiang , Zhou Xuan 
Published: January 2017

Abstract
Signal transducer and activator of transcription 3 (STAT3) is involved in the tumor growth and metastasis of human head and neck squamous cell carcinoma (HNSCC) and is therefore a target with therapeutic potential. In this study, we show that HJC0152, a recently developed anticancer agent and a STAT3 signaling inhibitor, exhibits promising antitumor effects against HNSCC both in vitro and in vivo via inactivating STAT3 and downstream miR-21/β-catenin axis. HJC0152 treatment efficiently suppressed HNSCC cell proliferation, arrested the cell cycle at the G0–G1 phase, induced apoptosis, and reduced cell invasion in both SCC25 and CAL27 cell lines. Moreover, HJC0152 inhibited nuclear translocation of phosphorylated STAT3 at Tyr705 and decreased VHL/β-catenin signaling activity via regulation of miR-21. Loss of function of VHL remarkably compromised the antitumor effect of HJC0152 in both cell lines. In our SCC25-derived orthotopic mouse models, HJC0152 treatment significantly abrogated STAT3/β-catenin expression in vivo, leading to a global decrease of tumor growth and invasion. With its favorable aqueous solubility and oral bioavailability, HJC0152 holds the potential to be translated into the clinic as a promising therapeutic strategy for patients with HNSCC. Mol Cancer Ther; 16(4); 578–90. ©2017 AACR.
Anti-KIT Monoclonal Antibody Treatment Enhances the Antitumor Activity of Immune Checkpoint Inhibitors by Reversing Tumor-Induced Immunosuppression
Authors: Garton Andrew J. , Seibel Scott , Lopresti-Morrow Lori , Crew Linda , Janson Neal , Mandiyan Sreekala , Trombetta E. Sergio , Pankratz Shannon , LaVallee Theresa M. , Gedrich Richard 
Published: January 2017

AbstractThe receptor tyrosine kinase KIT is an established oncogenic driver of tumor growth in certain tumor types, including gastrointestinal stromal tumors, in which constitutively active mutant forms of KIT represent an actionable target for small-molecule tyrosine kinase inhibitors. There is also considerable potential for KIT to influence tumor growth indirectly based on its expression and function in cell types of the innate immune system, most notably mast cells. We have evaluated syngeneic mouse tumor models for antitumor effects of an inhibitory KIT mAb, dosed either alone or in combination with immune checkpoint inhibitors. Anti-KIT mAb treatment enhanced the antitumor activity of anti–CTLA-4 and anti–PD-1 mAbs, and promoted immune responses by selectively reducing the immunosuppressive monocytic myeloid-derived suppressor cell population and by restoring CD8+ and CD4+ T-cell populations to levels observed in naïve mice. These data provide a rationale for clinical investigation of the human KIT-specific mAb KTN0158 in novel immuno-oncology combinations with immune checkpoint inhibitors and other immunotherapeutic agents across a range of tumor types. Mol Cancer Ther; 16(4); 671–80. ©2017 AACR.
Impact Assessment of Himawari-8 AHI Data Assimilation in NCEP GDAS/GFS with GSI
Authors: Ma Zaizhong , Maddy Eric S. , Zhang Banglin , Zhu Tong , Boukabara Sid Ahmed 
Published: January 2017

AbstractAs the first of the next-generation geostationary meteorological satellites, Himawari-8 was successfully launched in October 2014 by the Japan Meteorological Agency (JMA) and placed over the western Pacific Ocean domain at 140.7°E. It carries the Advanced Himawari Imager (AHI), which provides full-disk images of Earth at 16 bands in the visible and infrared domains every 10 min. Efforts are currently ongoing at the National Oceanic and Atmospheric Administration (NOAA)/National Environmental Satellite, Data, and Information Service (NESDIS)/Center for Satellite Applications and Research (STAR) to assimilate Himawari-8 AHI radiance measurements into the National Centers for Environmental Prediction (NCEP) Gridpoint Statistical Interpolation analysis system (GSI). All software development within the GSI to allow for assimilation of Himawari-8 AHI radiance has been completed.This study reports on the assessment of AHI preassimilation data quality by comparing observed clear-sky ocean-only radiances to those simulated using collocated ECMWF analysis, as well as describing procedures implemented for quality control. The impact of the AHI data assimilation on the resulting analyses and forecasts is then assessed using the NCEP Global Forecast System (GFS). A preliminary assessment of the assimilation of AHI data from infrared water vapor channels and atmospheric motion vectors (AMVs) on top of the current global observing system shows neutral to marginal positive impact on analysis and forecast skill relative to an assimilation without AHI data. The main positive impact occurs for short- to medium-range forecasts of global upper-tropospheric water vapor. The results demonstrate the feasibility of direct assimilation of AHI radiances and highlight how humidity information can be extracted within the assimilation system.
How emotional intelligence relates to job satisfaction and burnout in public service jobs
Authors: Lee Hyun Jung 
Published: January 2017

Public service workers require higher levels of emotional intelligence because most public service jobs involve emotionally intense work focused on service to the public. Moreover, such emotional work may lead to a high degree of burnout and job dissatisfaction, which directly relates to organizational outcomes. Focusing on public service workers, the present study investigates the relationships between the dimensions of emotional intelligence and job satisfaction, on the one hand, and the dimensions of emotional intelligence and burnout, on the other. In the sample of 167 public service workers in the US, using employed structural equation modeling, the findings reveal that emotion regulation is significantly and negatively related to burnout and that emotional self-awareness is significantly and positively related to job satisfaction. Points for practitioners This study contributes to understanding the relationship between the emotional intelligence dimension and burnout, and the emotional intelligence dimension and job satisfaction, in public service jobs. Emotional intelligence plays a significant role for public service workers whose work involves emotionally intense job characteristics. The findings show that training in emotional intelligence abilities may increase job satisfaction and decrease burnout. Practitioners and professionals working in public management and administration may consider measures of emotional intelligence, especially emotional self-awareness and emotion regulation, in the recruitment process to select potentially effective job applicants.