bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro
Susceptibility Testing of Tedizolid against Isolates of Nocardia
Authors: Brown-Elliott Barbara A. , Wallace Richard J. 
Published: September 2017

ABSTRACT

There is a paucity of efficacious antimicrobials (especially oral) against clinically relevant species of
Nocardia
. To date, all species of
Nocardia
have been susceptible to linezolid, the first commercially available oxazolidinone. Tedizolid is a new oxazolidinone with previously reported improved
in vitro
and
in vivo
(intracellular) potency against multidrug-resistant strains of
Mycobacterium
sp. and
Nocardia brasiliensis
. Using the current Clinical and Laboratory Standards Institute-recommended broth microdilution method, 101 isolates of
Nocardia
spp., including 29
Nocardia cyriacigeorgica
, 17
Nocardia farcinica
, 13
Nocardia nova
complex, 21
Nocardia brasiliensis
, 5
Nocardia pseudobrasiliensis
, and 5
Nocardia wallacei
isolates and 11 isolates of less common species, were tested for susceptibility to tedizolid and linezolid. For the most common clinically significant species of
Nocardia
, tedizolid MIC
50
values were 0.25 μg/ml for
N. nova
complex,
N. brasiliensis
,
N. pseudobrasiliensis
, and
N. wallacei
, compared to linezolid MIC
50
values of 1, 2, 0.5, and 1 μg/ml, respectively. Tedizolid and linezolid MIC
90
values were 2 μg/ml for
N. nova
complex and
N. brasiliensis
. Tedizolid MIC
50
and MIC
90
values for both
N. cyriacigeorgica
and
N. farcinica
were 0.5 μg/ml and 1 μg/ml, respectively, compared to linezolid MIC
50
and MIC
90
values of 2 and 4 μg/ml, respectively. Based on MIC
90
values, this study showed that tedizolid was 2- to 3-fold more active than linezolid
in vitro
against most common species of
Nocardia
, with the exception of the
N. nova
complex and
N. brasiliensis
, for which values were the same. These results may warrant evaluation of tedizolid as a potential treatment option for
Nocardia
infections.
Interplay among Resistance Profiles, High-Risk Clones, and Virulence in the Caenorhabditis elegansPseudomonas aeruginosa Infection Model
Authors: Sánchez-Diener Irina , Zamorano Laura , López-Causapé Carla , Cabot Gabriel , Mulet Xavier , Peña Carmen , del Campo Rosa , Cantón Rafael , Doménech-Sánchez Antonio , Martínez-Martínez Luis , Arcos Susana C. , Navas Alfonso , Oliver Antonio 
Published: September 2017

ABSTRACT

The increasing prevalence of nosocomial infections produced by multidrug-resistant (MDR) or extensively drug-resistant (XDR)
Pseudomonas aeruginosa
is frequently linked to widespread international strains designated high-risk clones. In this work, we attempted to decipher the interplay between resistance profiles, high-risk clones, and virulence, testing a large (
n
= 140) collection of well-characterized
P. aeruginosa
isolates from different sources (bloodstream infections, nosocomial outbreaks, cystic fibrosis, and the environment) in a
Caenorhabditis elegans
infection model. Consistent with previous data, we documented a clear inverse correlation between antimicrobial resistance and virulence in the
C. elegans
model. Indeed, the lowest virulence was linked to XDR profiles, which were typically linked to defined high-risk clones. However, virulence varied broadly depending on the involved high-risk clone; it was high for sequence type 111 (ST111) and ST235 but very low for ST175. The highest virulence of ST235 could be attributed to its
exoU
+
type III secretion system (TTSS) genotype, which was found to be linked with higher virulence in our
C. elegans
model. Other markers, such as motility or pigment production, were not essential for virulence in the
C. elegans
model but seemed to be related with the higher values of the statistical normalized data. In contrast to ST235, the ST175 high-risk clone, which is widespread in Spain and France, seems to be associated with a particularly low virulence in the
C. elegans
model. Moreover, the previously described G154R AmpR mutation, prevalent in ST175, was found to contribute to the reduced virulence, although it was not the only factor involved. Altogether, our results provide a major step forward for understanding the interplay between
P. aeruginosa
resistance profiles, high-risk clones, and virulence.
Antiviral Activity of Bictegravir and Cabotegravir against Integrase Inhibitor-Resistant SIVmac239 and HIV-1
Authors: Hassounah Said A. , Alikhani Ahmad , Oliveira Maureen , Bharaj Simrat , Ibanescu Ruxandra-Ilinca , Osman Nathan , Xu Hong-Tao , Brenner Bluma G. , Mesplède Thibault , Wainberg Mark A. 
Published: September 2017

ABSTRACT

Animal models are essential to study novel antiretroviral drugs, resistance-associated mutations (RAMs), and treatment strategies. Bictegravir (BIC) is a novel potent integrase strand transfer inhibitor (INSTI) that has shown promising results against HIV-1 infection
in vitro
and
in vivo
and against clinical isolates with resistance against INSTIs. BIC has a higher genetic barrier to the development of resistance than two clinically approved INSTIs, termed raltegravir and elvitegravir. Another clinically approved INSTI, dolutegravir (DTG) also possesses a high genetic barrier to resistance, while a fourth compound, termed cabotegravir (CAB), is currently in late phases of clinical development. Here we report the susceptibilities of simian immunodeficiency virus (SIV) and HIV-1 integrase (IN) mutants containing various RAMs to BIC, CAB, and DTG. BIC potently inhibited SIV and HIV-1 in single cycle infection with 50% effective concentrations (EC
50
s) in the low nM range. In single cycle SIV infections, none of the E92Q, T97A, Y143R, or N155H substitutions had a significant effect on susceptibility to BIC (≤4-fold increase in EC
50
), whereas G118R and R263K conferred ∼14-fold and ∼6-fold increases in EC
50
, respectively. In both single and multiple rounds of HIV-1 infections, BIC remained active against the Y143R, N155H, R263K, R263K/M50I, and R263K/E138K mutants (≤4-fold increase in EC
50
). In multiple rounds of infection, the G140S/Q148H combination of substitutions decreased HIV-1 susceptibility to BIC 4.8-fold compared to 16.8- and 7.4-fold for CAB and DTG, respectively. BIC possesses an excellent resistance profile in regard to HIV and SIV and could be useful in nonhuman primate models of HIV infection.
Experimental and Theoretical Approaches To Investigate the Immunogenicity of Taenia solium-Derived KE7 Antigen
Authors: Bobes Raúl J. , Navarrete-Perea José , Ochoa-Leyva Adrián , Anaya Víctor Hugo , Hernández Marisela , Cervantes-Torres Jacquelynne , Estrada Karel , Sánchez-Lopez Filiberto , Soberón Xavier , Rosas Gabriela , Nunes Cáris Maroni , García-Varela Martín , Sotelo-Mundo Rogerio Rafael , López-Zavala Alonso Alexis , Gevorkian Goar , Acero Gonzalo , Laclette Juan P. , Fragoso Gladis , Sciutto Edda 
Published: September 2017

ABSTRACT

Taenia solium
cysticercosis, a parasitic disease that affects human health in various regions of the world, is preventable by vaccination. Both the 97-amino-acid-long KETc7 peptide and its carboxyl-terminal, 18-amino-acid-long sequence (GK-1) are found in
Taenia crassiceps
. Both peptides have proven protective capacity against cysticercosis and are part of the highly conserved, cestode-native, 264-amino-acid long protein KE7. KE7 belongs to a ubiquitously distributed family of proteins associated with membrane processes and may participate in several vital cell pathways. The aim of this study was to identify the
T. solium
KE7 (TsKE7) full-length protein and to determine its immunogenic properties. Recombinant TsKE7 (rTsKE7) was expressed in
Escherichia coli
Rosetta2 cells and used to obtain mouse polyclonal antibodies. Anti-rTsKE7 antibodies detected the expected native protein among the 350 spots developed from
T. solium
cyst vesicular fluid in a mass spectrometry-coupled immune proteomic analysis. These antibodies were then used to screen a phage-displayed 7-random-peptide library to map B-cell epitopes. The recognized phages displayed 9 peptides, with the consensus motif Y(F/Y)PS sequence, which includes YYYPS (named GK-1M, for being a GK-1 mimotope), exactly matching a part of GK-1. GK-1M was recognized by 58% of serum samples from cysticercotic pigs with 100% specificity but induced weak protection against murine cysticercosis.
In silico
analysis revealed a universal T-cell epitope(s) in native TsKE7 potentially capable of stimulating cytotoxic T lymphocytes and helper T lymphocytes under different major histocompatibility complex class I and class II mouse haplotypes. Altogether, these results provide a rationale for the efficacy of the KETc7, rTsKE7, and GK-1 peptides as vaccines.
Ready Experimental Translocation of Mycobacterium canettii Yields Pulmonary Tuberculosis
Authors: Bouzid Fériel , Brégeon Fabienne , Lepidi Hubert , Donoghue Helen D. , Minnikin David E. , Drancourt Michel 
Published: September 2017

ABSTRACT

Mycobacterium canettii
, which has a smooth colony morphology, is the tuberculous organism retaining the most genetic traits from the putative last common ancestor of the rough-morphology
Mycobacterium tuberculosis
complex. To explore whether
M. canettii
can infect individuals by the oral route, mice were fed phosphate-buffered saline or 10
6
M. canettii
mycobacteria and sacrificed over a 28-day experiment. While no
M. canettii
was detected in negative controls,
M. canettii
-infected mice yielded granuloma-like lesions for 4/4 lungs at days 14 and 28 postinoculation (p.i.) and positive PCR detection of
M. canettii
for 5/8 mesenteric lymph nodes at days 1 and 3 p.i. and 5/6 pooled stools collected from day 1 to day 28 p.i. Smooth
M. canettii
colonies grew from 68% of lungs and 36% of spleens and cervical lymph nodes but fewer than 20% of axillary lymph nodes, livers, brown fat samples, kidneys, or blood samples throughout the 28-day experiment. Ready translocation in mice after digestive tract challenge demonstrates the potential of ingested
M. canettii
organisms to relocate to distant organs and lungs. The demonstration of this relocation supports the possibility that populations may be infected by environmental
M. canettii
.
Circuitry Linking the Global Csr- and σ
E
-Dependent Cell Envelope Stress Response Systems
Authors: Yakhnin Helen , Aichele Robert , Ades Sarah E. , Romeo Tony , Babitzke Paul 
Published: September 2017

ABSTRACT

CsrA of
Escherichia coli
is an RNA-binding protein that globally regulates a wide variety of cellular processes and behaviors, including carbon metabolism, motility, biofilm formation, and the stringent response. CsrB and CsrC are small RNAs (sRNAs) that sequester CsrA, thereby preventing CsrA-mRNA interaction. RpoE (σ
E
) is the extracytoplasmic stress response sigma factor of
E. coli
. Previous RNA sequencing (RNA-seq) studies identified
rpoE
mRNA as a CsrA target. Here, we explored the regulation of
rpoE
by CsrA and found that CsrA represses
rpoE
translation. Gel mobility shift, footprint, and toeprint studies identified three CsrA binding sites in the
rpoE
leader transcript, one of which overlaps the
rpoE
Shine-Dalgarno (SD) sequence, while another overlaps the
rpoE
translation initiation codon. Coupled
in vitro
transcription-translation experiments showed that CsrA represses
rpoE
translation by binding to these sites. We further demonstrate that σ
E
indirectly activates the transcription of
csrB
and
csrC
, leading to increased sequestration of CsrA, such that repression of
rpoE
by CsrA is reduced. We propose that the Csr system fine-tunes the σ
E
-dependent cell envelope stress response. We also identified a 51-amino-acid coding sequence whose stop codon overlaps the
rpoE
start codon and demonstrate that
rpoE
is translationally coupled with this upstream open reading frame (ORF51). The loss of coupling reduces
rpoE
translation by more than 50%. Identification of a translationally coupled ORF upstream of
rpoE
suggests that this previously unannotated protein may participate in the cell envelope stress response. In keeping with existing nomenclature, we named ORF51
rseD
, resulting in an operon arrangement of
rseD-rpoE-rseA-rseB-rseC
.

IMPORTANCE
CsrA posttranscriptionally represses genes required for bacterial stress responses, including the stringent response, catabolite repression, and the RpoS (σ
S
)-mediated general stress response. We show that CsrA represses the translation of
rpoE
, encoding the extracytoplasmic stress response sigma factor, and that σ
E
indirectly activates the transcription of
csrB
and
csrC
, resulting in reciprocal regulation of these two global regulatory systems. These findings suggest that extracytoplasmic stress leads to derepression of
rpoE
translation by CsrA, and CsrA-mediated repression helps reset RpoE abundance to prestress levels once envelope damage is repaired. The discovery of an ORF,
rseD
, translationally coupled with
rpoE
adds further complexity to translational control of
rpoE
.
Anti-CD137 Suppresses Tumor Growth by Blocking Reverse Signaling by CD137 Ligand
Authors: Kang Sang W. , Lee Sang C. , Park So H. , Kim Juyang , Kim Hyeon H. , Lee Hyeon-Woo , Seo Su K. , Kwon Byoung S. , Cho Hong R. , Kwon Byungsuk 
Published: September 2017

Abstract
CD137 (4-1BB) is a T-cell costimulatory molecule, and agonstic CD137 antibodies are currently being evaluated in the clinic as cancer immunotherapy. Recently, it was found that CD137−/− mice or mice injected with agonistic anti-CD137 antibodies exhibit heightened antitumor responses, contrary to expectations based on other knowledge of CD137 function. Here, we report findings related to reverse signaling by CD137 ligand (CD137L) in antigen-presenting dendritic cells (DC) in tumors that address these paradoxical results. Specifically, CD137L suppressed intratumoral differentiation of IL12-producing CD103+ DC and type 1 tumor-associated macrophages (TAM). Differentiation of these cell types is important because they are required to generate IFNγ-producing CD8+ cytotoxic T lymphocytes (Tc1). Notably, CD137L blockade increased levels of IL12 and IFNγ, which promoted intratumoral differentiation of IFNγ-producing Tc1, IL12-producing CD103+ DC, and type 1 TAM within tumors. Our results offer an explanation for the paradoxical effects of CD137 blockade, based on differential immunomodulatory effects of CD137 signaling and reverse signaling in T cells and DC, respectively. Further, they show how CD137L blockade can seed a forward-feedback loop for activation of CD103+ DC/type 1 TAM and Tc1 that can create a self-perpetuating cycle of highly effective immunosurveillance. Cancer Res; 77(21); 5989–6000. ©2017 AACR.
MetaLnc9 Facilitates Lung Cancer Metastasis via a PGK1-Activated AKT/mTOR Pathway
Authors: Yu Tao , Zhao Yingjun , Hu Zhixiang , Li Jing , Chu Dandan , Zhang Jiwei , Li Zhe , Chen Bing , Zhang Xiao , Pan Hongyu , Li Shengli , Lin Hechun , Liu Lei , Yan Mingxia , He Xianghuo , Yao Ming 
Published: September 2017

Abstract
Long noncoding RNAs (lncRNA) participate in carcinogenesis and tumor progression in lung cancer. Here, we report the identification of a lncRNA signature associated with metastasis of non–small cell lung cancer (NSCLC). In particular, elevated expression of LINC00963 (MetaLnc9) in human NSCLC specimens correlated with poor prognosis, promoted migration and invasion of NSCLC cells in vitro, and enhanced lung metastasis formation in vivo. Mechanistic investigations showed that MetaLnc9 interacted with the glycolytic kinase PGK1 and prevented its ubiquitination in NSCLC cells, leading to activation of the oncogenic AKT/mTOR signaling pathway. MetaLnc9 also interacted with P54nrb/NonO (NONO) to help mediate the activity of CRTC, a coactivator for the transcription factor CREB, reinforcing a positive feedback loop for metastasis. Taken together, our results establish MetaLnc9 as a driver of metastasis and a candidate therapeutic target for treating advanced NSCLC. Cancer Res; 77(21); 5782–94. ©2017 AACR.
In Silico Modeling of Immunotherapy and Stroma-Targeting Therapies in Human Colorectal Cancer
Authors: Kather Jakob Nikolas , Poleszczuk Jan , Suarez-Carmona Meggy , Krisam Johannes , Charoentong Pornpimol , Valous Nektarios A. , Weis Cleo-Aron , Tavernar Luca , Leiss Florian , Herpel Esther , Klupp Fee , Ulrich Alexis , Schneider Martin , Marx Alexander , Jäger Dirk , Halama Niels 
Published: September 2017

Abstract
Despite the fact that the local immunological microenvironment shapes the prognosis of colorectal cancer, immunotherapy has shown no benefit for the vast majority of colorectal cancer patients. A better understanding of the complex immunological interplay within the microenvironment is required. In this study, we utilized wet lab migration experiments and quantitative histological data of human colorectal cancer tissue samples (n = 20) including tumor cells, lymphocytes, stroma, and necrosis to generate a multiagent spatial model. The resulting data accurately reflected a wide range of situations of successful and failed immune surveillance. Validation of simulated tissue outcomes on an independent set of human colorectal cancer specimens (n = 37) revealed the model recapitulated the spatial layout typically found in human tumors. Stroma slowed down tumor growth in a lymphocyte-deprived environment but promoted immune escape in a lymphocyte-enriched environment. A subgroup of tumors with less stroma and high numbers of immune cells showed high rates of tumor control. These findings were validated using data from colorectal cancer patients (n = 261). Low-density stroma and high lymphocyte levels showed increased overall survival (hazard ratio 0.322, P = 0.0219) as compared with high stroma and high lymphocyte levels. To guide immunotherapy in colorectal cancer, simulation of immunotherapy in preestablished tumors showed that a complex landscape with optimal stroma permeabilization and immune cell activation is able to markedly increase therapy response in silico. These results can help guide the rational design of complex therapeutic interventions, which target the colorectal cancer microenvironment. Cancer Res; 77(22); 6442–52. ©2017 AACR.
Apoptotic Bodies Elicit Gas6-Mediated Migration of AXL-Expressing Tumor Cells
Authors: Zweemer Annelien J.M. , French Cory B. , Mesfin Joshua , Gordonov Simon , Meyer Aaron S. , Lauffenburger Douglas A. 
Published: September 2017

Abstract
Metastases are a major cause of cancer mortality. AXL, a receptor tyrosine kinase aberrantly expressed in many tumors, is a potent oncogenic driver of metastatic cell motility and has been identified as broadly relevant in cancer drug resistance. Despite its frequent association with changes in cancer phenotypes, the precise mechanism leading to AXL activation is incompletely understood. In addition to its ligand growth arrest specific-6 (Gas6), activation of AXL requires the lipid moiety phosphatidylserine (PS). Phosphatidylserine is only available to mediate AXL activation when it is externalized on cell membranes, an event that occurs during certain physiologic processes such as apoptosis. Here, it is reported that exposure of cancer cells to phosphatidylserine-containing vesicles, including synthetic liposomes and apoptotic bodies, contributes to enhanced migration of tumor cells via a PS–Gas6–AXL signaling axis. These findings suggest that anticancer treatments that induce fractional cell killing enhance the motility of surviving cells in AXL-expressing tumors, which may explain the widespread role of AXL in limiting therapeutic efficacy.
Implications: This study demonstrates that motility behavior of AXL-expressing tumor cells can be elicited by Gas6-bearing apoptotic bodies generated from tumor treatment with therapeutics that produce killing of a portion of the tumor cells present but not all, hence generating potentially problematic invasive and metastatic behavior of the surviving tumor cells. Mol Cancer Res; 15(12); 1656–66. ©2017 AACR.
Twenty‐Year Predictors of Peripheral Arterial Disease Compared With Coronary Heart Disease in the Scottish Heart Health Extended Cohort (SHHEC)
Authors: Tunstall‐Pedoe Hugh , Peters Sanne A. E. , Woodward Mark , Struthers Allan D. , Belch Jill J. F. 
Published: September 2017

Background

Coronary heart disease and peripheral arterial disease (
PAD
) affect different vascular territories. Supplementing baseline findings with assays from stored serum, we compared their 20‐year predictors.

Methods and Results

We randomly recruited 15 737 disease‐free men and women aged 30 to 75 years across Scotland between 1984 and 1995 and followed them through 2009 for death and hospital diagnoses. Of these, 3098 developed coronary heart disease (19.7%), and 499
PAD
(3.2%). Hazard ratios for 45 variables in the Cox model were adjusted for age and sex and for factors in the 2007
ASSIGN
cardiovascular risk score. Forty‐four of them were entered into parsimonious predictive models, tested by c‐statistics and net reclassification improvements. Many hazard ratios diminished with adjustment and parsimonious modeling, leaving significant survivors. The hazard ratios were mostly higher in
PAD
. New parsimonious models increased the c‐statistic and net reclassification improvements over
ASSIGN
variables alone but varied in their components and ranking. Coronary heart disease and
PAD
shared 7 of the 9 factors from
ASSIGN
: age, sex, family history, socioeconomic status, diabetes mellitus, tobacco smoking, and systolic blood pressure (but neither total nor high‐density lipoprotein cholesterol); plus 4 new ones:
NT
‐pro‐
BNP
, cotinine, high‐sensitivity C‐reactive protein, and cystatin‐C. The highest ranked hazard ratios for continuous factors in coronary heart disease were those for age, total cholesterol, high‐sensitivity troponin,
NT
‐pro‐
BNP
, cotinine, apolipoprotein A, and waist circumference (plus 10 more); in
PAD
they were age, high‐sensitivity C‐reactive protein, systolic blood pressure, expired carbon monoxide, cotinine, socioeconomic status, and lipoprotein (a) (plus 5 more).

Conclusions
The mixture of shared with disparate determinants for arterial disease in the heart and the legs implies nonidentical pathogenesis: cholesterol dominant in the former, and inflammation (high‐sensitivity C‐reactive protein, diabetes mellitus, smoking) in the latter.
Socio-Economic Factors in Companion Animal Relinquishment on the Sunshine Coast, Australia
Authors: Carter Jennifer , Taylor Clark Scott 
Published: September 2017

Abstract
There is a critical need to reduce the surrender rates of companion animals by understanding the socio-economic circumstances of caretakers. This research analyzed questionnaires with 117 relinquishers and 13 interviews. Interviews were conducted with relinquishers and staff at Sunshine Coast Animal Refuge Society and Sunshine Coast Animal Pound. Most companion animals relinquished were from litters and around half were de-sexed and micro-chipped. A caretaker’s living situation was a critical reason for relinquishment. Humans need to understand the time and space needs of companion species, how these might change with time, and the relationality between humans and companion animals. Alongside regulated breeding and accessible sterilization, shelter staff and other organizations might offer more tailored solutions, especially temporary care, during times of socio-economic crisis. Fundamentally, individuals need to critically examine their commitment to caretaking, but solutions are also structural and should be tailored to the underpinning socio-economic geography of different regions.