bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prolonged Entecavir Therapy Is Not Effective for HBeAg Seroconversion in Treatment-Naive Chronic Hepatitis B Patients with a Partial Virological Response
Authors: Lee Hyun Woong , Kwon Jae-Cheol , Oh In Soo , Chang Hye Young , Cha Young Joo , Choi Ik-Seong , Kim Hyung Joon 
Published: June 2015

ABSTRACT

The aims of this study were to investigate the efficacy of prolonged entecavir (ETV) therapy in treatment-naive chronic hepatitis B (CHB) patients and to determine whether continuous ETV therapy is feasible to achieve HBeAg seroconversion, particularly in patients with partial virological response (PVR). A total of 142 treatment-naive patients with CHB were enrolled. The mean duration of treatment was 65 (range, 26 to 90) months, and 86 patients (60.6%) were HBeAg positive. PVR was defined as detectable hepatitis B virus (HBV) DNA (>116 copies/ml) at year 1. The cumulative incidence of virological response (VR) increased from 54.9% at year 1 to 98.2% at year 7. HBeAg positivity (odds ratio [OR], 4.146;
P
= 0.001) and initial alanine aminotransferase (ALT) (OR, 0.997;
P
= 0.004) were independent risk factors for PVR. Among the 64 patients with PVR, 47 patients (73.4%) achieved VR within 4 years after prolonged ETV therapy without treatment adaptation. Three patients (2.1%) experienced virological breakthrough and HBV variants with genotypic resistance. The cumulative rate of HBeAg seroconversion was significantly higher in the patients with VR than in the patients with PVR (
P
= 0.018). None of the PVR patients with HBV DNA at ≥5,000 copies/ml at year 1 ever experienced HBeAg seroconversion. Multivariate analysis identified VR at year 1 as the only determinant of HBeAg seroconversion (hazard ratio [HR], 3.009;
P
= 0.010). In conclusion, although there were patients with PVR, prolonged ETV therapy showed excellent VR, with only 2.1% emergence of viral resistance during a 7-year follow-up. However, to achieve HBeAg seroconversion, drug modification is needed for HBeAg-positive patients with PVR (especially those with HBV DNA at ≥5,000 copies/ml at year 1).
Moraxella catarrhalis Binds Plasminogen To Evade Host Innate Immunity
Authors: Singh Birendra , Al-Jubair Tamim , Voraganti Chandrashekar , Andersson Tobias , Mukherjee Oindrilla , Su Yu-Ching , Zipfel Peter , Riesbeck Kristian 
Published: June 2015

ABSTRACT

Several bacterial species recruit the complement regulators C4b-binding protein, factor H, and vitronectin, resulting in resistance against the bactericidal activity of human serum. It was recently demonstrated that bacteria also bind plasminogen, which is converted to plasmin that degrades C3b and C5. In this study, we found that a series of clinical isolates (
n
= 58) of the respiratory pathogen
Moraxella catarrhalis
, which is commonly isolated from preschool children and adults with chronic obstructive pulmonary disease (COPD), significantly binds human plasminogen. Ubiquitous surface protein A2 (UspA2) and hybrid UspA2 (UspA2H) were identified as the plasminogen-binding factors in the outer membrane proteome of
Moraxella
. Furthermore, expression of a series of truncated recombinant UspA2 and UspA2H proteins followed by a detailed analysis of protein-protein interactions suggested that the N-terminal head domains bound to the kringle domains of plasminogen. The binding affinity constant (

K
D

) values of full-length UspA2
30–539
(amino acids 30 to 539 of UspA2) and full-length UspA2H
50–720
for immobilized plasminogen were 4.8 × 10
−8
M and 3.13 × 10
−8
M, respectively, as measured by biolayer interferometry. Plasminogen bound to intact
M. catarrhalis
or to recombinant UspA2/UspA2H was readily accessible for a urokinase plasminogen activator that converted the zymogen into active plasmin, as verified by the specific substrate S-2251 and a degradation assay with fibrinogen. Importantly, plasmin bound at the bacterial surface also degraded C3b and C5, which consequently may contribute to reduced bacterial killing. Our findings suggest that binding of plasminogen to
M. catarrhalis
may lead to increased virulence and, hence, more efficient colonization of the host.
Multiple Functions of Glutamate Uptake via Meningococcal GltT-GltM
l
-Glutamate ABC Transporter in Neisseria meningitidis Internalization into Human Brain Microvascular Endothelial Cells
Authors: Takahashi Hideyuki , Yanagisawa Tatsuo , Kim Kwang Sik , Yokoyama Shigeyuki , Ohnishi Makoto 
Published: June 2015

ABSTRACT

We previously reported that
Neisseria meningitidis
internalization into human brain microvasocular endothelial cells (HBMEC) was triggered by the influx of extracellular
l
-glutamate via the GltT-GltM
l
-glutamate ABC transporter, but the underlying mechanism remained unclear. We found that the Δ
gltT
Δ
gltM
invasion defect in assay medium (AM) was alleviated in AM without 10% fetal bovine serum (FBS) [AM(−S)]. The alleviation disappeared again in AM(−S) supplemented with 500 μM glutamate. Glutamate uptake by the Δ
gltT
Δ
gltM
mutant was less efficient than that by the wild-type strain, but only upon HBMEC infection. We also observed that both GltT-GltM-dependent invasion and accumulation of ezrin, a key membrane-cytoskeleton linker, were more pronounced when
N. meningitidis
formed larger colonies on HBMEC under physiological glutamate conditions. These results suggested that GltT-GltM-dependent meningococcal internalization into HBMEC might be induced by the reduced environmental glutamate concentration upon infection. Furthermore, we found that the amount of glutathione within the Δ
gltT
Δ
gltM
mutant was much lower than that within the wild-type
N. meningitidis
strain only upon HBMEC infection and was correlated with intracellular survival. Considering that the
l
-glutamate obtained via GltT-GltM is utilized as a nutrient in host cells,
l
-glutamate uptake via GltT-GltM plays multiple roles in
N. meningitidis
internalization into HBMEC.
Aminoimidazole Carboxamide Ribotide Exerts Opposing Effects on Thiamine Synthesis in Salmonella enterica
Authors: Bazurto Jannell V. , Heitman Nicholas J. , Downs Diana M. 
Published: June 2015

ABSTRACT

In
Salmonella enterica
, the thiamine biosynthetic intermediate 5-aminoimidazole ribotide (AIR) can be synthesized
de novo
independently of the early purine biosynthetic reactions. This secondary route to AIR synthesis is dependent on (i) 5-amino-4-imidazolecarboxamide ribotide (AICAR) accumulation, (ii) a functional phosphoribosylaminoimidazole-succinocarboxamide (SAICAR) synthetase (PurC; EC 6.3.2.6), and (iii) methionine and lysine in the growth medium. Studies presented here show that AICAR is a direct precursor to AIR
in vivo
. PurC-dependent conversion of AICAR to AIR was recreated
in vitro
. Physiological studies showed that exogenous nutrients (e.g., methionine and lysine) antagonize the inhibitory effects of AICAR on the ThiC reaction and decreased the cellular thiamine requirement. Finally, genetic results identified multiple loci that impacted the effect of AICAR on thiamine synthesis and implicated cellular aspartate levels in AICAR-dependent AIR synthesis. Together, the data here clarify the mechanism that allows conditional growth of a strain lacking the first five biosynthetic enzymes, and they provide additional insights into the complexity of the metabolic network and its plasticity.

IMPORTANCE
In bacteria, the pyrimidine moiety of thiamine is derived from aminoimidazole ribotide (AIR), an intermediate in purine biosynthesis. A previous study described conditions under which AIR synthesis is independent of purine biosynthesis. This work is an extension of that previous study and describes a new synthetic pathway to thiamine that depends on a novel thiamine precursor and a secondary activity of the biosynthetic enzyme PurC. These findings provide mechanistic details of redundancy in the synthesis of a metabolite that is essential for nucleotide and coenzyme biosynthesis. Metabolic modifications that allow the new pathway to function or enhance it are also described.
Identification of the Final Two Genes Functioning in Methanofuran Biosynthesis in Methanocaldococcus jannaschii
Authors: Wang Yu , Xu Huimin , Jones Michael K. , White Robert H. 
Published: June 2015

ABSTRACT

All methanofuran structural variants contain a basic core structure of 4-[
N
-(γ-
l
-glutamyl)-
p
-(β-aminoethyl)phenoxymethyl]-(aminomethyl)furan (APMF-Glu) but have different side chains depending on the source organism. Recently, we identified four genes (MfnA, MfnB, MfnC, and MfnD) that are responsible for the biosynthesis of the methanofuran precursor γ-glutamyltyramine and 5-(aminomethyl)-3-furanmethanol-phosphate (F1-P) from tyrosine, glutamate, glyceraldehyde-3-P, and alanine in
Methanocaldococcus jannaschii
. How γ-glutamyltyramine and F1-P couple together to form the core structure of methanofuran was previously unknown. Here, we report the identification of two enzymes encoded by the genes
mj0458
and
mj0840
that catalyze the formation of F1-PP from ATP and F1-P and the condensation of F1-PP with γ-glutamyltyramine, respectively, to form APMF-Glu. We have annotated these enzymes as MfnE and MfnF, respectively, representing the fifth and sixth enzymes in the methanofuran biosynthetic pathway to be identified. Although MfnE was previously reported as an archaeal adenylate kinase, our present results show that MfnE is a promiscuous enzyme and that its possible physiological role is to produce F1-PP. Unlike other enzymes catalyzing coupling reactions involving pyrophosphate as the leaving group, MfnF exhibits a distinctive α/β two-layer sandwich structure. By comparing MfnF with thiamine synthase and dihydropteroate synthase, a substitution nucleophilic unimolecular (S
N
-1) reaction mechanism is proposed for MfnF. With the identification of MfnE and MfnF, the biosynthetic pathway for the methanofuran core structure APMF-Glu is complete.

IMPORTANCE
This work describes the identification of the final two enzymes responsible for catalyzing the biosynthesis of the core structure of methanofuran. The gene products of
mj0458
and
mj0840
catalyze the formation of F1-PP and the coupling of F1-PP with γ-glutamyltyramine, respectively, to form APMF-Glu. Although the chemistry of such a coupling reaction is widespread in biochemistry, we provide here the first evidence that such a mechanism is used in methanofuran biosynthesis. MfnF belongs to the hydantoinase A family (PF01968) and exhibits a unique α/β two-layer sandwich structure that is different from the enzymes catalyzing similar reactions. Our results show that MfnF catalyzes the formation of an ether bond during methanofuran biosynthesis. Therefore, this work further expands the functionality of this enzyme family.
Predictors of hepatic decompensation after TACE for hepatocellular carcinoma
Authors: Kohla Mohamed A S , Abu Zeid Mai I , Al-Warraky Mohamed , Taha Hossam , Gish Robert G 
Published: June 2015

AimTo study predictive factors for hepatic decompensation after transarterial chemoembolisation (TACE) for hepatocellular carcinoma (HCC).MethodsBetween November 2009 and August 2010, of 254 patients with HCC who presented to our multidisciplinary HCC clinic for evaluation, 102 (40%) were amenable for TACE. In this prospective study, there were 102 patients with compensated cirrhosis with HCC and Child-Pugh Class A cirrhosis who underwent TACE at the National Liver Institute, Menoufiya University, Egypt. We excluded all patients with prior locoregional therapy, systemic therapy and/or surgical intervention. At baseline and at 1 month postprocedure, laboratory criteria, tumour criteria (size, number) and Child-Pugh score were recorded. Patients were classified into group 1 (no Child-Pugh point increase after TACE) and group 2 (one or more added Child-Pugh points after TACE, defining hepatic decompensation). Univariate and multivariate analyses were performed to identify factors predictive of hepatic decompensation.ResultsPatients were mostly males (82.4%) of mean age 58.4±8.1 years. The only significant changes in laboratory findings at 1 month after TACE were increased international normalised ratio, serum total bilirubin, alanine transaminase and aspartate transaminase and decreased serum albumin and α-fetoprotein (AFP). The statistically significant predictive factors for hepatic decompensation using univariate analysis were found to be baseline lower serum albumin, higher serum α-fetoprotein, more advanced Barcelona Clinic Liver Cancer (BCLC) stage, larger tumour size and a greater number of tumour nodules; with logistic regression, multivariate analysis found that at baseline larger tumour size (p=0.004 at 95% CI), higher serum AFP (p=0.046 at 95% CI) and lower serum albumin (p=0.033 at 95% CI) predicted decompensation; BCLC stage, number of tumour nodules and pre-TACE bilirubin did not predict changes in liver function.ConclusionsLower serum albumin and increased tumour burden (larger tumour size/more nodules and higher α-fetoprotein) at baseline may help predict post-TACE decompensation.
A stepped wedge, cluster controlled trial of an intervention to improve safety and quality on medical wards: the HEADS-UP study protocol
Authors: Pannick Samuel , Beveridge Iain , Ashrafian Hutan , Long Susannah J , Athanasiou Thanos , Sevdalis Nick 
Published: June 2015

IntroductionThe majority of preventable deaths in healthcare are due to errors on general wards. Staff perceptions of safety correlate with patient survival, but effectively translating ward teams’ concerns into tangibly improved care remains problematic. The Hospital Event Analysis Describing Significant Unanticipated Problems (HEADS-UP) trial evaluates a structured, multidisciplinary team briefing, capturing safety threats and adverse events, with rapid feedback to clinicians and service managers. This is the first study to rigorously assess a simpler intervention for general medical units, alongside an implementation model applicable to routine clinical practice.Methods/analysis7 wards from 2 hospitals will progressively incorporate the intervention into daily practice over 14 months. Wards will adopt HEADS-UP in a pragmatic sequence, guided by local clinical enthusiasm. Initial implementation will be facilitated by a research lead, but rapidly delegated to clinical teams. The primary outcome is excess length of stay (a surplus stay of 24 h or more, compared to peer institutions’ Healthcare Resource Groups-predicted length of stay). Secondary outcomes are 30-day readmission or excess length of stay; in-hospital death or death/readmission within 30 days; healthcare-acquired infections; processes of escalation of care; use of traditional incident-reporting systems; and patient safety and teamwork climates. HEADS-UP will be analysed as a stepped wedge cluster controlled trial. With 7840 patients, using best and worst case predictions, the study would achieve between 75% and 100% power to detect a 2–14% absolute risk reduction in excess length of stay (two-sided p<0.05). Regression analysis will use generalised linear mixed models or generalised estimating equations, and a time-to-event regression model. A qualitative analysis will evaluate facilitators and barriers to HEADS-UP implementation and impact.Ethics and disseminationParticipating institutions’ Research and Governance departments approved the study. Results will be published in peer-reviewed journals and at conference presentations.Trial registration numberISRCTN34806867.
Do women seeking termination of pregnancy need pre-abortion counselling?
Authors: Baron Charlotte , Cameron Sharon , Johnstone Anne 
Published: June 2015

BackgroundPre-termination counselling is currently voluntary in the UK; however, there has been political debate regarding the introduction of mandatory pre-termination counselling as well as who should be providing the abortion counselling services.ObjectiveTo quantify the proportion of women who use pre-termination counselling services and to evaluate their experience.MethodAn anonymous self-administered questionnaire of women requesting an abortion at Chalmers Sexual Health Centre and the Royal Infirmary of Edinburgh NHS Lothian from 6 October to 2 December 2014.ResultsOnly 18 (9%) of the 201 women surveyed reported using pre-termination counselling. The majority of women did not feel counselling was necessary because they were already certain of their decision. Nearly a quarter (22%) of women claimed to not know counselling was available. Women who did use counselling were satisfied with the services they received. The majority of counselling services were provided by the National Health Service and only one woman used a ‘pro-life’ charity. Women stated that they would prefer face-to-face counselling rather than telephone or Internet-based counselling.ConclusionsMost women do not seem to want or need pre-termination counselling therefore policies aimed at mandatory counselling, would be contrary to women's wishes. Counselling should be targeted at women with risk factors for psychological complications post-termination.
CASC15-S Is a Tumor Suppressor lncRNA at the 6p22 Neuroblastoma Susceptibility Locus
Authors: Russell Mike R. , Penikis Annalise , Oldridge Derek A. , Alvarez-Dominguez Juan R. , McDaniel Lee , Diamond Maura , Padovan Olivia , Raman Pichai , Li Yimei , Wei Jun S. , Zhang Shile , Gnanchandran Janahan , Seeger Robert , Asgharzadeh Shahab , Khan Javed , Diskin Sharon J. , Maris John M. , Cole Kristina A. 
Published: June 2015

Abstract
Chromosome 6p22 was identified recently as a neuroblastoma susceptibility locus, but its mechanistic contributions to tumorigenesis are as yet undefined. Here we report that the most highly significant single-nucleotide polymorphism (SNP) associations reside within CASC15, a long noncoding RNA that we define as a tumor suppressor at 6p22. Low-level expression of a short CASC15 isoform (CASC15-S) associated highly with advanced neuroblastoma and poor patient survival. In human neuroblastoma cells, attenuating CASC15-S increased cellular growth and migratory capacity. Gene expression analysis revealed downregulation of neuroblastoma-specific markers in cells with attenuated CASC15-S, with concomitant increases in cell adhesion and extracellular matrix transcripts. Altogether, our results point to CASC15-S as a mediator of neural growth and differentiation, which impacts neuroblastoma initiation and progression. Cancer Res; 75(15); 3155–66. ©2015 AACR.
Palbociclib for the Treatment of Estrogen Receptor–Positive, HER2-Negative Metastatic Breast Cancer
Authors: Morikawa Aki , Henry N. Lynn 
Published: June 2015

AbstractPalbociclib is a selective inhibitor of cyclin-dependent kinases 4 and 6 that acts by reducing phosphorylation of the tumor suppressor gene retinoblastoma. When added to the aromatase inhibitor letrozole in a randomized phase II trial for first-line therapy of estrogen receptor–positive, HER2-negative metastatic breast cancer, palbociclib significantly increased progression-free survival compared with letrozole alone [palbociclib + letrozole: 20.2 months; 95% confidence interval (CI), 13.8–27.5; letrozole: 10.2 months; 95% CI, 5.7–12.6; HR, 0.49; 95% CI, 0.32–0.75; P = 0.0004]. On the basis of these results, the drug was recently granted accelerated approval by the FDA, and confirmatory studies are ongoing. Because this drug has a rational target in an oncologic pathway, concurrent biomarker development is of interest. In breast cancer, the most useful predictive biomarkers identified thus far are estrogen receptor and HER2 receptor status, although additional studies are ongoing. In this article, we review the development of palbociclib and its use in treatment of hormone receptor–positive metastatic breast cancer in the context of other FDA-approved agents in this setting. Clin Cancer Res; 21(16); 3591–6. ©2015 AACR.
Mitochondrial Methylenetetrahydrofolate Dehydrogenase (MTHFD2) Overexpression Is Associated with Tumor Cell Proliferation and Is a Novel Target for Drug Development
Authors: Tedeschi Philip M. , Vazquez Alexei , Kerrigan John E. , Bertino Joseph R. 
Published: June 2015

Abstract
Rapidly proliferating tumors attempt to meet the demands for nucleotide biosynthesis by upregulating folate pathways that provide the building blocks for pyrimidine and purine biosynthesis. In particular, the key role of mitochondrial folate enzymes in providing formate for de novo purine synthesis and for providing the one-carbon moiety for thymidylate synthesis has been recognized in recent studies. We have shown a significant correlation between the upregulation of the mitochondrial folate enzymes, high proliferation rates, and sensitivity to the folate antagonist methotrexate (MTX). Burkitt lymphoma and diffuse large-cell lymphoma tumor specimens have the highest levels of mitochondrial folate enzyme expression and are known to be sensitive to treatment with MTX. A key enzyme upregulated in rapidly proliferating tumors but not in normal adult cells is the mitochondrial enzyme methylenetetrahydrofolate dehydrogenase (MTHFD2). This perspective outlines the rationale for specific targeting of MTHFD2 and compares known and generated crystal structures of MTHFD2 and closely related enzymes as a molecular basis for developing therapeutic agents against MTHFD2. Importantly, the development of selective inhibitors of mitochondrial methylenetetrahydrofolate dehydrogenase is expected to have substantial activity, and this perspective supports the investigation and development of MTHFD2 inhibitors for anticancer therapy. Mol Cancer Res; 13(10); 1361–6. ©2015 AACR.
Role of Prophylactic Bilateral Tonsillectomy as a Cancer Preventive Strategy
Authors: Misiukiewicz Krzysztof , Posner Marshall 
Published: June 2015

Abstract
The rate of vaccination against human papillomavirus (HPV) among adolescent girls and boys over the past few years has been stagnant in spite of the increase in incidence of HPV-positive oropharyngeal (OPX) squamous cell carcinoma (SCC). The indirect relationship between HPV cancer incidence and preventive vaccination poses a public health concern and has caused clinicians to search for other methods toward eradicating the ongoing oropharyngeal carcinoma epidemic. This alarming increase in OPX is motivating a search for therapeutic prevention strategies, including biomarker discovery, risk assessment, therapeutic vaccines, immunotherapy, and surgery. The current Danish Cancer Registry study by Fakhry and colleagues (in this issue) is the first to investigate the impact of prior tonsillectomy on the development of HPV OPX. They report that remote tonsillectomy resulted in a decreased incidence of tonsillar SCC. While thought-provoking, this study has a small sample size. Also, tonsillectomy does not address all anatomic sites at risk; there is lack of well-defined precancerous lesions or biomarkers to identify high-risk patients, and cost and morbidity make it impractical to justify prophylactic tonsillectomy as a cancer preventive strategy at present. The provocative clinical signal reported in this study supports further research and strategies that employ surgery when the technology and epidemiology can reliably be used to identify high-risk subjects. Cancer Prev Res; 8(7); 580–2. ©2015 AACR.
See related article by Fakhry et al., p. 583