bluuebunny/crossref_metadata_2025 huggingface dataset:
Involvement of Fe Uptake Systems and AmpC β-Lactamase in Susceptibility to the Siderophore Monosulfactam BAL30072 in Pseudomonas aeruginosa
Authors: van Delden Christian , Page Malcolm G. P. , Köhler Thilo
Published: February 2013

BAL30072 is a monosulfactam conjugated with an iron-chelating dihydroxypyridone moiety. It is active against Gram-negative bacteria, including multidrug-resistant
Pseudomonas aeruginosa
. We selected mutants with decreased susceptibilities to BAL30072 in
P. aeruginosa
PAO1 under a variety of conditions. Under iron-deficient conditions, mutants with overexpression of AmpC β-lactamase predominated. These mutants were cross-resistant to aztreonam and ceftazidime. Similar mutants were obtained after selection at >16× the MIC in iron-sufficient conditions. At 4× to 8× the MIC, mutants with elevated MIC for BAL30072 but unchanged MICs for aztreonam or ciprofloxacin were selected. The expression of
ampC
and the major efflux pump genes were also unchanged. These BAL30072-specific mutants were characterized by transcriptome analysis, which revealed upregulation of the Fe-dicitrate operon, FecIRA. Whole-genome sequencing showed that this resulted from a single nucleotide change in the Fur-box of the
fecI
promoter. Overexpression of either the FecI ECF sigma factor or the FecA receptor increased BAL30072 MICs 8- to 16-fold. A
fecI
mutant and a
fecA
mutant of PAO1 were hypersusceptible to BAL30072 (MICs < 0.06 μg/ml). The most downregulated gene belonged to the pyochelin synthesis operon, although mutants in pyochelin receptor or synthesis genes had unchanged MICs. The
piuC
gene, coding for a Fe(II)-dependent dioxygenase located next to the
piuA
iron receptor gene, was also downregulated. The MICs of BAL30072 for
piuC
and
piuA
transposon mutants were increased 8- and 16-fold, respectively. We conclude that the upregulation of the Fe-dicitrate system impacts the expression of other TonB-dependent iron transporters and that PiuA and PiuC contribute to the susceptibility of
P. aeruginosa
PAO1 to BAL30072.
Trichomonas vaginalis Contact-Dependent Cytolysis of Epithelial Cells
Authors: Lustig Gila , Ryan Christopher M. , Secor W. Evan , Johnson Patricia J.
Published: February 2013

Trichomonas vaginalis
is an extracellular protozoan parasite that binds to the epithelium of the human urogenital tract during infection. In this study, we examined the propensities of 26
T. vaginalis
strains to bind to and lyse prostate (BPH-1) and ectocervical (Ect1) epithelium and to lyse red blood cells (RBCs). We found that only three of the strains had a statistically significant preference for either BPH-1 (MSA1103) or Ect1 (LA1 and MSA1123). Overall, we observed that levels of adherence are highly variable among strains, with a 12-fold range of adherence on Ect1 cells and a 45-fold range on BPH-1 cells. Cytolysis levels displayed even greater variability, from no detectable cytolysis to 80% or 90% cytolysis of Ect1 and BPH-1, respectively. Levels of adherence and cytolysis correlate for weakly adherent/cytolytic strains, and a threshold of attachment was found to be necessary to trigger cytolysis; however, this threshold can be reached without inducing cytolysis. Furthermore, cytolysis was completely blocked when we prevented attachment of the parasites to host cells while allowing soluble factors complete access. We demonstrate that hemolysis was a rare trait, with only 4 of the 26 strains capable of lysing >20% RBCs with a 1:30 parasite/RBC ratio. Hemolysis also did not correlate with adherence to or cytolysis of either male (BPH-1)- or female (Ect1)-derived epithelial cell lines. Our results reveal that despite a broad range of pathogenic properties among different
T. vaginalis
strains, all strains show strict contact-dependent cytolysis.
Effect of the Leptin Receptor Q223R Polymorphism on the Host Transcriptome following Infection with Entamoeba histolytica
Authors: Mackey-Lawrence Nicole M. , Guo Xiaoti , Sturdevant Daniel E. , Virtaneva Kimmo , Hernandez Matthew M. , Houpt Eric , Sher Alan , Porcella Stephen F. , Petri William A.
Published: February 2013

Resistance to amebiasis is associated with a polymorphism in the leptin receptor. Previous studies demonstrated that humans with the ancestral Q223 leptin receptor allele were nearly four times less likely to be infected with
Entamoeba histolytica
than those carrying the mutant R223 allele. We hypothesized that the Q223 allele protected against
E. histolytica
via STAT3-mediated transcription of genes required for mucosal immunity. To test this, mice containing the humanized
LEPR
Q or R allele at codon 223 were intracecally infected with
E. histolytica
. Susceptibility to amebiasis was assessed, and cecal tissues were analyzed for changes in gene expression. By 72 h postchallenge, all Q223 mice had cleared
E. histolytica
, whereas 39% of 223R mice were infected. Thirty-seven genes were differentially expressed in response to infection at 72 h, including proinflammatory genes (
CXCL2
,
S100A8/9
,
PLA2G7
,
ITBG2
, and
MMP9
) and functions pertaining to the movement and activity of immune cells. A comparison at 12 h postchallenge of infected Q223 versus R223 mice identified a subset of differentially expressed genes, many of which were closely linked to leptin signaling. Further analyses indicated that the Q223 gene expression pattern was consistent with a suppressed apoptotic response to infection, while 223R showed increased cellular proliferation and recruitment. These studies are the first to illuminate the downstream effects of leptin receptor polymorphisms on intestinal infection by
E. histolytica
. As such, they are important for the insight that they provide into this previously uncharacterized mechanism of mucosal immunity.
A Quorum-Sensing-Induced Bacteriophage Defense Mechanism
Authors: Høyland-Kroghsbo Nina Molin , Mærkedahl Rasmus Baadsgaard , Svenningsen Sine Lo
Published: February 2013

One of the key determinants of the size, composition, structure, and development of a microbial community is the predation pressure by bacteriophages. Accordingly, bacteria have evolved a battery of antiphage defense strategies. Since maintaining constantly elevated defenses is costly, we hypothesize that some bacteria have additionally evolved the abilities to estimate the risk of phage infection and to adjust their strategies accordingly. One risk parameter is the density of the bacterial population. Hence, quorum sensing, i.e., the ability to regulate gene expression according to population density, may be an important determinant of phage-host interactions. This hypothesis was investigated in the model system of
Escherichia coli
and phage λ. We found that, indeed, quorum sensing constitutes a significant, but so far overlooked, determinant of host susceptibility to phage attack. Specifically,
E. coli
reduces the numbers of λ receptors on the cell surface in response to
N
-acyl-
l
-homoserine lactone (AHL) quorum-sensing signals, causing a 2-fold reduction in the phage adsorption rate. The modest reduction in phage adsorption rate leads to a dramatic increase in the frequency of uninfected survivor cells after a potent attack by virulent phages. Notably, this mechanism may apply to a broader range of phages, as AHLs also reduce the risk of χ phage infection through a different receptor.

IMPORTANCE
To enable the successful manipulation of bacterial populations, a comprehensive understanding of the factors that naturally shape microbial communities is required. One of the key factors in this context is the interactions between bacteria and the most abundant biological entities on Earth, namely, the bacteriophages that prey on bacteria. This proof-of-principle study shows that quorum sensing plays an important role in determining the susceptibility of
E. coli
to infection by bacteriophages λ and χ. On the basis of our findings in the classical
Escherichia  coli
-λ model system, we suggest that quorum sensing may serve as a general strategy to protect bacteria specifically under conditions of high risk of infection.
SILK flow diverter for treatment of intracranial aneurysms: initial experience and cost analysis
Authors: Shankar Jai Jai Shiva , Vandorpe Robert , Pickett Gwynedd , Maloney William
Published: February 2013

Background

The flow diverting stent is a new and expansive tool in the endovascular therapy of complex intracranial aneurysms. We present our experience using SILK flow diverter (SFD) in patients with complex intracranial aneurysms, and a cost analysis.

Methods

Between September 2010 and May 2012, 19 consecutive patients with 29 complex intracranial aneurysms were treated with SFD without the adjunctive use of coils. We retrospectively evaluated the technical aspects, thromboembolic events, adjunctive therapies, and short term results in patients with complex intracranial aneurysms treated with SFD. A cost analysis of patients who were treated with SFD was performed and compared with similar sized aneurysms coiled with stent assisted coiling.

Results

The primary technical success rate was 100%. An adjunctive device was required in two of our patients. The technique related complication rate and the 30 day mortality and morbidity rates were 5% (1/20) and 10% (2/20), respectively. We had a total of 263 patient months of clinical and 166 patient months of imaging follow-up. Follow-up imaging revealed two asymptomatic occlusions of the parent artery. Complete occlusion of the aneurysm with fully patent parent artery was observed in 59% of patients where follow-up images were available. The cost analysis showed that the mean cost of treatment with SFD was significantly cheaper compared with the presumed cost of stent assisted coiling (p<0.001).

Conclusions

The SFD provides a very feasible, efficient, relatively safe, and cost effective method to treat complex intracranial aneurysms without the use of adjunct coiling.
PERFORMANCE OF DIFFERENT INTEGRATION SCHEMES IN FACING DISCONTINUITIES IN THE FINITE CELL METHOD
Authors: ABEDIAN ALIREZA , PARVIZIAN JAMSHID , DÜSTER ALEXANDER , KHADEMYZADEH HASSAN , RANK ERNST
Published: February 2013

In many extended versions of the finite element method (FEM) the mesh does not conform to the physical domain. Therefore, discontinuity of variables is expected when some elements are cut by the boundary. Thus, the integrands are not continuous over the whole integration domain. Apparently, none of the well developed integration schemes such as Gauss quadrature can be used readily. This paper investigates several modifications of the Gauss quadrature to capture the discontinuity within an element and to perform a more precise integration. The extended method used here is the finite cell method (FCM), an extension of a high-order approximation space with the aim of simple meshing. Several examples are included to evaluate different modifications.
Cenozoic pure-shear collapse of the southern Menderes Massif, Turkey
Authors: Iredale Lindsay J. , Teyssier Christian , Whitney Donna L.
Published: February 2013

A transition from construction to collapse of the Alpine orogen in Middle to Late Eocene time is recorded in the structural fabrics of gneissic rocks in the southern Menderes Massif, western Turkey. Augen gneiss in the southern Menderes Massif indicates a spatial switch of shear sense along a north–south section through the complex (top-to-north shear in the north and top-to-south in the south). This ‘kinematic hinge’ corresponds to a broad zone of dominant pure shear where crust underwent vertical thinning and approximate north–south extension. During this extension, foliation became corrugated with fold axes parallel to lineation, indicating inflow from neighbouring crust to the east and the west. Published geochronologic work suggests a Middle to Late Eocene age for this dominant fabric. Thermal weakening of felsic Menderes crust beneath Alpine nappes may have triggered this orogenic collapse. Deformation fabrics developed at temperatures of
c.
550 °C, and progressive cooling during collapse generated strain localization within a kilometre-thick shear zone at the southern margin of the Menderes Massif. In the southern Menderes, the corrugation of foliation indicates that Middle to Late Eocene flow was constricted into an orogen-perpendicular direction. This behaviour is similar to the collapse and orogen-parallel extension of the European Alps (Lepontine dome, Tauern Window).
Late Palaeozoic–Cenozoic tectonic development of carbonate platform, margin and oceanic units in the Eastern Taurides, Turkey
Authors: Robertson A. H. F. , Parlak O. , Metİn Y. , Vergİlİ Ö. , Tasli K. , İnan N. , Soycan H.
Published: February 2013

Continental margin-type, ophiolitic and mélange units are exposed throughout central eastern Turkey (e.g. Gürün, Hekimhan and Pınarbaşı areas). These restore as a north-verging Triassic-rifted continental margin that underwent Jurassic–Early Cretaceous passive margin subsidence. Chemically ‘enriched’ basaltic lavas of seamount type are interbedded with and overlain by Middle Jurassic–Early Cretaceous ribbon cherts. Ophiolitic rocks (e.g. Pınarbaşı, Dağlıca, Kuluncak, Hekimhan, Divriği) formed by spreading above a Late Cretaceous northwards-dipping intra-oceanic subduction zone. Emplacement of continental margin units, mélanges and ophiolites onto the East Tauride platform was driven by trench-margin collision during latest Cretaceous. The northern part of the East Tauride neritic carbonate platform detached and overthrust the continent to the south (Malatya Metamorphics) which was deeply underthrust, metamorphosed at least to greenschist facies and exhumed by latest Cretaceous. Collision-related Mid-Eocene southwards thrusting strongly affected the western part of the region (e.g. Pınarbaşı), whereas areas further east (e.g. Darende, Hekimhan, Divriği, Sivas) mainly experienced folding. Taking account of the regional tectonic setting, we infer that the Gürün platform, with its distinctive unbroken up to Lutetian-aged succession, represents a small exotic terrane that was translated from a relatively southerly (‘internal’) part of the Tauride platform (Geyik Dağ), related to strike-slip displacement (syn/post-Eocene to pre-Pliocene).

Supplementary material:

Two supplementary tables giving the GPS coordinates of the samples of basic intrusive and extrusive igneous rocks that were analyzed during this work are available at
www.geolsoc.org.uk/SUP18569
Plio-Quaternary stress regime in Eşen Çay Basin, SW Turkey
Authors: Över Semir , Özden Süha , Yilmaz Hüseyin , Pinar Ali , Ünlügenç Ulvi Can , Kamaci Zuheyr
Published: February 2013

The Plio-Quaternary Eşen Çay Basin is situated at the junction of Hellenic and Cyprus arcs in southwestern Turkey. The basin is important for understanding the tectonic evolution of the region in relation to the Hellenic and Cyprus arcs. Fault data from unconsolidated Pliocene and Quaternary deposits, as well as from pre-Pliocene lithologies, are analysed in order to reconstruct the evolution of the stress field evolution from Pliocene onwards. Inversion of measured fault slip vector data identifies two main stress states: extensional and strike-slip. Both states are characterized by a NE–SW-trending minimum horizontal stress axis (σ
Hmin
=σ
3
). The mean
R
value is 0.67, indicating a triaxial state of stress. The inversion also indicates the existence of extensional and strike-slip faulting characterized by a NW–SE-trending σ
3
axis. This indicates a change in the direction of the minimum horizontal stress axis (σ
3
) from a NW–SE-trending σ
3
that dominated prior to Quaternary to a NE–SW-trending σ
3
that dominated during Quaternary up to actual time.
The Strength-Interval Curve in Cardiac Tissue
Authors: Kandel Sunil M. , Roth Bradley J.
Published: February 2013

The bidomain model describes the electrical properties of cardiac tissue and is often used to simulate the response of the heart to an electric shock. The strength-interval curve summarizes how refractory tissue is excited. This paper analyzes calculations of the strength-interval curve when a stimulus is applied through a unipolar electrode. In particular, the bidomain model is used to clarify why the cathodal and anodal strength-interval curves are different, and what the mechanism of the “dip” in the anodal strength-interval curve is.
The Development and Validation of a Measure of Health-Related Quality of Life for Non-Hodgkin’s Lymphoma: The Functional Assessment of Cancer Therapy—Lymphoma (FACT-Lym)
Authors: Hlubocky Fay J. , Webster Kimberly , Cashy John , Beaumont Jennifer , Cella David
Published: February 2013

Background. The individual concerns of non-Hodgkin’s lymphoma (NHL) patients require identification and assessment during clinical research proposing to measure patients’ outcomes. The FACT-Lym was developed as part of the FACIT measurement system to address health-related quality-of-life (HRQL) issues for NHL patients. Patients and Methods. Items for the FACT lymphoma subscale (LymS) were generated from healthcare provider interviews, published literature, and content validity patient interviews. The FACT-Lym was validated on a sample of 84 NHL patients, with additional measures at baseline (T1), 3–7 days (T2), and 8–12 weeks (T3). Results. Item correlations, expert relevance ratings, and patient input on content shortened the initial 22-item LymS to 15 items. The validation sample included 56% female, 76.2% white, 60% indolent disease, and 85% receiving treatment. Internal consistency coefficients for the 15-item LymS (.79, .85, and .84 T1–T3) and test-retest stability (.84) indicated good reliability. Correlations between LymS and SF-36 physical (r=.62) and mental (r=.48) summary scores reflect concurrent validity. Responsiveness to ECOG performance status and treatment status exceeded established FACT subscale scores. The FACT-LymS differentiated patients’ retrospective ratings of change in each of the three groups (better; unchanged; worse), P<0.001. Conclusions. These results support the validity of the FACT-Lym and suggest it will be a useful targeted endpoint in NHL clinical research.
Surgical Treatment and Survival in Patients with Liver Metastases from Neuroendocrine Tumors: A Meta-Analysis of Observational Studies
Authors: Bacchetti Stefano , Bertozzi Serena , Londero Ambrogio P. , Uzzau Alessandro , Pasqual Enrico Maria
Published: February 2013

Introduction. The role of hepatic resection in patients with liver metastases from gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is still poorly defined. Therefore, we examined the results obtained with surgical resection and other locoregional or systemic therapies by reviewing the recent literature on this topic. We performed the meta-analysis for comparing surgical resection of hepatic metastases with other treatments.Materials and Methods. In this systematic review and meta-analysis of observational studies, the literature search was undertaken between 1990 and 2012 looking for studies evaluating the different survivals between patients treated with surgical resection of hepatic metastases and with other surgical or nonsurgical therapies. The studies were evaluated for quality, publication bias, and heterogeneity. Pooled hazard ratio (HR) estimates and 95% confidence intervals (CI.95) were calculated using fixed-effects model.Results. We selected six studies in the review, five of which were suitable for meta-analysis. We found a significant longer survival in patients treated with hepatic resection than embolisation HR 0.34 (CI.95 0.21–0.55) or all other nonsurgical treatments HR 0.45 (CI.95 0.34–0.60). Only one study compared surgical resection with liver transplantation and meta-analysis was not feasible.Conclusions. Our meta-analysis provides evidence supporting the hypothesis that hepatic resection increases overall survival in patients with liver metastases from GEP-NETs. Further randomized clinical trials are needed to confirm these findings and it would be desirable to identify new markers to properly select patients for surgical treatment.
Surgical Resection of a Leiomyosarcoma of the Inferior Vena Cava Mimicking Hepatic Tumor
Authors: Ueda Junji , Yoshida Hiroshi , Mamada Yasuhiro , Taniai Nobuhiko , Yoshioka Masato , Kawano Youichi , Mizuguchi Yoshiaki , Shimizu Tetsuya , Takata Hideyuki , Uchida Eiji
Published: February 2013

Introduction. Leiomyosarcomas of vascular origin are particularly rare tumors occurring mainly in the inferior vena cava (IVC). They are malignant, slow-growing tumors with a poor prognosis. This paper reports on a rare case of surgical resection of an IVC leiomyosarcoma mimicking a hepatic tumor.Case Presentation. A 65-year-old Japanese male was admitted for evaluation of an abdominal tumor. Enhanced computed tomography of the abdomen revealed a slightly enhanced heterogeneous tumor, 18 mm in diameter, between the Spiegel lobe of the liver and the IVC in early-phase images, with no enhancement or washout in late-phase images. We diagnosed this tumor as either a hepatic tumor in the Spiegel lobe or a retroperitoneal tumor such as leiomyosarcoma or liposarcoma and performed a laparotomy. On the basis of surgical findings, we extirpated the tumor by performing a wedge resection of the wall of the IVC and suturing the primary IVC wall. Pathological findings led to a further diagnosis of the tumor as a leiomyosarcoma originating in the IVC. Thirty-seven months after the operation, multiple liver and lung metastases were detected, and the patient died from multiple organic failures.Conclusion. We experienced a rare case of a leiomyosarcoma of IVC mimicking hepatic tumor.
Hypercoordinated Organosilicon(IV) and Organotin(IV) Complexes: Syntheses, Spectral Studies, and Antimicrobial Activity In Vitro
Authors: Singh Kiran , Puri Parvesh , Kumar Yogender , Sharma Chetan
Published: February 2013

This paper deals with the syntheses and structural features of some new diorganosilicon(IV) and diorganotin(IV) complexes having general formulae (CH3)2MCl(L1), (CH3)2MCl(L2), (CH3)2M(L1)2, and (CH3)2M(L2)2 with new Schiff bases (M = Si and Sn). The Schiff bases HL1 and HL2 have been derived from the condensation of 3-bromobenzaldehyde with 4-amino-3-ethyl-5-mercapto-1,2,4-triazole and 4-amino-5-mercapto-3-propyl-1,2,4-triazole, respectively. The compounds have been characterized by the elemental analyses, molar conductance, and spectral (UV, IR, 1H, 13C, 29Si, and 119Sn NMR) studies. The resulting complexes have been proposed to have trigonal bipyramidal and octahedral geometries. In vitro antimicrobial activities of the compounds have been carried out.
Resveratrol Downregulates Interleukin-6-Stimulated Sonic Hedgehog Signaling in Human Acute Myeloid Leukemia
Authors: Su Yu-Chieh , Li Szu-Chin , Wu Yin-Chi , Wang Li-Min , Chao K. S. Clifford , Liao Hui-Fen
Published: February 2013

IL-6 and sonic hedgehog (Shh) signaling molecules are considered to maintain the growth of cancer stem cells (CSCs). Resveratrol, an important integrant in traditional Chinese medicine, possesses certain antitumor effects. However, the mechanisms on regulating acute myeloid leukemia (AML) are unclear. This study first used human subjects to demonstrate that the plasma levels of IL-6 and IL-1βin AML patients were higher and lower, respectively, than healthy donors. The expression of Shh preproproteins, and C- and N-terminal Shh peptides increased in bone marrow and peripheral blood mononuclear cells isolated from AML patients, and the plasma N-Shh secretion was greater. To further clarify the effect of IL-6 and resveratrol in Shh signaling, human AML HL-60 cells were tested. IL-6 upregulated Shh and Gli-1 expression and was accompanied by an increase of cell viability. Resveratrol significantly decreased CSC-related Shh expression, Gli-1 nuclear translocation, and cell viability in IL-6-treated HL-60 cells and had synergistic effect with Shh inhibitor cyclopamine on inhibiting cell growth.Conclusions. IL-6 stimulated the growth of AML cells through Shh signaling, and this effect might be blocked by resveratrol. Further investigations of Shh as a prognostic marker and resveratrol as a therapeutic drug target to CSCs in AML are surely warranted.
On Structural Patterns of Mechanical Systems with Impacts with One and Two Degrees-of-Freedom
Authors: Blazejczyk-Okolewska Barbara
Published: February 2013

Structural patterns of mechanical systems with impacts with one degree-of-freedom and two degrees-of-freedom, with elastic connections, have been identified and described. For their identification, a general method proposed by the author has been applied. This method uses (i) a matrix representation of the system with impacts, (ii) procedures that enable generations of all combinations of such systems as well as their identification and elimination of redundant equivalent combinations, and (iii) a procedure for elimination of disconnected systems.
Gallic Acid Induces a Reactive Oxygen Species-Provoked c-Jun NH2-Terminal Kinase-Dependent Apoptosis in Lung Fibroblasts
Authors: Chen Chiu-Yuan , Chen Kun-Chieh , Yang Tsung-Ying , Liu Hsiang-Chun , Hsu Shih-Lan
Published: February 2013

Idiopathic pulmonary fibrosis is a chronic lung disorder characterized by fibroblasts proliferation and extracellular matrix accumulation. Induction of fibroblast apoptosis therefore plays a crucial role in the resolution of this disease. Gallic acid (3,4,5-trihydroxybenzoic acid), a common botanic phenolic compound, has been reported to induce apoptosis in tumor cell lines and renal fibroblasts. The present study was undertaken to examine the role of mitogen-activated protein kinases (MAPKs) in lung fibroblasts apoptosis induced by gallic acid. We found that treatment with gallic acid resulted in activation of c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and protein kinase B (PKB, Akt), but not p38MAPK, in mouse lung fibroblasts. Inhibition of JNK using pharmacologic inhibitor (SP600125) and genetic knockdown (JNK specific siRNA) significantly inhibited p53 accumulation, reduced PUMA and Fas expression, and abolished apoptosis induced by gallic acid. Moreover, treatment with antioxidants (vitamin C, N-acetyl cysteine, and catalase) effectively diminished gallic acid-induced hydrogen peroxide production, JNK and p53 activation, and cell death. These observations imply that gallic acid-mediated hydrogen peroxide formation acts as an initiator of JNK signaling pathways, leading to p53 activation and apoptosis in mouse lung fibroblasts.
Cytokine Response of Cultured Skeletal Muscle Cells Stimulated with Proinflammatory Factors Depends on Differentiation Stage
Authors: Podbregar Matej , Lainscak Mitja , Prelovsek Oja , Mars Tomaz
Published: February 2013

Myoblast proliferation and myotube formation are critical early events in skeletal muscle regeneration. The attending inflammation and cytokine signaling are involved in regulation of skeletal muscle cell proliferation and differentiation. Secretion of muscle‐derived cytokines upon exposure to inflammatory factors may depend on the differentiation stage of regenerating muscle cells. Cultured human myoblasts and myotubes were exposed to 24‐hour treatment with tumor necrosis factor (TNF)‐α or lipopolysaccharide (LPS). Secretion of interleukin 6 (IL‐6), a major muscle‐derived cytokine, and interleukin 1 (IL‐1), an important regulator of inflammatory response, was measured 24 hours after termination of TNF‐α or LPS treatment. Myoblasts pretreated with TNF‐α or LPS displayed robustly increased IL‐6 secretion during the 24‐hour period after removal of treatments, while IL‐1 secretion remained unaltered. IL‐6 secretion was also increased in myotubes, but the response was less pronounced compared with myoblasts. In contrast to myoblasts, IL‐1 secretion was markedly stimulated in LPS‐pretreated myotubes. We demonstrate that preceding exposure to inflammatory factors stimulates a prolonged upregulation of muscle‐derived IL‐6 and/or IL‐1 in cultured skeletal muscle cells. Our findings also indicate that cytokine response to inflammatory factors in regenerating skeletal muscle partially depends on the differentiation stage of myogenic cells.
Novel Application of a Multiscale Entropy Index as a Sensitive Tool for Detecting Subtle Vascular Abnormalities in the Aged and Diabetic
Authors: Wu Hsien-Tsai , Lo Men-Tzung , Chen Guan-Hong , Sun Cheuk-Kwan , Chen Jian-Jung
Published: February 2013

Although previous studies have shown the successful use of pressure-induced reactive hyperemia as a tool for the assessment of endothelial function, its sensitivity remains questionable. This study aims to investigate the feasibility and sensitivity of a novel multiscale entropy index (MEI) in detecting subtle vascular abnormalities in healthy and diabetic subjects. Basic anthropometric and hemodynamic parameters, serum lipid profiles, and glycosylated hemoglobin levels were recorded. Arterial pulse wave signals were acquired from the wrist with an air pressure sensing system (APSS), followed by MEI and dilatation index (DI) analyses. MEI succeeded in detecting significant differences among the four groups of subjects: healthy young individuals, healthy middle-aged or elderly individuals, well-controlled diabetic individuals, and poorly controlled diabetic individuals. A reduction in multiscale entropy reflected age- and diabetes-related vascular changes and may serve as a more sensitive indicator of subtle vascular abnormalities compared with DI in the setting of diabetes.
Reliable RANSAC Using a Novel Preprocessing Model
Authors: Wang Xiaoyan , Zhang Hui , Liu Sheng
Published: February 2013

Geometric assumption and verification with RANSAC has become a crucial step for corresponding to local features due to its wide applications in biomedical feature analysis and vision computing. However, conventional RANSAC is very time-consuming due to redundant sampling times, especially dealing with the case of numerous matching pairs. This paper presents a novel preprocessing model to explore a reduced set with reliable correspondences from initial matching dataset. Both geometric model generation and verification are carried out on this reduced set, which leads to considerable speedups. Afterwards, this paper proposes a reliable RANSAC framework using preprocessing model, which was implemented and verified using Harris and SIFT features, respectively. Compared with traditional RANSAC, experimental results show that our method is more efficient.
Does Early Decompressive Craniectomy Improve Outcome? Experience from an Active UK Recruiter Centre
Authors: García Vicente E. , Garnelo Rey V. , Manikon M. , Ashworth S. , Wilson M. H.
Published: February 2013

Introduction. The results of the recent DECRA study suggest that although craniectomy decreases ICP and ICU length of stay, it is also associated with worst outcomes. Our experience, illustrated by these two striking cases, supports that early decompressive craniectomy may significantly improve the outcome in selected patients.Case Reports. The first patient, a 20-year-old man who suffered severe brain contusion and subarachnoid haemorrhage after a fall downstairs, with refractory ICP of 35 mmHg, despite maximal medical therapy, eventually underwent decompressive craniectomy. After 18 days in intensive care, he was discharged for rehabilitation. The second patient, a 23-year-old man was found at the scene of a road accident with a GCS of 3 and fixed, dilated pupils who underwent extensive unilateral decompressive craniectomy for refractory intracranial hypertension. After three weeks of cooling, paralysis, and neuroprotection, he eventually left ICU for rehabilitation.Outcomes. Four months after leaving ICU, the first patient abseiled 40 m down the main building of St. Mary’s Hospital to raise money for the Trauma Unit. He has returned to part-time work. The second patient, was decannulated less than a month later and made a full cognitive recovery. A year later, with a titanium skull prosthesis, he is back to part-time work and to playing football.Conclusions. Despite the conclusions of the DECRA study, our experience of the use of early decompressive craniectomy has been associated with outstanding outcomes. We are currently actively recruiting patients into the RESCUEicp trial and have high hopes that it will clarify the role of the decompressive craniectomy in traumatic brain injury and whether it effectively improves outcomes.
Aneurysm of the Vein of Galen Diagnosed with MRI
Authors: Dagklis Themistoklis , Margioula-Siarkou Chrysoula , Petousis Stamatios , Xenidis Theodoros , Sapidis Aggelos , Kalogiannidis Ioannis , Rousso David
Published: February 2013

We describe the case of a neonate with aneurysm of vein of Galen that was diagnosed prenatally in the 33rd gestational week by MRI. A 27-year-old woman, gravida 2, para 2, was admitted to our department at 33 weeks of gestation with suspected fetal hydrocephaly. Ultrasound examination after admission demonstrated an anechoic, supratentorial, and median mass with regular borders, raising the possible diagnosis of an aneurysm of the vein of Galen. MRI confirmed the presence of an aneurysm of the vein of Galen. An elective caesarean section was performed at 33 weeks of gestation. The newborn was admitted to the Neonatal Intensive Care Unit. Despite the full respiratory and medical support given, the sustainment of cardiac failure resulted in neonatal death just one day following its admission.
New Strategies in Diagnosing Cancer in Thyroid Nodules: Impact of Molecular Markers
Authors: Nikiforov Yuri E. , Yip Linwah , Nikiforova Marina N.
Published: February 2013

Thyroid cancer is the most common type of endocrine malignancy, with approximately 55,000 new cases diagnosed in the United States in 2012. However, thyroid nodules are much more prevalent, particularly with increased age, and only a small fraction of those are malignant. Therefore, the major clinical challenge is to reliably differentiate those nodules that are malignant and need to be treated surgically from the majority of nodules that are benign and do not require surgery. The traditional diagnostic approach to this clinical situation is ultrasound-guided fine-needle aspiration (FNA) of the thyroid nodule followed by cytologic examination, which together reliably establish the diagnosis in 70% to 80% of cases. However, in the rest of nodules the presence of cancer cannot be ruled out by FNA cytology, hampering appropriate surgical management and frequently resulting in unnecessary surgical interventions. New approaches to diagnosis of cancer in thyroid nodules are based on mutational and other molecular markers, which can be reliably detected in cells aspirated during the FNA procedure. These markers offer significant improvement in the diagnostic accuracy of FNA cytology and are poised to make a profound effect on the management of patients with thyroid nodules. In addition to the molecular markers that have recently become available for clinical use, rapid development of new sequencing techniques is expected to further improve the accuracy of cancer diagnosis in thyroid nodules and allow for a fully individualized approach to the management of patients with thyroid nodules. Clin Cancer Res; 19(9); 2283–8. ©2013 AACR.
Promoter CpG Island Hypermethylation of the DNA Repair Enzyme MGMT Predicts Clinical Response to Dacarbazine in a Phase II Study for Metastatic Colorectal Cancer
Authors: Amatu Alessio , Sartore-Bianchi Andrea , Moutinho Catia , Belotti Alessandro , Bencardino Katia , Chirico Giuseppe , Cassingena Andrea , Rusconi Francesca , Esposito Anna , Nichelatti Michele , Esteller Manel , Siena Salvatore
Published: February 2013

Purpose: O6-methylguanine-DNA-methyltransferase (MGMT) is a DNA repair protein removing mutagenic and cytotoxic adducts from O6-guanine in DNA. Approximately 40% of colorectal cancers (CRC) display MGMT deficiency due to the promoter hypermethylation leading to silencing of the gene. Alkylating agents, such as dacarbazine, exert their antitumor activity by DNA methylation at the O6-guanine site, inducing base pair mismatch; therefore, activity of dacarbazine could be enhanced in CRCs lacking MGMT. We conducted a phase II study with dacarbazine in CRCs who had failed standard therapies (oxaliplatin, irinotecan, fluoropyrimidines, and cetuximab or panitumumab if KRAS wild-type).

Experimental Design: All patients had tumor tissue assessed for MGMT as promoter hypermethylation in double-blind for treatment outcome. Patients received dacarbazine 250 mg/m2 intravenously every day for four consecutive days, every 21 days, until progressive disease or intolerable toxicity. We used a Simon two-stage design to determine whether the overall response rate would be 10% or more. Secondary endpoints included association of response, progression-free survival, and disease control rate with MGMT status.

Results: Sixty-eight patients were enrolled from May 2011 to March 2012. Patients received a median of three cycles of dacarbazine (range 1–12). Grades 3 and 4 toxicities included: fatigue (41%), nausea/vomiting (29%), constipation (25%), platelet count decrease (19%), and anemia (18%). Overall, two patients (3%) achieved partial response and eight patients (12%) had stable disease. Disease control rate (partial response + stable disease) was significantly associated with MGMT promoter hypermethylation in the corresponding tumors.

Conclusion: Objective clinical responses to dacarbazine in patients with metastatic CRC are confined to those tumors harboring epigenetic inactivation of the DNA repair enzyme MGMT. Clin Cancer Res; 19(8); 2265–72. ©2013 AACR.
Combined Serum CA19-9 and miR-27a-3p in Peripheral Blood Mononuclear Cells to Diagnose Pancreatic Cancer
Authors: Wang Wan-Sheng , Liu Ling-Xiao , Li Guo-Ping , Chen Yi , Li Chang-Yu , Jin Da-Yong , Wang Xiao-Lin
Published: February 2013

MicroRNAs are potentially very useful biomarkers in the diagnosis of cancer. We sought to identify specific microRNAs in peripheral blood mononuclear cells (PBMCs) whose levels might facilitate diagnosis of pancreatic cancer. We investigated PBMC microRNA expression in three independent cohorts [healthy, benign pancreatic/peripancreatic diseases (BPD), and pancreatic cancer], comprising a total of 352 participants. First, we used sequencing technology to identify differentially expressed microRNAs in PBMC of pancreatic cancer, BPD, and healthy controls (n = 20 in each group). Then the selected microRNAs were analyzed using the quantitative reverse transcriptase PCR assays in the remaining 292 samples. The predictive value of the microRNAs was evaluated by logistic regression models and the receiver operating characteristic curve (AUC). We found that miR-27a-3p level in PBMCs could discriminate pancreatic cancer from BPD with a sensitivity of 82.2% and specificity of 76.7% (AUC = 0.840; 95% CI, 0.787–0.885%). Combination of PBMC miR-27a-3p and serum CA19-9 levels provided a higher diagnostic accuracy with a sensitivity of 85.3% and specificity of 81.6% (AUC = 0.886; 95% CI, 0.837–0.923%). The satisfactory diagnostic performance of the panel persisted regardless of disease status (AUCs for tumor-node-metastasis stages I–III were 0.881, 0.884, and 0.893, respectively). PBMC miR-27a-3p level represents a potential marker for pancreatic cancer screening. A panel combining serum CA19-9 and PBMC miR-27a-3p level could have considerable clinical value in diagnosing pancreatic cancer. Cancer Prev Res; 6(4); 331–8. ©2013 AACR.
Therapeutic Response Assessment of Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma: Ultrasonography, CT and MR Imaging
Authors: Minami Yasunori , Kudo Masatoshi
Published: February 2013

Two randomized controlled trials identified that transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) shows a significant survival benefit compared with controls, after a long-term controversy. Thus, TACE is the current standard of care for patients presenting with multinodular HCC. Monitoring tumor response to TACE is part of the clinical management of HCC patients. Imaging, including ultrasonography, computed tomography and magnetic resonance imaging, has an important role in assessing therapeutic effects earlier and more objectively. Imaging assessment needs to detect not only a reduction in overall tumor load but also a reduction in viable tumor. Here, we give an overview of the current status of the imaging assessment of HCC response to TACE.
Is It Time to Adopt External Beam Radiotherapy in the NCCN Guidelines as a Therapeutic Strategy for Intermediate/Advanced Hepatocellular Carcinoma?
Authors: Jiang Wei , Zeng Zhao-Chong
Published: February 2013

Objective: External beam radiotherapy (EBRT) is recommended as a therapeutic strategy for stage III hepatocellular carcinoma (HCC) in national guidelines of the Chinese Society of Liver Disease and in Korea Liver Cancer Study Group practice guidelines, but has not been considered a therapeutic option for HCC in Western countries. In this study, we review evidence supporting EBRT as an option for HCC treatment. Methods: Retrospective investigation was made of 775 patient records of intermediate/advanced HCC treated in our hospital during the last 10 years, including 98 patients with confined intrahepatic tumor, 181 with portal vein (PV) or inferior vena cava (IVC) tumor thrombi, 191 with lymph node metastases, 55 with adrenal gland metastases, 205 with bone metastases, 13 with lung metastases and 32 with brain metastases. Results: Transcatheter arterial chemoembolization combined with radiotherapy was found to constitute an improved therapeutic strategy for unresectable but confined intrahepatic HCC with poor lipid accumulation. Survival of HCC patients with PV/IVC tumor thrombi was prolonged to 10.7 months by radiotherapy, and it was 8.0 months in patients with abdominal lymph node metastasis. Radiotherapy also shrinks adrenal and lung metastatic HCC lesions, resulting in median survival times of 13.6 and progression-free survival of 13.4 months, respectively. In bone metastatic HCC, radiotherapy significantly relieved symptoms, although median survival time was only 7.4 months. Radiotherapy is effective for treatment of intermediate/advanced stages of HCC. Although our finding is based only on retrospective analysis, no therapeutic option that provides better treatment than EBRT in this indication has thus far been identified. Because sorafenib has been recommended as a treatment strategy by the National Comprehensive Cancer Network (NCCN) for HCC, we compared the survival after EBRT with sorafenib treatment on the basis of published clinical data. From this comparison, we found that EBRT treatment was more effective than sorafenib for improving patient survival when tested on tumors of comparable metastatic size. Conclusion: Based on the evidence reviewed, we propose that EBRT be included in the NCCN guideline as a treatment strategy for intermediate/advanced HCC.
Recent Advancements in Comprehensive Genetic Analyses for Human Hepatocellular Carcinoma
Authors: Nishida Naoshi , Kudo Masatoshi
Published: February 2013

Hepatocellular carcinoma (HCC) typically develops in the liver with chronic hepatitis and cirrhosis, and activation of oncogenes and inactivation of tumor suppressor genes occurs during carcinogenesis via genetic and epigenetic mechanisms. Recent advancements in the development of analyses for examining the cancer genome have revealed information regarding genetic alterations in HCC tissues. According to previous studies, the incidence of recurrent genetic alterations in individual genes was thought to be relatively rare and limited to a subset of a few cancer-specific genes such as tumor suppressor p53, RB genes and oncogenes such as CTNNB1. However, recent whole-genome analyses and exome sequencing of tumor DNA have revealed numerous novel alterations of cancer-related genes and pathways critical for HCC development. In addition, various risk factors for HCC, such as the presence or absence of hepatitis B and C virus, may affect the mutation profile of the corresponding cancer genome. On the other hand, genome-wide association studies have also identified important single-nucleotide polymorphisms involved in HCC development, which may allow detection of a group at high risk of HCC emergence. Such analyses will clarify how this malignancy can be treated, diagnosed and prevented more effectively.
High-Density Lipoprotein Subfractions - What the Clinicians Need to Know
Authors: Pirillo Angela , Norata Giuseppe Danilo , Catapano Alberico Luigi
Published: February 2013

Although the inverse relationship between plasma levels of high-density lipoprotein (HDL) and cardiovascular disease has been largely demonstrated, many observations have suggested that the assessment of HDL functionality might be more informative than a simple measurement of HDL-cholesterol plasma levels. HDLs are a class of structurally and functionally heterogeneous particles; in atherosclerosis-related diseases, changes in HDL subfraction levels and functions are frequently observed. Circulating levels of large HDL particles are decreased in dyslipidaemic conditions, while levels of small dense HDL particles are increased in patients with coronary heart disease. Furthermore, specific genetic defects in proteins involved in HDL metabolism significantly impact the distribution of HDL subpopulations. Finally, many drugs used for dyslipidaemia induce changes in HDL subfractions strictly related to cardiovascular disease. Although several methods exist to evaluate HDL subclass levels, most of them are not easily applicable in clinical practice, due to the costs and high variability. However, the possibility to measure the levels of specific HDL subfractions in patients with atherosclerosis-related diseases might help to better define their cardiovascular risk.
Somatic Cell Genomics of Brain Disorders: A New Opportunity to Clarify Genetic-Environmental Interactions
Authors: Iourov I.Y. , Vorsanova S.G. , Yurov Y.B.
Published: February 2013

Recent genomic advances have exacerbated the problem of interpreting genome-wide association studies aimed at uncovering genetic basis of brain disorders. Despite of a plethora of data on candidate genes determining the susceptibility to neuropsychiatric diseases, no consensus is reached on their intrinsic contribution to the pathogenesis, and the influence of the environment on these genes is incompletely understood. Alternatively, single-cell analyses of the normal and diseased human brain have shown that somatic genome/epigenome variations (somatic mosaicism) do affect neuronal cell populations and are likely to mediate pathogenic processes associated with brain dysfunctions. Such (epi-)genomic changes are likely to arise from disturbances in genome maintenance and cell cycle regulation pathways as well as from environmental exposures. Therefore, one can suggest that, at least in a proportion of cases, inter- and intragenic variations (copy number variations (CNVs) or single nucleotide polymorphisms (SNPs)) associated with major brain disorders (i.e. schizophrenia, Alzheimer's disease, autism) lead to genetic dysregulation resulting in somatic genetic and epigenetic mosaicism. In addition, environmental influences on malfunctioning cellular machinery could trigger a cascade of abnormal processes producing genomic/chromosomal instability (i.e. brain-specific aneuploidy). Here, a brief analysis of a genome-wide association database has allowed us to support these speculations. Accordingly, an ontogenetic 2-/multiple-hit mechanism of brain diseases was hypothesized. Finally, we speculate that somatic cell genomics approach considering both genome-wide associations and somatic (epi-)genomic variations is likely to have bright perspectives for disease-oriented genome research.