bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular evidence for the bi-clonal origin of neuroendocrine tumor derived metastases
Authors: Rinner Beate , Gallè Birgit , Trajanoski Slave , Fischer Carina , Hatz Martina , Maierhofer Theresa , Michelitsch Gabriele , Moinfar Farid , Stelzer Ingeborg , Pfragner Roswitha , Guelly Christian 
Published: November 2012

Abstract

Background
Reports on common mutations in neuroendocrine tumors (NET) are rare and clonality of NET metastases has not been investigated in this tumor entity yet. We selected one NET and the corresponding lymph node and liver metastases as well as the derivative cell lines to screen for somatic mutations in the primary NET and to track the fate of genetic changes during metastasis and in vitro progression.

Results
Applying microarray based sequence capture resequencing including 4,935 Exons from of 203 cancer-associated genes and high-resolution copy number and genotype analysis identified multiple somatic mutations in the primary NET, affecting BRCA2, CTNNB1, ERCC5, HNF1A, KIT, MLL, RB1, ROS1, SMAD4, and TP53. All mutations were confirmed in the patients’ lymph node and liver metastasis tissue as well as early cell line passages. In contrast to the tumor derived cell line, higher passages of the metastases derived cell lines lacked somatic mutations and chromosomal alterations, while expression of the classical NET marker serotonin was maintained.

Conclusion
Our study reveals that both metastases have evolved from the same pair of genetically differing NET cell clones. In both metastases, the in vivo dominating “mutant” tumor cell clone has undergone negative selection in vitro being replaced by the “non-mutant” tumor cell population. This is the first report of a bi-clonal origin of NET derived metastases, indicating selective advantage of interclonal cooperation during metastasis. In addition, this study underscores the importance to monitor cell line integrity using high-resolution genome analysis tools.
Detection of Burkholderia pseudomallei O-antigen serotypes in near-neighbor species
Authors: Stone Joshua K , Mayo Mark , Grasso Stephanie A , Ginther Jennifer L , Warrington Stephanie D , Allender Christopher J , Doyle Adina , Georgia Shalamar , Kaestli Mirjam , Broomall Stacey M , Karavis Mark A , Insalaco Joseph M , Hubbard Kyle S , McNew Lauren A , Gibbons Henry S , Currie Bart J , Keim Paul , Tuanyok Apichai 
Published: November 2012

Abstract

Background

Burkholderia pseudomallei is the etiological agent of melioidosis and a CDC category B select agent with no available effective vaccine. Previous immunizations in mice have utilized the lipopolysaccharide (LPS) as a potential vaccine target because it is known as one of the most important antigenic epitopes in B. pseudomallei. Complicating this strategy are the four different B. pseudomallei LPS O-antigen types: A, B, B2, and rough. Sero-crossreactivity is common among O-antigens of Burkholderia species. Here, we identified the presence of multiple B. pseudomallei O-antigen types and sero-crossreactivity in its near-neighbor species.

Results
PCR screening of O-antigen biosynthesis genes, phenotypic characterization using SDS-PAGE, and immunoblot analysis showed that majority of B. mallei and B. thailandensis strains contained the typical O-antigen type A. In contrast, most of B. ubonensis and B. thailandensis-like strains expressed the atypical O-antigen types B and B2, respectively. Most B. oklahomensis strains expressed a distinct and non-seroreactive O-antigen type, except strain E0147 which expressed O-antigen type A. O-antigen type B2 was also detected in B. thailandensis 82172, B. ubonensis MSMB108, and Burkholderia sp. MSMB175. Interestingly, B. thailandensis-like MSMB43 contained a novel serotype B positive O-antigen.

Conclusions
This study expands the number of species which express B. pseudomallei O-antigen types. Further work is required to elucidate the full structures and how closely these are to the B. pseudomallei O-antigens, which will ultimately determine the efficacy of the near-neighbor B serotypes for vaccine development.
Risk of fractures in patients with multiple sclerosis: record-linkage study
Authors: Ramagopalan Sreeram V , Seminog Olena , Goldacre Raphael , Goldacre Michael J 
Published: November 2012

Abstract

Background
Patients with multiple sclerosis (MS) have been reported to be at higher risk of fracture than other people. We sought to test this hypothesis in a large database of hospital admissions in England.

Methods
We analysed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999–2010). Rate ratios for fractures were determined, comparing fracture rates in a cohort of all people in England admitted with MS and rates in a comparison cohort.

Results
Significantly elevated risk for all fractures was found in patients with MS (rate ratio (RR) = 1.99, 95% confidence interval (CI) = 1.93-2.05)). Risks were particularly high for femoral fractures (femoral neck fracture RR = 2.79 (2.65-2.93); femoral shaft fracture RR 6.69 (6.12-7.29)), and fractures of the tibia or ankle RR = 2.81 (2.66-2.96).

Conclusions
Patients with MS have an increased risk of fractures. Caregivers should aim to optimize bone health in MS patients.
Left ventricular function in acute inflammatory peri-myocardial diseases – new insights and long-term follow-up
Authors: Leitman Marina , Tyomkin Vladimir , Peleg Eli , Copel Laurian , Vered Zvi ,   FACC, FESC
Published: November 2012

Abstract

Background
Until recently acute inflammatory peri-myocardial syndromes have been associated with global rather regional left ventricular (LV) dysfunction. Recent advances in cardiac imaging with echocardiographic techniques and magnetic resonance imaging (MRI) permit comprehensive evaluation of global and regional LV function. Our study was aimed to assess regional LV function in 100 patients with acute perimyocarditis, and correlate these findings with the clinical presentation.

Methods
We report on 100 patients with acute perimyocarditis admitted during 2008–2011, in whom LV function was assessed by semi-quantitative wall motion score analysis on conventional echo. Long-term mortality and recurrent hospitalization were also assessed.

Results
Wall motion score in 100 patients with acute perimyocarditis demonstrated a significant predominance of regional wall motion abnormalities in the infero-postero-lateral LV wall. These data correspond well with speckle tracking results of a subgroup of these patients published earlier. Recent MRI data show frequent late enhancement of contrast in the infero-lateral region of the LV in patients with perimyocarditis. These observations were useful in re-classification of our patients into one of the following groups: pure or predominant pericarditis, and pure or predominant myocarditis. Over a mean period of 37 months, there was no mortality. Though recurrent hospitalizations were rather frequent, no significant differences were observed among groups.

Conclusions
Regional wall motion abnormalities in the infero-postero-lateral segments of the LV are frequent in patients with acute perimyocarditis. Detailed echocardiographic examination early in the course of the disease should become a major factor in the clinical differentiation among the various clinical presentations of acute inflammatory peri-myocardial syndromes. The long-term outcome of these patients appears to be benign, though recurrent hospitalizations are not infrequent.
HLA-A*0201-restricted CD8+T-cell epitopes identified in dengue viruses
Authors: Duan Zhi-Liang , Li Qiang , Wang Zhi-Bin , Xia Ke-Dong , Guo Jiang-Long , Liu Wen-Quan , Wen Jin-Sheng 
Published: November 2012

AbstractBackgroundAll four dengue virus (DV) serotypes (D1V, D2V, D3V and D4V) can cause a series of disorders, ranging from mild dengue fever (DF) to severe dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). Previous studies have revealed that DV serotype-specific CD8+T cells are involved in controlling DV infection. Serotype cross-reactive CD8+T-cells may contribute to the immunopathogenesis of DHF/DSS. The aim of the study was to identify HLA-A*0201-binding peptides from four DV serotypes. We then examined their immunogenicityin vivoand cross-reactivity within heterologous peptides.MethodsD1V-derived candidate CD8+T-cell epitopes were synthesized and evaluated for their affinity to the HLA-A*0201 molecule. Variant peptides representing heterologous D2V, D3V, D4V serotypes were synthesized. The immunogenicity of the high-affinity peptides were evaluated in HLA-A*0201 transgenic mice.ResultsOf the seven D1V-derived candidate epitopes [D1V-NS4a56–64(MLLALIAVL), D1V-C46–54(LVMAFMAFL), D1V-NS4b562–570(LLATSIFKL), D1V-NS2a169–177(AMVLSIVSL), D1V-NS4a140–148(GLLFMILTV), D1V-NS2a144–152(QLWAALLSL) and D1V-NS4b183–191(LLMRTTWAL)], three peptides [D1V-NS4a140–148, D1V-NS2a144–152and D1V-NS4b183–191] had a high affinity for HLA-A*0201 molecules. Moreover, their variant peptides for D2V, D3V and D4V [D2V-NS4a140–148(AILTVVAAT), D3V-NS4a140-148(GILTLAAIV), D4V-NS4a140-148(TILTIIGLI), D2V-NS2a144–152(QLAVTIMAI), D3V-NS2a144–152(QLWTALVSL), D4V-NS2a143–151(QVGTLALSL), D2V-NS4b182–190(LMMRTTWAL),D3V-NS4b182–190(LLMRTSWAL) and D4V-NS4b179–187(LLMRTTWAF)] also had a high affinity for HLA-A*0201 molecules. Furthermore, CD8+T cells directed to these twelve peptides were induced in HLA-A*0201 transgenic mice following immunization with these peptides. Additionally, cross-reactivity within four peptides (D1V-NS4b183–191, D2V-NS4b182–190,D3V-NS4b182–190and D4V-NS4b179–187) was observed.ConclusionsTwo novel serotype-specific HLA-A*0201-restricted CD8+T-cell epitopes (NS4a140-148and NS2a144–152) and one cross-reactive HLA-A*0201-restricted CD8+T-cell epitopes which is similar to a previously identified epitope were identified in D1V-D4V. Combining prediction algorithms and HLA transgenic mice is an effective strategy to identify HLA-restricted epitopes. Serotype-specific epitopes would be used to determine the protective role of serotype-specific CD8+T cells, while cross-reactive epitopes may provide assistance in exploring the role of serotype cross-reactive CD8+T cells in the immunopathogenesis of DHF/DSS.
Citrullination of fibronectin modulates synovial fibroblast behavior
Authors: Shelef Miriam A , Bennin David A , Mosher Deane F , Huttenlocher Anna 
Published: November 2012

Abstract
Introduction
Rheumatoid arthritis is an autoimmune arthritis characterized by joint destruction. Anti-citrullinated protein antibodies are pathologic in rheumatoid arthritis, but the role of the citrullinated proteins themselves is much less clear. Citrullination is the conversion of the arginine residues of a protein to citrulline. In the inflamed rheumatoid joint there is increased protein citrullination. Several proteins are citrullinated in rheumatoid arthritis, including collagen type II, fibrinogen, and fibronectin. Fibronectin is thought to mediate the adhesion of joint-invading synovial fibroblasts to the rheumatoid cartilage in addition to regulating other synovial fibroblast functions. However, the effect of citrullinated fibronectin on synovial fibroblasts is unknown.

Methods
To investigate the effect of citrullinated fibronectin on synovial fibroblast behavior, we cultured normal murine, arthritic murine, and human rheumatoid synovial fibroblasts. We then compared several synovial fibroblast functions in the presence of fibronectin versus citrullinated fibronectin. We assessed adhesion with time-lapse microscopy, migration with transwell assays, focal adhesion kinase and paxillin phosphorylation by western blot, and focal matrix degradation by fluorescent gelatin degradation.

Results
Normal synovial fibroblasts have impaired adhesion, spreading, migration, and integrin-mediated phosphorylation of focal adhesion kinase and paxillin on citrullinated fibronectin. Murine arthritic and human rheumatoid synovial fibroblasts also have impaired adhesion and spreading on citrullinated fibronectin, but focal matrix degradation is unaffected by citrullinated fibronectin.

Conclusion
Citrullination of fibronectin alters synovial fibroblast behavior and may affect how these cells adhere to and invade the joint and travel through the bloodstream. This work suggests an important role for the interaction of synovial fibroblasts with citrullinated matrix in the pathophysiology of rheumatoid arthritis.
Effect of autologous platelet-rich plasma-releasate on intervertebral disc degeneration in the rabbit anular puncture model: a preclinical study
Authors: Obata Shuji , Akeda Koji , Imanishi Takao , Masuda Koichi , Bae Won , Morimoto Ryo , Asanuma Yumiko , Kasai Yuichi , Uchida Atsumasa , Sudo Akihiro 
Published: November 2012

Abstract
Introduction
Platelet-rich plasma (PRP) is a fraction of plasma in which several growth factors are concentrated at high levels. The active soluble releasate isolated following platelet activation of PRP (PRP-releasate) has been demonstrated to stimulate the metabolism of IVD cells in vitro. The in vivo effect of PRP-releasate on degenerated IVD remains unknown. The purpose of this study was to determine the reparative effects of autologous PRP-releasate on degenerated intervertebral discs (IVDs).

Methods
To induce disc degeneration, New Zealand white rabbits (n = 12) received anular puncture in two noncontiguous discs. Autologous PRP and PPP (platelet-poor plasma) were isolated from fresh blood using two centrifugation techniques. Four weeks after the initial puncture, releasate isolated from clotted PPP or PRP (PPP- or PRP-releasate), or phosphate-buffered saline (PBS; control) was injected into the punctured discs. Disc height, magnetic resonance imaging (MRI) T2-mapping and histology were assessed.

Results
Anular puncture produced a consistent disc narrowing within four weeks. PRP-releasate induced a statistically significant restoration of disc height (PRP vs. PPP and PBS, P<0.05). In T2-quantification, the mean T2-values of the nucleus pulposus (NP) and anulus fibrosus (AF) of the discs were not significantly different among the three treatment groups. Histologically, the number of chondrocyte-like cells was significantly higher in the discs injected with PRP-releasate compared to that with PBS.

Conclusions
The administration of active PRP-releasate induced a reparative effect on rabbit degenerated IVDs. The results of this study suggest that the use of autologous PRP-releasate is safe and can lead to a clinical application for IVD degeneration.
Outcome of ICU patients with Clostridium difficile infection
Authors: Zahar Jean-Ralph , Schwebel Carole , Adrie Christophe , Garrouste-Orgeas Maité , Français Adrien , Vesin Aurélien , Nguile-Makao Molière , Tabah Alexis , Laupland Kevin , Le-Monnier Alban , Timsit Jean-François ,   the OUTCOMEREA study group
Published: November 2012

Abstract
Introduction
As data from Clostridium difficile infection (CDI) in intensive care unit (ICU) are still scarce, our objectives were to assess the morbidity and mortality of ICU-acquired CDI.

Methods
We compared patients with ICU-acquired CDI (watery or unformed stools occurring ≥ 72 hours after ICU admission with a stool sample positive for C. difficile toxin A or B) with two groups of controls hospitalized at the same time in the same unit. The first control group comprised patients with ICU-acquired diarrhea occurring ≥ 72 hours after ICU admission with a stool sample negative for C. difficile and for toxin A or B. The second group comprised patients without any diarrhea.

Results
Among 5,260 patients, 512 patients developed one episode of diarrhea. Among them, 69 (13.5%) had a CDI; 10 (14.5%) of them were community-acquired, contrasting with 12 (17.4%) that were hospital-acquired and 47 (68%) that were ICU-acquired. A pseudomembranous colitis was associated in 24/47 (51%) ICU patients. The median delay between diagnosis and metronidazole administration was one day (25th Quartile; 75th Quartile (0; 2) days). The case-fatality rate for patients with ICU-acquired CDI was 10/47 (21.5%), as compared to 112/443 (25.3%) for patients with negative tests. Neither the crude mortality (cause specific hazard ratio; CSHR = 0.70, 95% confidence interval; CI 0.36 to 1.35, P = 0.3) nor the adjusted mortality to confounding variables (CSHR = 0.81, 95% CI 0.4 to 1.64, P = 0.6) were significantly different between CDI patients and diarrheic patients without CDI. Compared to the general ICU population, neither the crude mortality (SHR = 0.64, 95% CI 0.34 to 1.21, P = 0.17), nor the mortality adjusted to confounding variables (CSHR = 0.71, 95% confidence interval (CI) 0.38 to 1.35, P = 0.3), were significantly different between the two groups. The estimated increase in the duration of stay due to CDI was 8.0 days ± 9.3 days, (P = 0.4) in comparison to the diarrheic population, and 6.3 days ± 4.3 (P = 0.14) in comparison to the general ICU population.

Conclusions
If treated early, ICU-acquired CDI is not independently associated with an increased mortality and impacts marginally the ICU length of stay.
Impaired Response of FGF-23 to Oral Phosphate in Patients with Type 2 Diabetes: A Possible Mechanism of Atherosclerosis
Authors: Yoda Koichiro , Imanishi Yasuo , Yoda Maki , Mishima Takashi , Ichii Mitsuru , Yamada Shinsuke , Mori Katsuhito , Emoto Masanori , Inaba Masaaki 
Published: November 2012

Background:
Fibroblast growth factor (FGF)-23, secreted from osteocytes/osteoblasts, plays major roles in phosphate (Pi)-mediated stimulation of PTH secretion and consequently in regulation of serum Pi. Osteocyte/osteoblast dysfunction develops in patients with type 2 diabetes mellitus (DM).

Objective:
Our objective was to examine whether increases in serum FGF-23 and PTH after oral Pi stimulation are impaired in type 2 DM.

Design and Methods:
The subjects were 10 DM and 10 non-DM patients without chronic kidney disease stage 3–5. Serum FGF-23, intact PTH (iPTH), and Pi were measured serially after oral Pi administration at a daily dose of 2.0 g.

Results:
Pi administration caused significant increases of FGF-23 by 2 h and iPTH by 4 h in non-DM patients. These increases were attenuated in DM patients. After 2 d of Pi stimulation, serum FGF-23 and iPTH remained elevated in non-DM patients but not in DM. In all subjects, initial changes of serum FGF-23 (0–2 h) and iPTH (0–4 h) were positively correlated (r = 0.528) and showed significant negative correlations with later changes in serum Pi (2–4 h) (r = −0.457 and r = −0.673, respectively). Serum Pi (2–4 h) significantly increased in DM patients, consistent with the lack of change in serum FGF-23 and iPTH, whereas serum Pi did not change significantly in non-DM patients.

Conclusion:
These results show that increases of serum FGF-23 and PTH in response to Pi stimulation are impaired in type 2 DM and that serum Pi is significantly increased thereafter. This may be a mechanism underlying advanced atherosclerosis in type 2 DM.
First-Principles Molecular Dynamics Insight into Fe2+ Complexes Adsorbed on Edge Surfaces of Clay Minerals
Authors: Liu Xiandong , Meijer Evert Jan , Lu Xiancai , Wang Rucheng 
Published: November 2012

AbstractUsing first-principles molecular-dynamics simulations, probable inner-sphere complexes of Fe2+ adsorbed on the edge surfaces of clay minerals were investigated. Ferrous ions are important reductants in natural processes and their properties can be altered significantly by complexation on edge surfaces of clay minerals. However, the microscopic picture of adsorption sites and structures of Fe2+ is difficult to reveal with modern experimental techniques and, therefore, remains unclear. From the results of first-principles molecular-dynamics simulations, evidence has been provided that complexes on ≡Si—O sites were the most stable forms, which should be responsible for the experimentally observed pH-dependent uptake. Such complexation was found to be strong enough to distort the local coordination structures of Si—O tetrahedra in the substrate. Analyses showed that Fe2+—Owater coordination structures were dominated by the solvent with surface groups participating in the complexes via H bonding. The present study provided a microscopic basis for understanding the chemical processes involving surface-complexed Fe2+ ions.
On the Problems of Total Specific Surface Area and Cation Exchange Capacity Measurements in Organic-Rich Sedimentary Rocks
Authors: Derkowski Arkadiusz , Bristow Thomas F. 
Published: November 2012

AbstractThe increasing exploration and exploitation of hydrocarbon resources hosted by oil and gas shales demands the correct measurement of certain properties of sedimentary rocks rich in organic matter (OM). Two essential properties of OM-rich shales, the total specific surface area (TSSA) and cation exchange capacity (CEC), are primarily controlled by the rock’s clay mineral content (i.e. the type and quantity). This paper presents the limitations of two commonly used methods of measuring bulk-rock TSSA and CEC, ethylene glycol monoethyl ether (EGME) retention and visible light spectrometry of Co(III)-hexamine, in OM-rich rocks. The limitations were investigated using a suite of OM-rich shales and mudstones that vary in origin, age, clay mineral content, and thermal maturity.Ethylene glycol monoethyl ether reacted strongly with and was retained by natural OM, producing excess TSSA if calculated using commonly applied adsorption coefficients. Although the intensity of the reaction seems to depend on thermal maturity, OM in all the samples analyzed reacted with EGME to an extent that made TSSA values unreliable; therefore, EGME is not recommended for TSSA measurements on samples containing >3% OM.Some evidence indicated that drying at ⩾200°C may influence bulk-rock CEC values by altering OM in early mature rocks. In light of this evidence, drying at 110°C is recommended as a more suitable pretreatment for CEC measurements in OM-rich shales. When using visible light spectrometry for CEC determination, leachable sample components contributed to the absorbance of the measured wavelength (470 nm), decreasing the calculated bulk rock CEC value. A test of sample-derived excess absorbance with zero-absorbance solutions (i.e. NaCl) and the introduction of corrections to the CEC calculation are recommended.