bluuebunny/crossref_metadata_2025_split huggingface dataset:
Management of pediatric hepatocellular carcinoma: A multimodal approach
Authors: Kohorst Mira A. , Warad Deepti M. , Matsumoto Jane M. , Heimbach Julie K. , El‐Youssef Mounif , Arndt Carola A. S. , Rodriguez Vilmarie , Nageswara Rao Amulya A. 
Published: June 2017

AbstractHCC is rare in the pediatric population, but is the second most common liver malignancy in children. Survival rates for primary unresectable HCC have been dismal. The objective of this study was to describe our experience with a multimodal approach for the management of unresectable HCC in two adolescent patients and to review the literature. Both patients are currently alive with no recurrence at 51 and 29 months post‐transplant. Multimodality treatment involving chemotherapy with doxorubicin, cisplatin, and sorafenib; TACE; timely liver transplantation; and post‐transplant therapy with sorafenib and mTOR inhibitors may help improve outcomes and prolong survival in pediatric patients with unresectable HCC.
Identification of Glyceraldehyde‐3‐Phosphate and Alcohol Dehydrogenases as Autoantigens in Doberman Hepatitis
Authors: Dyggve H. , Jarva H. , Spillmann T. , Speeti M. , Meri S. 
Published: June 2017

AbstractAn autoimmune background is suspected for Doberman hepatitis (DH). It is based on the finding of mononuclear cell infiltrates in the liver, strong female bias, association to the homozygous risk factor dog leucocyte antigen (DLA) allele DRB1*00601 and aberrant major histocompatibility complex (MHC) class II expression on hepatocytes that correlates with the degree of inflammation in the liver. The aim of this study was to search for autoantibodies against liver‐related antigens associated with DH. Twenty‐five Dobermans with subclinical DH (SDH), 13 that clinically manifest DH (CDH) and 17 healthy controls were studied. Immunoblotting analysis detected specific antibodies in the DH sera. By mass spectrometry the targets were identified as liver‐related enzymes glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) and alcohol dehydrogenase (ADH). Using ELISA, anti‐GAPDH IgG was detected in 36% (9/25) of SDH dogs and 69.2% (9/13) of the CDH dogs compared to healthy controls (0/17) (P < 0.0005). Anti‐ADH IgG was detected in 72% (18/25) of SDH dogs and 76.9% (10/13) of CDH dogs and only in one (1/17) control (P < 0.0005). The finding of novel autoantigens, GAPDH and ADH strengthen the hypothesis that DH is an autoimmune disease of the liver. These findings suggest that DH could be diagnosed by screening for autoantibodies against the defined antigens.
Tests for Structural Changes in Time Series of Counts
Authors: Hudecová Šárka , Hušková Marie , Meintanis Simos G. 
Published: June 2017

AbstractWe propose methods for detecting structural changes in time series with discrete‐valued observations. The detector statistics come in familiar L2‐type formulations incorporating the empirical probability generating function. Special emphasis is given to the popular models of integer autoregression and Poisson autoregression. For both models, we study mainly structural changes due to a change in distribution, but we also comment for the classical problem of parameter change. The asymptotic properties of the proposed test statistics are studied under the null hypothesis as well as under alternatives. A Monte Carlo power study on bootstrap versions of the new methods is also included along with a real data example.
Reversing the Negative Experience of Unemployment: A Mediating Role for Social Policies?
Authors: Sage Daniel 
Published: June 2017

AbstractThis article examines why unemployment is often experienced in a profoundly negative way, and explores the potentially mediating role of social policies. Three dominant theories of unemployment are described, which are often treated as competing, mutually exclusive explanations of the deleterious effects of unemployment. Subsequently, and through drawing upon a qualitative study of unemployed people, it is argued that all three theories are of worth and can be synthesized into a broader explanation of the experience of unemployment as an overarching process of loss. Three forms of loss are identified: loss of agency; loss of the functions of paid work; and loss of social status. The article then explores how these forms of loss can be both ameliorated and intensified through social policy interventions. Concluding, it offers policy recommendations to increase the efficacy of social policies in reversing the negative experience of unemployment, with the conclusion that this will require significant reform of the UK welfare state.
Pet ownership increases human risk of encountering ticks
Authors: Jones E. H. , Hinckley A. F. , Hook S. A. , Meek J. I. , Backenson B. , Kugeler K. J. , Feldman K. A. 
Published: June 2017

SummaryWe examined whether pet ownership increased the risk for tick encounters and tickborne disease among residents of three Lyme disease‐endemic states as a nested cohort within a randomized controlled trial. Information about pet ownership, use of tick control for pets, property characteristics, tick encounters and human tickborne disease were captured through surveys, and associations were assessed using univariate and multivariable analyses. Pet‐owning households had 1.83 times the risk (95% CI = 1.53, 2.20) of finding ticks crawling on and 1.49 times the risk (95% CI = 1.20, 1.84) of finding ticks attached to household members compared to households without pets. This large evaluation of pet ownership, human tick encounters and tickborne diseases shows that pet owners, whether of cats or dogs, are at increased risk of encountering ticks and suggests that pet owners are at an increased risk of developing tickborne disease. Pet owners should be made aware of this risk and be reminded to conduct daily tick checks of all household members, including the pets, and to consult their veterinarian regarding effective tick control products.
Pyrazinamide Susceptibility and
pncA
Mutation Profiles of Mycobacterium tuberculosis among Multidrug-Resistant Tuberculosis Patients in Bangladesh
Authors: Rahman Arfatur , Ferdous Sara Sabrina , Ahmed Shahriar , Rahman S. M. Mazidur , Uddin Mohammad Khaja Mafij , Pholwat Suporn , Gratz Jean , Houpt Eric , Banu Sayera 
Published: June 2017

ABSTRACT

Pyrazinamide (PZA) is a frontline antituberculosis (anti-TB) drug used in both first- and second-line treatment regimens. However, due to complex laboratory requirements, the PZA susceptibility test is rarely performed, leading to a scarcity of data on susceptibility to PZA. Bangladesh is a country with a burden of high rates of both TB and multidrug-resistant TB (MDR-TB), but to our knowledge, published data on rates of PZA susceptibility (PZA
s
), especially among MDR-TB patients, are limited. We aimed to analyze the PZA susceptibility patterns of
Mycobacterium tuberculosis
isolates from MDR-TB patients and to correlate the
pncA
mutation with PZA resistance in Bangladesh. A total of 169 confirmed MDR
M. tuberculosis
isolates from a pool of specimens collected in a nationwide surveillance study were included in this analysis. All the isolates were tested for phenotypic PZA susceptibility in Bactec mycobacterial growth indicator tube (MGIT) culture medium, and the
pncA
gene was sequenced. We also correlated different types of clinical information and treatment outcomes with PZA susceptibility. We found that 45% of isolates were phenotypically PZA resistant. Sequencing of the
pncA
gene revealed a high concordance (82.2%) between the
pncA
gene sequence and the phenotypic assay results. A total of 64 different mutations were found, and 9 isolates harbored multiple mutations. We detected 27 new
pncA
mutations. We did not find any significant correlation between the different clinical categories, the genetic lineage, or treatment outcome group and PZA susceptibility. Considering the turnaround time, sequencing would be the more feasible option to determine PZA susceptibility, and further studies to investigate the MIC of PZA should be conducted to determine an effective dose of the drug.
Identifying Spectra of Activity and Therapeutic Niches for Ceftazidime-Avibactam and Imipenem-Relebactam against Carbapenem-Resistant Enterobacteriaceae
Authors: Haidar Ghady , Clancy Cornelius J. , Chen Liang , Samanta Palash , Shields Ryan K. , Kreiswirth Barry N. , Nguyen M. Hong 
Published: June 2017

ABSTRACT

We determined imipenem, imipenem-relebactam, ceftazidime, and ceftazidime-avibactam MICs against 100 CRE isolates that underwent whole-genome sequencing.
Klebsiella pneumoniae
carbapenemases (KPCs) were the most common carbapenemases. Forty-six isolates carried extended-spectrum β-lactamases (ESBLs). With the addition of relebactam, imipenem susceptibility increased from 8% to 88%. With the addition of avibactam, ceftazidime susceptibility increased from 0% to 85%. Neither imipenem-relebactam nor ceftazidime-avibactam was active against metallo-β-lactamase (MBL) producers. Ceftazidime-avibactam (but not imipenem-relebactam) was active against OXA-48-like producers, including a strain not harboring any ESBL. Major OmpK36 porin mutations were independently associated with higher imipenem-relebactam MICs (
P
< 0.0001) and showed a trend toward independent association with higher ceftazidime-avibactam MICs (
P
= 0.07). The presence of variant KPC-3 was associated with ceftazidime-avibactam resistance (
P
< 0.0001). In conclusion, imipenem-relebactam and ceftazidime-avibactam had overlapping spectra of activity and niches in which each was superior. Major OmpK36 mutations in KPC-
K. pneumoniae
may provide a foundation for stepwise emergence of imipenem-relebactam and ceftazidime-avibactam resistance.
Topical Antimicrobial Treatments Can Elicit Shifts to Resident Skin Bacterial Communities and Reduce Colonization by Staphylococcus aureus Competitors
Authors: SanMiguel Adam J. , Meisel Jacquelyn S. , Horwinski Joseph , Zheng Qi , Grice Elizabeth A. 
Published: June 2017

ABSTRACT

The skin microbiome is a complex ecosystem with important implications for cutaneous health and disease. Topical antibiotics and antiseptics are often employed to preserve the balance of this population and inhibit colonization by more pathogenic bacteria. However, despite their widespread use, the impact of these interventions on broader microbial communities remains poorly understood. Here, we report the longitudinal effects of topical antibiotics and antiseptics on skin bacterial communities and their role in
Staphylococcus aureus
colonization resistance. In response to antibiotics, cutaneous populations exhibited an immediate shift in bacterial residents, an effect that persisted for multiple days posttreatment. By contrast, antiseptics elicited only minor changes to skin bacterial populations, with few changes to the underlying microbiota. While variable in scope, both antibiotics and antiseptics were found to decrease colonization by commensal
Staphylococcus
spp. by sequencing- and culture-based methods, an effect which was highly dependent on baseline levels of
Staphylococcus
. Because
Staphylococcus
residents have been shown to compete with the skin pathogen
S. aureus
, we also tested whether treatment could influence
S. aureus
levels at the skin surface. We found that treated mice were more susceptible to exogenous association with
S. aureus
and that precolonization with the same
Staphylococcus
residents that were previously disrupted by treatment reduced
S. aureus
levels by over 100-fold. In all, the results of this study indicate that antimicrobial drugs can alter skin bacterial residents and that these alterations can have critical implications for cutaneous host defense.
Pharmacokinetics, Safety, and Tolerability of Single-Dose Intravenous (ZTI-01) and Oral Fosfomycin in Healthy Volunteers
Authors: Wenzler E. , Ellis-Grosse E. J. , Rodvold K. A. 
Published: June 2017

ABSTRACT

The pharmacokinetics, safety, and tolerability of intravenous (i.v.) fosfomycin disodium (ZTI-01) and oral fosfomycin tromethamine were evaluated after a single dose in 28 healthy adult subjects. Subjects received a single 1-h i.v. infusion of 1 g and 8 g fosfomycin disodium and a single dose of 3 g oral fosfomycin tromethamine in a phase I, randomized, open-label, three-period crossover study. Serial blood and urine samples were collected before and up to 48 h after dosing. The mean pharmacokinetic parameters ± standard deviations of fosfomycin in plasma after 1 g and 8 g i.v., respectively, were the following: maximum clearance of drug in serum (
C
max
), 44.3 ± 7.6 and 370 ± 61.9 μg/ml; time to maximum concentration of drug in serum (
T
max
), 1.1 ± 0.05 and 1.08 ± 0.01 h; volume of distribution (
V
), 29.7 ± 5.7 and 31.5 ± 10.4 liters; clearance (CL), 8.7 ± 1.7 and 7.8 ± 1.4 liters/h; renal clearance (CL
R
), 6.6 ± 1.9 and 6.3 ± 1.6 liters/h; area under the concentration-time curve from 0 to infinity (AUC
0–∞
), 120 ± 28.5 and 1,060 ± 192 μg·h/ml; and half-life (
t
1/2
), 2.4 ± 0.4 and 2.8 ± 0.6 h. After oral administration, the parameters were the following:
C
max
, 26.8 ± 6.4 μg/ml;
T
max
, 2.25 ± 0.4 h;
V
/F, 204 ± 70.7 liters; CL/F, 17 ± 4.7 liters/h; CL
R
, 6.5 ± 1.8 liters/h; AUC
0–∞
, 191 ± 57.6 μg · h/ml; and
t
1/2
, 9.04 ± 4.5 h. The percent relative bioavailability of orally administered fosfomycin was 52.8% in relation to the 1-g i.v. dose. Approximately 74% and 80% of the 1-g and 8-g i.v. doses were excreted unchanged in the urine by 48 h compared to 37% after oral administration, with the majority of this excretion occurring by 12 h regardless of dosage form. No new safety concerns were identified during this study. The results of this study support further investigation of i.v. fosfomycin in the target patient population, including patients with complicated urinary tract infections and pyelonephritis.
The Enterohemorrhagic Escherichia coli Effector EspW Triggers Actin Remodeling in a Rac1-Dependent Manner
Authors: Sandu Pamela , Crepin Valerie F. , Drechsler Hauke , McAinsh Andrew D. , Frankel Gad , Berger Cedric N. 
Published: June 2017

ABSTRACT

Enterohemorrhagic
Escherichia coli
(EHEC) is a diarrheagenic pathogen that colonizes the gut mucosa and induces attaching-and-effacing lesions. EHEC employs a type III secretion system (T3SS) to translocate 50 effector proteins that hijack and manipulate host cell signaling pathways, which allow bacterial colonization and subversion of immune responses and disease progression. The aim of this study was to characterize the T3SS effector EspW. We found
espW
in the sequenced O157:H7 and non-O157 EHEC strains as well as in
Shigella boydii
. Furthermore, a truncated version of EspW, containing the first 206 residues, is present in EPEC strains belonging to serotype O55:H7. Screening a collection of clinical EPEC isolates revealed that
espW
is present in 52% of the tested strains. We report that EspW modulates actin dynamics in a Rac1-dependent manner. Ectopic expression of EspW results in formation of unique membrane protrusions. Infection of Swiss cells with an EHEC
espW
deletion mutant induces a cell shrinkage phenotype that could be rescued by Rac1 activation via expression of the bacterial guanine nucleotide exchange factor, EspT. Furthermore, using a yeast two-hybrid screen, we identified the motor protein Kif15 as a potential interacting partner of EspW. Kif15 and EspW colocalized in cotransfected cells, while ectopically expressed Kif15 localized to the actin pedestals following EHEC infection. The data suggest that Kif15 recruits EspW to the site of bacterial attachment, which in turn activates Rac1, resulting in modifications of the actin cytoskeleton that are essential to maintain cell shape during infection.
Regulation of Type III Secretion of Translocon and Effector Proteins by the EsaB/EsaL/EsaM Complex in Edwardsiella tarda
Authors: Liu Lu Yi , Nie Pin , Yu Hong Bing , Xie Hai Xia 
Published: June 2017

ABSTRACT

The type III secretion system (T3SS) plays a crucial role in the pathogenesis of many Gram-negative bacteria, including
Edwardsiella tarda
, an important fish pathogen. Within the
E. tarda
T3SS, there are three proteins (EsaB/EsaL/EsaM) that are homologous to proteins present in many other bacteria, including SpiC/SsaL/SsaM in
Salmonella
, SepD/SepL/CesL in enteropathogenic
Escherichia coli
(EPEC) and enterohemorrhagic
E. coli
(EHEC), and YscB/YopN/SycN in
Yersinia
. EsaL was found to interact with both EsaB and EsaM within the bacterial cell, as revealed by a coimmunoprecipitation assay. Moreover, EsaM is required for EsaB stability, and the two proteins interact with each other. EsaB, EsaL, and EsaM are all indispensable for the secretion of the T3SS translocon protein EseC into supernatants under pH 5.5 and pH 7.2 conditions. Unlike EseC, EseG is a T3SS effector whose secretion is suppressed by EsaL at pH 7.2 while it is promoted at pH 5.5 condition. Despite this finding, mutant strains lacking EsaB, EsaL, or EsaM (i.e., the Δ
esaB
, Δ
esaL
, or Δ
esaM
strain, respectively) were all outcompeted by wild-type
E. tarda
during a coinfection model. These results demonstrate that EsaB/EsaL/EsaM form a ternary complex controlling the secretion of T3SS translocon and effector proteins and contributing to
E. tarda
pathogenesis.
Polar Organizing Protein PopZ Is Required for Chromosome Segregation in Agrobacterium tumefaciens
Authors: Ehrle Haley M. , Guidry Jacob T. , Iacovetto Rebecca , Salisbury Anne K. , Sandidge D. J. , Bowman Grant R. 
Published: June 2017

ABSTRACT

Despite being perceived as relatively simple organisms, many bacteria exhibit an impressive degree of subcellular organization. In
Caulobacter crescentus
, the evolutionarily conserved polar organizing protein PopZ facilitates cytoplasmic organization by recruiting chromosome centromeres and regulatory proteins to the cell poles. Here, we characterize the localization and function of PopZ in
Agrobacterium tumefaciens
, a genetically related species with distinct anatomy. In this species, we find that PopZ molecules are relocated from the old pole to the new pole in the minutes following cell division. PopZ is not required for the localization of the histidine kinases DivJ and PdhS1, which become localized to the old pole after PopZ relocation is complete. The histidine kinase PdhS2 is temporally and spatially related to PopZ in that it localizes to transitional poles just before they begin to shed PopZ and disappears from the old pole after PopZ relocalization. At the new pole, PopZ is required for tethering the centromere of at least one of multiple replicons (chromosome I), and the loss of
popZ
results in a severe chromosome segregation defect, aberrant cell division, and cell mortality. After cell division, the daughter that inherits polar PopZ is shorter in length and delayed in chromosome I segregation compared to its sibling. In this cell type, PopZ completes polar relocation well before the onset of chromosome segregation. While
A. tumefaciens
PopZ resembles its
C. crescentus
homolog in chromosome tethering activity, other aspects of its localization and function indicate distinct properties related to differences in cell organization.

IMPORTANCE
Members of the
Alphaproteobacteria
exhibit a wide range of phenotypic diversity despite sharing many conserved genes. In recent years, the extent to which this diversity is reflected at the level of subcellular organization has become increasingly apparent. However, which factors control such organization and how they have changed to suit different body plans are poorly understood. This study focuses on PopZ, which is essential for many aspects of polar organization in
Caulobacter crescentus
, but its role in other species is unclear. We explore the similarities and differences in PopZ functions between
Agrobacterium tumefaciens
and
Caulobacter crescentus
and conclude that PopZ lies at a point of diversification in the mechanisms that control cytoplasmic organization and cell cycle regulation in
Alphaproteobacteria
.
DNA Damage and Repair Biomarkers of Immunotherapy Response
Authors: Mouw Kent W. , Goldberg Michael S. , Konstantinopoulos Panagiotis A. , D'Andrea Alan D. 
Published: June 2017

Abstract
DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the antitumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies.
Significance: Only a subset of patients respond to immune checkpoint blockade, and reliable predictive biomarkers of response are needed to guide therapy decisions. DNA repair deficiency is common among tumors, and emerging experimental and clinical evidence suggests that features of genomic instability are associated with response to immune-directed therapies. Cancer Discov; 7(7); 675–93. ©2017 AACR.
Multiparametric Model for Penumbral Flow Prediction in Acute Stroke
Authors: Livne Michelle , Kossen Tabea , Madai Vince I. , Zaro-Weber Olivier , Moeller-Hartmann Walter , Mouridsen Kim , Heiss Wolf-Dieter , Sobesky Jan 
Published: June 2017

Background and Purpose—
Identification of salvageable penumbra tissue by dynamic susceptibility contrast magnetic resonance imaging is a valuable tool for acute stroke patient stratification for treatment. However, prior studies have not attempted to combine the different perfusion maps into a predictive model. In this study, we established a multiparametric perfusion imaging model and cross-validated it using positron emission tomography perfusion for detection of penumbral flow.

Methods—
In a retrospective analysis of 17 subacute stroke patients with consecutive magnetic resonance imaging and H2O15 positron emission tomography scans, perfusion maps of cerebral blood flow, cerebral blood volume, mean transit time, time-to-maximum, and time-to-peak were constructed and combined using a generalized linear model (GLM). Both the GLM maps and the single perfusion maps alone were cross-validated with positron emission tomography-cerebral blood flow scans to predict penumbral flow on a voxel-wise level. Performance was tested by receiver-operating characteristics curve analysis, that is, the area under the curve, and the models’ fits were compared using the likelihood ratio test.

Results—

The GLM demonstrated significantly improved model fit compared with each of the single perfusion maps (
P
<1×e-5) and demonstrated higher performance, with an area under the curve of 0.91. However, the absolute difference between the performance of GLM and the best-performing single perfusion parameter (time-to-maximum) was relatively low (area under the curve difference =0.04).

Conclusions—
Our results support a dynamic susceptibility contrast magnetic resonance imaging–based GLM as an improved model for penumbral flow prediction in stroke patients. With given perfusion maps, this model is a straightforward and observer-independent alternative for therapy stratification.