bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Single Amino Acid Replacement in the Sensor Kinase LiaS Contributes to a Carrier Phenotype in Group A Streptococcus
Authors: Flores Anthony R. , Jewell Brittany E. , Yelamanchili Dedipya , Olsen Randall J. , Musser James M. 
Published: August 2015

ABSTRACT

Despite the high frequency of asymptomatic carriage of bacterial pathogens, we understand little about the bacterial molecular genetic underpinnings of this phenomenon. To obtain new information about the molecular genetic mechanisms underlying carriage of group A
Streptococcus
(GAS), we performed whole-genome sequencing of GAS strains recovered from a single individual during acute pharyngitis and subsequent asymptomatic carriage. We discovered that compared to the initial infection isolate, the strain recovered during asymptomatic carriage contained three single nucleotide polymorphisms, one of which was in a highly conserved region of a gene encoding a sensor kinase,
liaS
, resulting in an arginine-to-glycine amino acid replacement at position 135 of LiaS (LiaS
R135G
). Using gene replacement, we demonstrate that introduction of the carrier allele (
liaS
R135G
) into a serotype-matched invasive strain increased mouse nasopharyngeal colonization and adherence to cultured human epithelial cells. The carrier mutation also resulted in a reduced ability to grow in human blood and reduced virulence in a mouse model of necrotizing fasciitis. Repair of the mutation in the GAS carrier strain restored virulence and decreased adherence to cultured human epithelial cells. We also provide evidence that the carrier mutation alters the GAS transcriptome, including altered transcription of GAS virulence genes, providing a potential mechanism for the pleiotropic phenotypic effects. Our data obtained using isogenic strains suggest that the
liaS
R135G
mutation in the carrier strain contributes to the transition from disease to asymptomatic carriage and provides new information about this poorly described regulatory system in GAS.
Simultaneous Host-Pathogen Transcriptome Analysis during Granulibacter bethesdensis Infection of Neutrophils from Healthy Subjects and Patients with Chronic Granulomatous Disease
Authors: Greenberg David E. , Sturdevant Daniel E. , Marshall-Batty Kimberly R. , Chu Jessica , Pettinato Anthony M. , Virtaneva Kimmo , Lane John , Geller Bruce L. , Porcella Stephen F. , Gallin John I. , Holland Steven M. , Zarember Kol A. 
Published: August 2015

ABSTRACT

Polymorphonuclear leukocytes (PMN) from patients with chronic granulomatous disease (CGD) fail to produce microbicidal concentrations of reactive oxygen species (ROS) due to mutations in NOX2. Patients with CGD suffer from severe, life-threatening infections and inflammatory complications.
Granulibacter bethesdensis
is an emerging Gram-negative pathogen in CGD that resists killing by PMN of CGD patients (CGD PMN) and inhibits PMN apoptosis through unknown mechanisms. Microarray analysis was used to study mRNA expression in PMN from healthy subjects (normal PMN) and CGD PMN during incubation with
G. bethesdensis
and, simultaneously, in
G. bethesdensis
with normal and CGD PMN. We detected upregulation of antiapoptotic genes (e.g., XIAP and GADD45B) and downregulation of proapoptotic genes (e.g., CASP8 and APAF1) in infected PMN. Transcript and protein levels of inflammation- and immunity-related genes were also altered. Upon interaction with PMN,
G. bethesdensis
altered the expression of ROS resistance genes in the presence of normal but not CGD PMN. Levels of bacterial stress response genes, including the ClpB gene, increased during phagocytosis by both normal and CGD PMN demonstrating responses to oxygen-independent PMN antimicrobial systems. Antisense knockdown demonstrated that ClpB is dispensable for extracellular growth but is essential for bacterial resistance to both normal and CGD PMN. Metabolic adaptation of
Granulibacter
growth in PMN included the upregulation of pyruvate dehydrogenase. Pharmacological inhibition of pyruvate dehydrogenase by triphenylbismuthdichloride was lethal to
Granulibacter
. This study expands knowledge of microbial pathogenesis of
Granulibacter
in cells from permissive (CGD) and nonpermissive (normal) hosts and identifies potentially druggable microbial factors, such as pyruvate dehydrogenase and ClpB, to help combat this antibiotic-resistant pathogen.
The Mga Regulon but Not Deoxyribonuclease Sda1 of Invasive M1T1 Group A Streptococcus Contributes to
In Vivo
Selection of CovRS Mutations and Resistance to Innate Immune Killing Mechanisms
Authors: Liu Guanghui , Feng Wenchao , Li Dengfeng , Liu Mengyao , Nelson Daniel C. , Lei Benfang 
Published: August 2015

ABSTRACT

Invasive M1T1 group A
Streptococcus
(GAS) can have a mutation in the regulatory system CovRS, and this mutation can render strains hypervirulent. Interestingly, via mechanisms that are not well understood, the host innate immune system's neutrophils select spontaneous M1T1 GAS CovRS hypervirulent mutants, thereby enhancing the pathogen's ability to evade immune killing. It has been reported that the DNase Sda1 is critical for the resistance of M1T1 strain 5448 to killing in human blood and provides pressure for
in vivo
selection of CovRS mutations. We reexamined the role of Sda1 in the selection of CovRS mutations and in GAS innate immune evasion. Deletion of
sda1
or all DNase genes in M1T1 strain MGAS2221 did not alter emergence of CovRS mutants during murine infection. Deletion of
sda1
in strain 5448 resulted in Δ
sda1
mutants with (5448 Δ
sda1
M+
strain) and without (5448 Δ
sda1
M−
strain) M protein production. The 5448 Δ
sda1
M+
strain accumulated CovRS mutations
in vivo
and resisted killing in the bloodstream, whereas the 5448 Δ
sda1
M−
strain lost
in vivo
selection of CovRS mutations and was sensitive to killing. The deletion of
emm
and a spontaneous Mga mutation in MGAS2221 reduced and prevented
in vivo
selection for CovRS mutants, respectively. Thus, in contrast to previous reports, Sda1 is not critical for
in vivo
selection of invasive M1T1 CovRS mutants and GAS resistance to innate immune killing mechanisms. In contrast, M protein and other Mga-regulated proteins contribute to the
in vivo
selection of M1T1 GAS CovRS mutants. These findings advance the understanding of the progression of invasive M1T1 GAS infections.
Regulation of DNA Replication Initiation by Chromosome Structure
Authors: Magnan David , Bates David 
Published: August 2015

ABSTRACT

Recent advancements in fluorescence imaging have shown that the bacterial nucleoid is surprisingly dynamic in terms of both behavior (movement and organization) and structure (density and supercoiling). Links between chromosome structure and replication initiation have been made in a number of species, and it is universally accepted that favorable chromosome structure is required for initiation in all cells. However, almost nothing is known about whether cells use changes in chromosome structure as a regulatory mechanism for initiation. Such changes could occur during natural cell cycle or growth phase transitions, or they could be manufactured through genetic switches of topoisomerase and nucleoid structure genes. In this review, we explore the relationship between chromosome structure and replication initiation and highlight recent work implicating structure as a regulatory mechanism. A three-component origin activation model is proposed in which thermal and topological structural elements are balanced with
trans
-acting control elements (DnaA) to allow efficient initiation control under a variety of nutritional and environmental conditions. Selective imbalances in these components allow cells to block replication in response to cell cycle impasse, override once-per-cell-cycle programming during growth phase transitions, and promote reinitiation when replication forks fail to complete.
Early functional rehabilitation or cast immobilisation for the postoperative management of acute Achilles tendon rupture? A systematic review and meta-analysis of randomised controlled trials
Authors: McCormack R , Bovard J 
Published: August 2015

ObjectiveTo determine which postoperative rehabilitation regime is superior following surgical repair of acute Achilles tendon rupture. The primary outcomes were patient safety and satisfaction.DesignIntervention meta-analysis.Data sourcesThe MEDLINE and CINAHL electronic databases were searched from their date of inception until June 2015 using keywords related to acute Achilles tendon rupture, surgical repair and rehabilitation. The electronic database search was supplemented with forward citation tracking using the Web of Science.Eligibility criteriaRandomised controlled trials comparing clinical and/or patient-reported outcomes between patients receiving early functional postoperative ankle motion and weight bearing (bracing group), and traditional ankle immobilisation with a non-weight bearing rigid cast (cast group) were eligible for inclusion. Fourteen articles were identified as potentially eligible; 10 sufficient-quality randomised controlled trials involving 570 patients were included for meta-analysis.Main resultsA high proportion of patients were able to return to prior employment and sporting activity in both groups. Five of the six trials measuring the time interval showed a faster return to prior sporting level in the bracing group. Subjective patient outcomes were significantly better in the bracing group (for good and excellent results, p=0.01; OR, 3.13; 95% CI 1.30 to 7.53). There was no difference in major complications between the two groups (p=0.21; RD, −0.03; 95% CI −0.06 to 0.01). Dynamometry and anthropometry measurements favoured functional rehabilitation at 6–12 weeks postoperation; however, by 6 months postoperative, the differences were negligible.ConclusionsCompared to traditional ankle immobilisation, with a non-weight bearing cast following surgical repair of acute Achilles tendon rupture, early dynamic functional rehabilitation is as safe with higher patient satisfaction.
Re-treatment of patients with chronic hepatitis C virus genotype 4 infection with pegylated interferon and ribavirin: a meta-analysis
Authors: Zhang Bing , Nguyen Nghia H , Yee Brittany E , Yip Benjamin , Nguyen Mindie H 
Published: August 2015

BackgroundAn estimated 170 million people worldwide are infected with hepatitis C virus (HCV). HCV genotype 4 (HCV-4)—the most prevalent hepatitis C strain in the Middle East and Africa—is difficult to treat, with an estimated sustained virological response (SVR) of 53% when using pegylated interferon and ribavirin (P/R) in treatment-naïve patients with HCV-4 infection. In regions where access to direct-acting antivirals is limited, re-treatment of patients who failed therapy with another course of P/R may be an option if the success rate is acceptable.ObjectivesWe aimed to determine the SVR from retreatment with P/R in treatment-experienced patients with HCV-4 infection.MethodsWe performed a meta-analysis using MEDLINE and EMBASE searches, and by reviewing article bibliographies and abstracts from recent Liver Society Meetings. Original studies featuring at least 10 adult, treatment-experienced patients with HCV-4 infection failing prior interferon-based therapy and receiving subsequent re-treatment with P/R were included.Results3 studies were included. Overall pooled SVR was 32.7%, or 41/126 patients. No significant heterogeneity existed among the studies. One study reported higher SVR of 50% in previous relapsers, compared with 23% in previous non-responders.ConclusionsAs expected, treatment-experienced patients achieved lower rate of SVR compared with previously reported SVR for treatment-naïve patients with HCV-4 infection. The abysmal rate of success from re-treatment with P/R supports the use of direct-acting antivirals whenever re-treatment is considered, even in resource-limited regions.
Do pneumonia readmissions flagged as potentially preventable by the 3M PPR software have more process of care problems? A cross-sectional observational study
Authors: Borzecki Ann M , Chen Qi , Restuccia Joseph , Mull Hillary J , Shwartz Michael , Gupta Kalpana , Hanchate Amresh , Strymish Judith , Rosen Amy 
Published: August 2015

BackgroundIn the USA, administrative data-based readmission rates such as the Centers for Medicare and Medicaid Services’ all-cause readmission measures are used for public reporting and hospital payment penalties. To improve this measure and identify better quality improvement targets, 3M developed the Potentially Preventable Readmissions (PPRs) measure. It matches clinically related index admission and readmission diagnoses that may indicate readmissions resulting from admission- or post-discharge-related quality problems.ObjectiveTo examine whether PPR software-flagged pneumonia readmissions are associated with poorer quality of care.MethodsUsing a retrospective observational study design and Veterans Health Administration (VA) data, we identified pneumonia discharges associated with 30-day readmissions, and then flagged cases as PPR–yes or PPR–no using the PPR software. To assess quality of care, we abstracted electronic medical records of 100 random readmissions using a tool containing explicit care processes organised into admission work-up, in-hospital evaluation/treatment, discharge readiness and post-discharge period. We derived quality scores, scaled to a maximum of 25 per section (maximum total score=100) and compared cases by total and section-specific mean scores using t tests and effect size (ES) to characterise the clinical significance of findings.ResultsOur abstraction sample was selected from 11 278 pneumonia readmissions (readmission rate=16.5%) during 1 October 2005–30 September 2010; 77% were flagged as PPR–yes. Contrary to expectations, total and section mean quality scores were slightly higher, although non-significantly, among PPR–yes (N=77) versus PPR–no (N=23) cases (respective total scores, 71.2±8.7 vs 65.8±11.5, p=0.14); differences demonstrated ES >0.30 overall and for admission work-up and post-discharge period sections.ConclusionsAmong VA pneumonia readmissions, PPR categorisation did not produce the expected quality of care findings. Either PPR–yes cases are not more preventable, or preventability assessment requires other data collection methods to capture poorly documented processes (eg, direct observation).
Correlation betweenDPYDgene variation andKRASwild type status in colorectal cancer
Authors: Kleist Britta , Kempa Marcel , Meurer Thuja , Poetsch Micaela 
Published: August 2015

AimsFailure and side effects of combined cytotoxic therapy are challenges in the treatment of metastatic colorectal cancer (CRC).DPYDgene variations can potentially predict toxicity to 5-fluorouracil (FU)-based therapy andKRAS-,NRAS-,BRAF-,PIK3CA-wild type status is a known prerequisite for epidermal growth factor receptor (EGFR) inhibitor therapy. This study was performed to search for a possible link between these therapeutic markers.MethodsTheDPYDgene variations c.496A>G, c.1679T>G, c.2846A>T andKRAS/NRAS/BRAF/PIK3CAmutational status were determined in non-neoplastic, primary CRC and metastatic CRC tissue from 115 patients.ResultsThe polymorphism c.496A>G was theDPYDgene variant with the highest detection rate (12.9%), occurred predominantly in females (86.7%, p=0.0044) and was exclusively seen inKRASwild type primary CRC (15/65 (23.1%) vs 0/51 (0%) inKRAS-mutated primary CRC, respectively, p=0.0001).ConclusionsThis genetic profile could define a patient group requiring alternative combined therapeutic approaches. Global testing of large patient cohorts is necessary to prove this concept.
High Ki67 expression is an independent good prognostic marker in colorectal cancer
Authors: Melling Nathaniel , Kowitz Charlotte Marie , Simon Ronald , Bokemeyer Carsten , Terracciano Luigi , Sauter Guido , Izbicki Jakob Robert , Marx Andreas Holger 
Published: August 2015

AimsTo correlate Ki67 expression with outcome in colorectal cancer (CRC).MethodsKi67 labelling index (Ki67LI) was analysed by immunohistochemistry on a tissue microarray containing 1800 CRCs. The results were compared with clinicopathological and molecular parameters.ResultsKi67LI was considered low in 26.3%, moderate in 56.7% and high in 17.0% of 1653 interpretable CRCs. High Ki67 expression was associated with low tumour stage (p<0.0001) and nodal status (p=0.0315), but not with tumour grade (p=0.8639), histological tumour type (p=0.1542) or tumour localisation, and was an independent prognosticator of favourable survival (p=0.0121). High Ki67 expression was also significantly associated with high-level nuclear β-catenin and p53 expression (p<0.0001 and p=0.0095, respectively).ConclusionsIn summary, our data show that high Ki67 expression in CRCs is associated with good clinical outcome. Ki67, p53 and β-catenin overexpression seem to be linked to CRC, and indicate a cellular state of high proliferative activity. Finally, our findings strongly argue for a clinical utility of Ki67 immunostaining as an independent prognostic biomarker in CRC.
An immunohistochemical comparison of two TTF-1 monoclonal antibodies in atypical squamous lesions and sarcomatoid carcinoma of the lung, and pleural malignant mesothelioma*
Authors: Klebe Sonja , Swalling Adam , Jonavicius Lisa , Henderson Douglas W 
Published: August 2015

Immunohistochemical detection of thyroid transcription factor-1 (TTF-1) plays an important role in the diagnosis and subclassification of non-small cell carcinomas of the lung in biopsy and some cytology samples, specifically for identification of squamous cell carcinoma (classically negative) and non-mucinous adenocarcinoma (positive in most cases) and for discrimination between lung adenocarcinoma and pleural malignant mesothelioma (classically negative).Aims and methodsWe carried out a comparison of the widely used mouse monoclonal TTF-1 antibody based on the 8G7G3/1 clone versus the more recently introduced rabbit monoclonal antibody (MAb) based on the SP141 clone.ResultsBoth antibodies labelled alveolar epithelium in normal lung parenchyma, but the SP141 antibody also labelled bronchial mucosal basal cells. All 13 cases of atypical squamous lesions (including one case of bronchial squamous dysplasia) were negative with the 8G7G3/1 antibody, but 6/13 cases of squamous carcinoma/dysplasia showed positive nuclear labelling with the SP141 antibody in the same tissue biopsy. All 35 cases of adenocarcinoma of the lung were positive with both antibodies. For 12 cases of sarcomatoid carcinoma of the lung, two cases were labelled with the 8G7G3/1 antibody, whereas positive labelling of 4/12 cases was observed with SP141. All 66 cases of epithelioid malignant mesothelioma were negative with both antibodies, but 8/19 cases of sarcomatoid mesothelioma showed positive nuclear labelling with the SP141 antibody (0/19 with 8G7G3/1).ConclusionsOur findings indicate differences in the rates of positive and negative labelling with these two antibodies, and suggest the potential for misclassification of a proportion of squamous carcinomas of the lung as adenocarcinoma, and for misdiagnosis of some sarcomatoid mesotheliomas as sarcomatoid carcinoma of the lung. If the results of SP141 are assigned overriding significance, our findings further indicate that in isolation, neither negative labelling with either 8G7G3/1 or SP141 nor positive labelling with the SP141 MAb discriminates between sarcomatoid carcinoma and sarcomatoid mesothelioma, whereas positive labelling with the 8G7G3/1 MAb favours a diagnosis of sarcomatoid carcinoma. The literature suggests that these seemingly ‘aberrant’ results with the SP141 antibody are not ‘false’ positives, but rather real detection of low levels of TTF-1 protein in a broader range of tumours than is widely recognised.
β-Blockers are associated with a reduction in COPD exacerbations
Authors: Bhatt Surya P , Wells James M , Kinney Gregory L , Washko George R , Budoff Matthew , Kim Young-il , Bailey William C , Nath Hrudaya , Hokanson John E , Silverman Edwin K , Crapo James , Dransfield Mark T 
Published: August 2015

BackgroundWhile some retrospective studies have suggested that β-blocker use in patients with COPD is associated with a reduction in the frequency of acute exacerbations and lower mortality, there is concern that their use in patients with severe COPD on home oxygen may be harmful.MethodsSubjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2–4 COPD participating in a prospective follow-up of the COPDGene cohort, a multicentre observational cohort of current and former smokers were recruited. Total and severe exacerbation rates were compared between groups categorised by β-blocker use on longitudinal follow-up using negative binomial regression analyses, after adjustment for demographics, airflow obstruction, %emphysema on CT, respiratory medications, presence of coronary artery disease, congestive heart failure and coronary artery calcification, and after adjustment for propensity to prescribe β-blockers.Results3464 subjects were included. During a median of 2.1 years of follow-up, β-blocker use was associated with a significantly lower rate of total (incidence risk ratio (IRR) 0.73, 95% CI 0.60 to 0.90; p=0.003) and severe exacerbations (IRR 0.67, 95% CI 0.48 to 0.93; p=0.016). In those with GOLD stage 3 and 4 and on home oxygen, use of β-blockers was again associated with a reduction in the rate of total (IRR 0.33, 95% CI 0.19 to 0.58; p<0.001) and severe exacerbations (IRR 0.35, 95% CI 0.16 to 0.76; p=0.008). Exacerbation reduction was greatest in GOLD stage B. There was no difference in all-cause mortality with β-blocker use.Conclusionsβ-Blockers are associated with a significant reduction in COPD exacerbations regardless of severity of airflow obstruction. The findings of this study should be tested in a randomised, placebo-controlled trial.Trial registration number(ClinicalTrials.gov NCT00608764).
STAT3 Blockade Inhibits Radiation-Induced Malignant Progression in Glioma
Authors: Lau Jasmine , Ilkhanizadeh Shirin , Wang Susan , Miroshnikova Yekaterina A. , Salvatierra Nicolas A. , Wong Robyn A. , Schmidt Christin , Weaver Valerie M. , Weiss William A. , Persson Anders I. 
Published: August 2015

Abstract
High grade gliomas (HGG) are classified into four subgroups based on transcriptional signatures and phenotypic characteristics. In particular, the proneural-to-mesenchymal transition (PMT) is associated with increased malignancy, poor prognosis, and disease recurrence, but the underlying causes of PMT are still unclear. In this study, we investigated whether radiotherapy promotes PMT using a genetically engineered mouse model of proneural HGG. We found that cranial ionizing radiation induced robust and durable PMT in tumors. Additionally, we isolated primary proneural HGG cells from mouse and human tumors and demonstrate that radiation induced a sustained cell-intrinsic mesenchymal transition associated with increased invasiveness and resistance to the alkylating agent temozolomide. Expectedly, irradiation-induced PMT was also associated with activation of the STAT3 transcription factor, and the combination of STAT3 blockade using JAK2 inhibitors with radiation abrogated the mesenchymal transition and extended survival of mice. Taken together, our data suggest that clinical JAK2 inhibitors should be tested in conjunction with radiation in patients with proneural HGG as a new strategy for blocking the emergence of therapy-resistant mesenchymal tumors at relapse. Cancer Res; 75(20); 4302–11. ©2015 AACR.