bluuebunny/crossref_metadata_2025_split huggingface dataset:
The avidity of tumor‐specific T cells amplified by a plasmacytoid dendritic cell‐based assay can predict the clinical evolution of melanoma patients
Authors: Charles Julie , Chaperot Laurence , Revol Bruno , Baudin Marine , Mouret Stephane , Hamon Agnes , Leccia Marie‐Therese , Plumas Joel , Aspord Caroline 
Published: July 2017

SummaryThe advent of immune checkpoint blockers and targeted therapies has changed the outcome of melanoma. However, many patients experience relapses, emphasizing the need for predictive and prognostic biomarkers. We developed a strategy based on plasmacytoid dendritic cells (pDCs) loaded with melanoma tumor antigens that allows eliciting highly efficient antitumor T‐cell responses. We used it to investigate antitumor T‐cell functionality in peripheral blood mononuclear cells and tumor‐infiltrating lymphocytes from melanoma patients. The pDCs elicited tumor‐specific T cells in different proportions and displaying diverse functional features, dependent upon the stage of the disease, but independent of the histological parameters at diagnosis. Strikingly, the avidity of the MelA‐specific T cells triggered by the pDCs was found to predict patient relapse time and overall survival. Our findings highlighted unexplored aspects of antitumor T‐cell responsiveness in melanoma, and revealed for the first time the structural avidity of tumor‐specific T cells as a crucial feature for predicting clinical evolution.
Clustered Multistate Models with Observation Level Random Effects, Mover–Stayer Effects and Dynamic Covariates: Modelling Transition Intensities and Sojourn Times in a Study of Psoriatic Arthritis
Authors: Yiu Sean , Farewell Vernon T. , Tom Brian D. M. 
Published: July 2017

SummaryIn psoriatic arthritis, it is important to understand the joint activity (represented by swelling and pain) and damage processes because both are related to severe physical disability. The paper aims to provide a comprehensive investigation into both processes occurring over time, in particular their relationship, by specifying a joint multistate model at the individual hand joint level, which also accounts for many of their important features. As there are multiple hand joints, such an analysis will be based on the use of clustered multistate models. Here we consider an observation level random-effects structure with dynamic covariates and allow for the possibility that a subpopulation of patients is at minimal risk of damage. Such an analysis is found to provide further understanding of the activity–damage relationship beyond that provided by previous analyses. Consideration is also given to the modelling of mean sojourn times and jump probabilities. In particular, a novel model parameterization which allows easily interpretable covariate effects to act on these quantities is proposed.
The Effects of Regional and Distance Education on the Supply of Qualified Teachers in Rural Iceland
Authors: Bjarnason Thoroddur , Thorarinsdottir Brynhildur 
Published: July 2017

AbstractDifficulties in recruiting qualified teachers have been traced to insufficient services and amenities in rural areas, an urban emphasis in teacher education, few local students becoming teachers and a lack of teacher mobility. This study maps the mobility of recently graduated teachers in urban, exurban, micropolitan and other rural areas of Iceland. The graduation rate of teachers was found to be higher in rural than urban areas, yet rural teachers are less likely to remain after graduation. Relatively few rural teachers return from on‐campus studies in the either the capital area or the northern regional centre. Rural distance students are however almost equally likely as urban on‐campus students to stay in their home areas after graduation, and they are the majority of teachers in rural areas. From a policy perspective, distance education appears more effective than regional campuses in increasing the supply of qualified teachers in rural and remote areas.
Does real exchange rate depreciation increase productivity? Analysis using Korean firm‐level data
Authors: Choi Bo‐Young , Pyun Ju Hyun 
Published: July 2017

AbstractWe examine the effects of real exchange rate (RER) depreciation shocks on firm productivity. Using the firm‐level data of Korean manufacturing industries for 2006–13, we distinguish between yearly RER movement and persistent RER depreciation during 2007–09 and analyse how each affects productivity. We find the positive effect of RER depreciation on productivity among exporters, and this positive effect increases with higher export exposure. However, the positive productivity gain disappears when the depreciation persists. Our findings suggest that while immediate depreciation leads to productivity upgrade via price competitiveness and scale expansion, persistent depreciation nullifies the productivity gain by slackening the innovation effort.
Hazardous Area Classification for Surface Well Testing Equipment
Authors: Gupta Ashish 
Published: July 2017

Hazardous area classification or zoning is a method of analyzing and classifying the environment in which explosive gas atmospheres may occur to facilitate the proper selection and installation of equipment to be used safely in that environment. In several oil and gas companies, hazardous area classification is carried out as an integral step of the risk assessment exercise to identify areas where controls over ignition sources are required on the rigs. In this paper, one example of such an exercise is presented. The recommendations from the exercise were used in updating the company’s guidelines on zoning and eventually improving the fire safety of its operations.
The paper discusses these factors and their impact on zoning.
Structural Insights into the TLA-3 Extended-Spectrum β-Lactamase and Its Inhibition by Avibactam and OP0595
Authors: Jin Wanchun , Wachino Jun-ichi , Yamaguchi Yoshihiro , Kimura Kouji , Kumar Anupriya , Yamada Mototsugu , Morinaka Akihiro , Sakamaki Yoshiaki , Yonezawa Minoru , Kurosaki Hiromasa , Arakawa Yoshichika 
Published: July 2017

ABSTRACT

The development of effective inhibitors that block extended-spectrum β-lactamases (ESBLs) and restore the action of β-lactams represents an effective strategy against ESBL-producing
Enterobacteriaceae
. We evaluated the inhibitory effects of the diazabicyclooctanes avibactam and OP0595 against TLA-3, an ESBL that we identified previously. Avibactam and OP0595 inhibited TLA-3 with apparent inhibitor constants (

K
i

app
) of 1.71 ± 0.10 and 1.49 ± 0.05 μM, respectively, and could restore susceptibility to cephalosporins in the TLA-3-producing
Escherichia coli
strain. The value of the second-order acylation rate constant (
k
2
/
K
, where
k
2
is the acylation rate constant and
K
is the equilibrium constant) of avibactam [(3.25 ± 0.03) × 10
3
M
−1
· s
−1
] was closer to that of class C and D β-lactamases (
k
2
/
K
, <10
4
M
−1
· s
−1
) than that of class A β-lactamases (
k
2
/
K
, >10
4
M
−1
· s
−1
). In addition, we determined the structure of TLA-3 and that of TLA-3 complexed with avibactam or OP0595 at resolutions of 1.6, 1.6, and 2.0 Å, respectively. TLA-3 contains an inverted Ω loop and an extended loop between the β5 and β6 strands (insertion after Ser237), which appear only in PER-type class A β-lactamases. These structures might favor the accommodation of cephalosporins harboring bulky R1 side chains. TLA-3 presented a high catalytic efficiency (
k
cat
/

K
m

) against cephalosporins, including cephalothin, cefuroxime, and cefotaxime. Avibactam and OP0595 bound covalently to TLA-3 via the Ser70 residue and made contacts with residues Ser130, Thr235, and Ser237, which are conserved in ESBLs. Additionally, the sulfate group of the inhibitors formed polar contacts with amino acid residues in a positively charged pocket of TLA-3. Our findings provide a structural template for designing improved diazabicyclooctane-based inhibitors that are effective against ESBL-producing
Enterobacteriaceae
.
Assessment of Bactericidal Drug Activity and Treatment Outcome in a Mouse Tuberculosis Model Using a Clinical Beijing Strain
Authors: Mourik Bas C. , de Knegt Gerjo J. , Verbon Annelies , Mouton Johan W. , Bax Hannelore I. , de Steenwinkel Jurriaan E. M. 
Published: July 2017

ABSTRACT

Mycobacterium tuberculosis
Beijing strains are associated with lower treatment success rates in tuberculosis (TB) patients. In contrast, laboratory strains such as H37Rv are often used in preclinical tuberculosis models. Therefore, we explored the impact of using a clinical Beijing strain on treatment outcome in our mouse tuberculosis model. Additionally, the predictive value of bactericidal activity on treatment outcome was assessed. BALB/c mice were infected with a Beijing strain and treated with one of 10 different combinations of conventional anti-TB drugs. Bactericidal activity was assessed by determining reductions in mycobacterial load after 7, 14, and 28 days and after 2, 3, and 6 months of treatment. Treatment outcome was evaluated after a 6-month treatment course and was based on lung culture status 3 months posttreatment. None of the anti-TB drug regimens tested could achieve 100% treatment success. Treatment outcome depended critically on rifampin. Four non-rifampin-containing regimens showed 0% treatment success compared to success rates between 81 and 95% for six rifampin-containing regimens. Bactericidal activity was predictive only for treatment outcome after 3 months of treatment. Our data advocate the use of multiple mycobacterial strains, including a Beijing strain, to increase the translational value of mouse TB models evaluating treatment outcome. Additionally, our findings support the notion that bactericidal activity in the first 2 months of treatment, as measured in clinical phase IIa/b trials, has limited predictive value for tuberculosis treatment outcome, thus emphasizing the need for better parameters to guide future phase IIII trials.
In Vitro
Drug Susceptibility of Bedaquiline, Delamanid, Linezolid, Clofazimine, Moxifloxacin, and Gatifloxacin against Extensively Drug-Resistant Tuberculosis in Beijing, China
Authors: Pang Yu , Zong Zhaojing , Huo Fengmin , Jing Wei , Ma Yifeng , Dong Lingling , Li Yunxu , Zhao Liping , Fu Yuhong , Huang Hairong 
Published: July 2017

ABSTRACT

Extensively drug-resistant tuberculosis (XDR-TB) is a deadly form of TB that can be incurable due to its extreme drug resistance. In this study, we aimed to explore the
in vitro
susceptibility to bedaquiline (BDQ), delamanid (DMD), linezolid (LZD), clofazimine (CLO), moxifloxacin (MFX), and gatifloxacin (GAT) of 90 XDR-TB strains isolated from patients in China. We also describe the genetic characteristics of XDR-TB isolates with acquired drug resistance. Resistance to MFX, GAT, LZD, CLO, DMD, and BDQ was found in 82 (91.1%), 76 (84.4%), 5 (5.6%), 5 (5.6%), 4 (4.4%), and 3 (3.3%) isolates among the XDR-TB strains, respectively. The most frequent mutations conferring fluoroquinolone resistance occurred in codon 94 of the
gyrA
gene (57.8%), and the strains with these mutations (69.2%) were associated with high-level MFX resistance compared to strains with mutations in codon 90 (25.0%) (
P
< 0.01). All 5 CLO-resistant isolates exhibited ≥4-fold upward shifts in the BDQ MIC, which were attributed to mutations of codons 53 (60.0%) and 157 (20.0%) in the Rv0678 gene. Additionally, mutation in codon 318 of the
fbiC
gene was identified as the sole mutation related to DMD resistance. In conclusion, our data demonstrate that the XDR-TB strains exhibit a strikingly high proportion of resistance to the current anti-TB drugs, whereas BDQ, DMD, LZD, and CLO exhibit excellent
in vitro
activity against XDR-TB in the National Clinical Center on TB of China. The extensive cross-resistance between OFX and later-generation fluoroquinolones indicates that MFX and GAT may have difficulty in producing the desired effect for XDR-TB patients.
Resistance to Ceftazidime-Avibactam Is Due to Transposition of KPC in a Porin-Deficient Strain of Klebsiella pneumoniae with Increased Efflux Activity
Authors: Nelson Kirk , Hemarajata Peera , Sun Dongxu , Rubio-Aparicio Debora , Tsivkovski Ruslan , Yang Shangxin , Sebra Robert , Kasarskis Andrew , Nguyen Hoan , Hanson Blake M. , Leopold Shana , Weinstock George , Lomovskaya Olga , Humphries Romney M. 
Published: July 2017

ABSTRACT

Ceftazidime-avibactam is an antibiotic with activity against serine beta-lactamases, including
Klebsiella pneumoniae
carbapenemase (KPC). Recently, reports have emerged of KPC-producing isolates resistant to this antibiotic, including a report of a wild-type KPC-3 producing sequence type 258
Klebsiella pneumoniae
that was resistant to ceftazidime-avibactam. We describe a detailed analysis of this isolate, in the context of two other closely related KPC-3 producing isolates, recovered from the same patient. Both isolates encoded a nonfunctional OmpK35, whereas we demonstrate that a novel T333N mutation in OmpK36, present in the ceftazidime-avibactam resistant isolate, reduced the activity of this porin and impacted ceftazidime-avibactam susceptibility. In addition, we demonstrate that the increased expression of
bla
KPC-3
and
bla
SHV-12
observed in the ceftazidime-avibactam-resistant isolate was due to transposition of the Tn
4401
transposon harboring
bla
KPC-3
into a second plasmid, pIncX3, which also harbored
bla
SHV-12
, ultimately resulting in a higher copy number of

bla
KPC

-3
in the resistant isolate. pIncX3 plasmid from the ceftazidime-avibactam resistant isolate, conjugated into a OmpK35/36-deficient
K. pneumoniae
background that harbored a mutation to the
ramR
regulator of the
acrAB
efflux operon recreated the ceftazidime-avibactam-resistant MIC of 32 μg/ml, confirming that this constellation of mutations is responsible for the resistance phenotype.
Multicenter, International Study of MIC/MEC Distributions for Definition of Epidemiological Cutoff Values for Sporothrix Species Identified by Molecular Methods
Authors: Espinel-Ingroff A. , Abreu D. P. B. , Almeida-Paes R. , Brilhante R. S. N. , Chakrabarti A. , Chowdhary A. , Hagen F. , Córdoba S. , Gonzalez G. M. , Govender N. P. , Guarro J. , Johnson E. M. , Kidd S. E. , Pereira S. A. , Rodrigues A. M. , Rozental S. , Szeszs M. W. , Ballesté Alaniz R. , Bonifaz A. , Bonfietti L. X. , Borba-Santos L. P. , Capilla J. , Colombo A. L. , Dolande M. , Isla M. G. , Melhem M. S. C. , Mesa-Arango A. C. , Oliveira M. M. E. , Panizo M. M. , Pires de Camargo Z. , Zancope-Oliveira R. M. , Meis J. F. , Turnidge J. 
Published: July 2017

ABSTRACTClinical and Laboratory Standards Institute (CLSI) conditions for testing the susceptibilities of pathogenicSporothrixspecies to antifungal agents are based on a collaborative study that evaluated five clinically relevant isolates ofSporothrixschenckii sensu latoand some antifungal agents. With the advent of molecular identification, there are two basic needs: to confirm the suitability of these testing conditions for all agents andSporothrixspecies and to establish species-specific epidemiologic cutoff values (ECVs) or breakpoints (BPs) for the species. We collected available CLSI MICs/minimal effective concentrations (MECs) of amphotericin B, five triazoles, terbinafine, flucytosine, and caspofungin for 301Sporothrix schenckii sensu stricto, 486S. brasiliensis, 75S. globosa, and 13S. mexicanamolecularly identified isolates. Data were obtained in 17 independent laboratories (Australia, Europe, India, South Africa, and South and North America) using conidial inoculum suspensions and 48 to 72 h of incubation at 35°C. Sufficient and suitable data (modal MICs within 2-fold concentrations) allowed the proposal of the following ECVs forS. schenckiiandS. brasiliensis, respectively: amphotericin B, 4 and 4 μg/ml; itraconazole, 2 and 2 μg/ml; posaconazole, 2 and 2 μg/ml; and voriconazole, 64 and 32 μg/ml. Ketoconazole and terbinafine ECVs forS. brasiliensiswere 2 and 0.12 μg/ml, respectively. Insufficient or unsuitable data precluded the calculation of ketoconazole and terbinafine (or any other antifungal agent) ECVs forS. schenckii, as well as ECVs forS. globosaandS. mexicana. These ECVs could aid the clinician in identifying potentially resistant isolates (non-wild type) less likely to respond to therapy.
Emergence of
mcr-1
in Raoultella ornithinolytica and Escherichia coli Isolates from Retail Vegetables in China
Authors: Luo Juan , Yao Xu , Lv Luchao , Doi Yohei , Huang Xiuyu , Huang Sicheng , Liu Jian-Hua 
Published: July 2017

ABSTRACT

The presence of
mcr-1
among
Enterobacteriaceae
isolates collected from retail vegetables in China between 2015 and 2016 was investigated. Two
Raoultella ornithinolytica
and seven
Escherichia coli
strains recovered from lettuce and tomato samples were identified as MCR-1-producers. Similar to isolates from animals and humans, the
mcr-1
gene was located on the IncHI2/ST3, IncI2, or IncX4 plasmids. The presence of MCR-1-producing organisms in ready-to-eat food samples represents a serious risk for human health.
Clinical Characteristics and Treatment Outcomes of Patients with Acquired Macrolide-Resistant Mycobacterium abscessus Lung Disease
Authors: Choi Hayoung , Kim Su-Young , Kim Dae Hun , Huh Hee Jae , Ki Chang-Seok , Lee Nam Yong , Lee Seung-Heon , Shin Soyoun , Shin Sung Jae , Daley Charles L. , Koh Won-Jung 
Published: July 2017

ABSTRACT

Macrolide antibiotics are mainstays in the treatment of lung disease due to the
Mycobacterium abscessus
complex. Although previous studies have reported development of acquired macrolide resistance in this species, limited data are available on the outcomes of lung disease due to macrolide-resistant
Mycobacterium abscessus
subsp.
abscessus
. This study evaluated the clinical features, treatment outcomes, and molecular characteristics of macrolide-resistant isolates of
M. abscessus
subsp.
abscessus
. We performed a retrospective review of medical records and genetic analysis of clinical isolates from 13 patients who had acquired macrolide-resistant
M. abscessus
subsp.
abscessus
lung disease between November 2006 and March 2016. Eleven (85%) patients had the nodular bronchiectatic form of the disease, and two (15%) patients had the fibrocavitary form. When acquired macrolide resistance was detected, 10 (77%) patients were on antibiotic therapy for
M. abscessus
subsp.
abscessus
, and three (23%) patients were on therapy for lung disease due to other nontuberculous mycobacteria. The median treatment duration after detecting resistance was 24.0 months (interquartile range, 16.0 to 43.0 months). Treatment outcomes were poor, and final sputum culture conversion was achieved in only one (8%) patient, after resectional surgery. All 13 clinical isolates demonstrated point mutations at position 2058 (
n
= 10) or 2059 (
n
= 3) of the 23S rRNA gene, which resulted in acquired macrolide resistance. This study indicates that treatment outcomes are very poor after the development of acquired macrolide resistance in patients with
M. abscessus
subsp.
abscessus
lung disease. Thus, more effective measures are needed to prevent development and effectively treat macrolide-resistant
M. abscessus
subsp.
abscessus
lung disease.
Transfersomal Phage Cocktail Is an Effective Treatment against Methicillin-Resistant Staphylococcus aureus-Mediated Skin and Soft Tissue Infections
Authors: Chhibber Sanjay , Shukla Ashu , Kaur Sandeep 
Published: July 2017

ABSTRACTThe emergence of drug resistance has rekindled interest in phage therapy as an alternative treatment option; its potency, safety, and proven efficacy are worth noting. However, phage therapy still suffers from issues of poor stability, narrow spectra, and poor pharmacokinetic profiles. Therefore, it is essential to look into the use of drug delivery systems for efficient delivery of lytic phagesin vivo. The present study evaluated the use of nanostructured lipid-based carriers, i.e., transfersomes, as transdermal delivery systems for encapsulating a methicillin-resistantStaphylococcus aureus(MRSA) phage cocktail. Furthermore, the therapeutic potential of the encapsulated phage cocktail in resolving experimental soft tissue infections in rats was studied. Results fromin vitrostability andin vivophage titer experiments indicated that the transfersome-entrapped phage cocktail showed better persistence and stability than did free phages. Rats treated with the transfersome-entrapped phage cocktail resolved the experimental thigh infections within a period of 7 days, unlike the 20-day period required for untreated animals. The findings of the present study support the use of transfersomes as delivery agents to enhance the stability andin vivopersistence of the encapsulated phages. In addition, this study highlights the advantages offered by transfersome-encapsulated phages in providing better therapeutic options than free phages for treating skin and soft tissue infections. The transfersome-entrapped phage cocktail was able to protect all test animals (with no deaths) even when administered with a delay of 12 h postinfection, unlike free phages, thus making this treatment option more suitable for clinical settings.
Interleukin-17A Aggravates Middle Ear Injury Induced by Streptococcus pneumoniae through the p38 Mitogen-Activated Protein Kinase Signaling Pathway
Authors: Wang Wei , Liu Wenbin , Liu Jiali , Wang Zimeng , Fan Fangmei , Ma Yurong , Jin Chunfang , Xiang Yun , Huang Yifei , Zhang Xuemei , Xu Wenchun , Yin Yibing , He Yujuan 
Published: July 2017

ABSTRACT

Acute otitis media (AOM) is one of the most common bacterial infectious diseases in children aged 2 to 7 years worldwide. We previously demonstrated that interleukin-17A (IL-17A) promotes an acute inflammatory response characterized by the influx of neutrophils into the middle ear cavity during
Streptococcus pneumoniae
-induced AOM. In general, the inflammatory response is viewed as an effector that frequently causes local tissue damage. However, little is known about the pathogenic effects of IL-17A in AOM. Here, we investigated the pathogenic effects of IL-17A by using wild-type (WT) and IL-17A knockout (KO) mouse models. The results showed that the pathogenic effects of AOM, including weight loss, histopathological changes, and proinflammatory cytokine production, were more severe in WT mice than in IL-17A KO mice, suggesting that IL-17A aggravates tissue damage in AOM. Furthermore, these pathogenic effects were found to be dependent on p38 mitogen-activated protein kinase (MAPK) and could be reversed in the presence of a p38 MAPK-specific inhibitor. It was also demonstrated that IL-17A promoted the production of neutrophil myeloperoxidase (MPO) through the p38 MAPK signaling pathway, which was responsible for the middle ear tissue injury. These data support the conclusion that IL-17A contributes to middle ear injury through the p38 MAPK signaling pathway.