bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss of MTBP expression is associated with reduced survival in a biomarker‐defined subset of patients with squamous cell carcinoma of the head and neck
Authors: Vlatković Nikolina , El‐Fert Ashraf , Devling Timothy , Ray‐Sinha Arpita , Gore David M. , Rubbi Carlos P. , Dodson Andy , Jones Andrew S. , Helliwell Tim R. , Jones Terence M. , Boyd Mark T.
Published: January 2011

BACKGROUND:

Recent genetic studies have implicated p53 mutation as a significant risk factor for therapeutic failure in squamous cell carcinoma of the head and neck (SCCHN). However, in a recent meta‐analysis in the literature of p53 from major anatomical subsites (larynx, oral cavity, oropharynx/hypopharynx), associations between patient survival and p53 status were ambiguous.

METHODS:

The authors examined a cohort of SCCHNs using a previously developed biomarker combination that likely predicts p53 status based on p53/MDM2 expression levels determined by immunohistochemistry (IHC). In addition, the authors generated and validated an antibody to MTBP (an MDM2 binding protein that alters p53/MDM2 homeostasis and may contribute to metastatic suppression) and have incorporated data for MTBP expression into the current analyses.

RESULTS:

Analysis of expression data for p53 and MDM2 in 198 SCCHN patient samples revealed that the biomarker combination p53 + ve/MDM2‐low (likely indicative of p53 mutation) was significantly associated with reduced overall survival (log‐rank P = .035) and was an independent prognostic factor (P = .013; HR, 1.705; 95% CI, 1.12‐2.60); thus, these data were compatible with earlier genetic analyses. By using IHC for p53 and MDM2 to dichotomize patients, the authors found that loss of MTBP expression was significantly associated with reduced survival (log‐rank P = .004) and was an independent prognostic factor (P = .004; HR, 2.78; 95% CI, 1.39‐5.54) in p53 + ve/MDM2‐low patients.

CONCLUSIONS:

These results represent the first examination of MTBP expression in human tissues and provide evidence for a p53 status‐dependent role for MTBP in suppressing disease progression in SCCHN patients as well as confirming a role for p53 pathway function in delaying disease progression. Cancer 2011. © 2011 American Cancer Society.
Glucose, not glutamine, is the dominant energy source required for proliferation and survival of head and neck squamous carcinoma cells
Authors: Sandulache Vlad C. , Ow Thomas J. , Pickering Curtis R. , Frederick Mitchell J. , Zhou Ge , Fokt Izabela , Davis‐Malesevich Melinda , Priebe Waldemar , Myers Jeffrey N.
Published: January 2011

BACKGROUND:

Tumor metabolism is an essential contributor to disease progression and response to treatment. An understanding of the metabolic phenotype of head and neck squamous cell carcinoma (HNSCC) will allow the development of appropriate antimetabolic strategies for this tumor type.

METHODS:

A panel of 15 HNSCC cell lines was assayed for glucose and glutamine dependence and sensitivity to metabolic inhibitors. In addition, broad‐spectrum metabolomic analysis using mass spectrometry/liquid chromatography was combined with individual measurements of reducing potential, adenosine triphosphate, and lactate production to characterize cellular metabolic phenotypes.

RESULTS:

HNSCC energy and reducing potential levels closely mirrored extracellular glucose concentrations. Glucose starvation induced cell death despite the activation of secondary energetic pathways. Conversely, glutamine was not required for HNSCC survival and did not serve as a significant source of energy. 2‐deoxyglucose (2‐DG) and its fluorinated derivative decreased glycolytic and Krebs cycle activity, cellular energy, and reducing potential and inhibited HNSCC cell proliferation. 2‐DG effects were potentiated by the addition of metformin, but not by inhibitors of the pentose phosphate pathway or glutaminolysis. Despite dependence on glucose catabolism, the authors identified a subset of cell lines with relative resistance to starvation. Exploration of 1 such cell line (HN30) suggested that the presence of wild‐type p53 can partially protect tumor cells from glucose starvation.

CONCLUSIONS:

HNSCC tumor cells are dependent on glucose, not glutamine, for energy production and survival, providing a rationale for treatment strategies that target glucose catabolism. However, antimetabolic strategies may need to be tailored to the tumor background, more specifically, p53 status. Cancer 2011. © 2011 American Cancer Society.
Clinical prognostic factors in patients with locally advanced (stage III) nonsmall cell lung cancer treated with hyperfractionated radiation therapy with and without concurrent chemotherapy
Authors: Jeremić Branislav , Miličić Biljana , Milisavljevic Slobodan
Published: January 2011

BACKGROUND:

Influence of potential clinical prognostic factors on overall survival (OS), local progression‐free survival (PFS), and distant metastasis‐free survival (MFS) in patients with locally advanced nonsmall cell lung cancer treated with hyperfractionated radiation therapy (HFX RT) with or without concurrent chemotherapy was investigated.

METHODS:

Three phase 3 and 2 phase 2 studies have been designed and executed with a total of 600 patients. HFX RT alone was given in 127 and HFX RT‐chemotherapy was given in 473 patients. HFX RT doses were either 64.8 grays (Gy) or 69.6 Gy using 1.2 Gy twice daily, or 67.6 Gy using 1.3 Gy twice daily. Chemotherapy consisted of concurrent carboplatin and etoposide in 409 patients and concurrent carboplatin and paclitaxel in 64 patients. Sex, age, Karnofsky performance score (KPS), weight loss (>5%), stage, histology, interfraction interval, and treatment (the addition of concurrent chemotherapy) were investigated as potential prognostic factors.

RESULTS:

The median OS, median local PFS, and median distant MFS times were 19, 21, and 23 months, respectively. Five‐year OS, local PFS, and distant MFS rates were 19%, 29%, and 35%, respectively. Univariate and multivariate analysis showed that only age did not influence OS and local PFS, whereas female sex, lower KPS, less pronounced weight loss, lower stage, squamous histology, shorter interfraction interval, and treatment independently predicted better OS and local PFS. Only age and treatment did not influence distant MFS, whereas histology was of borderline significance.

CONCLUSIONS:

This study identified independent prognosticators of treatment outcome. These results may have implications for future studies in this disease. Cancer 2011. © 2011 American Cancer Society.
Highly Athletic Terrestrial Mammals: Horses and Dogs
Authors: Poole David C. , Erickson Howard H.
Published: January 2011

Evolutionary forces drive beneficial adaptations in response to a complex array of environmental conditions. In contrast, over several millennia, humans have been so enamored by the running/athletic prowess of horses and dogs that they have sculpted their anatomy and physiology based solely upon running speed. Thus, through hundreds of generations, those structural and functional traits crucial for running fast have been optimized. Central among these traits is the capacity to uptake, transport and utilize oxygen at spectacular rates. Moreover, the coupling of the key systems—pulmonary‐cardiovascular‐muscular is so exquisitely tuned in horses and dogs that oxygen uptake response kinetics evidence little inertia as the animal transitions from rest to exercise. These fast oxygen uptake kinetics minimize Intramyocyte perturbations that can limit exercise tolerance. For the physiologist, study of horses and dogs allows investigation not only of a broader range of oxidative function than available in humans, but explores the very limits of mammalian biological adaptability. Specifically, the unparalleled equine cardiovascular and muscular systems can transport and utilize more oxygen than the lungs can supply. Two consequences of this situation, particularly in the horse, are profound exercise‐induced arterial hypoxemia and hypercapnia as well as structural failure of the delicate blood‐gas barrier causing pulmonary hemorrhage and, in the extreme, overt epistaxis. This chapter compares and contrasts horses and dogs with humans with respect to the structural and functional features that enable these extraordinary mammals to support their prodigious oxidative and therefore athletic capabilities. © 2011 American Physiological Society.Compr Physiol1:1‐37, 2011.
Fear, anxiety, and control in the zebrafish
Authors: Jesuthasan Suresh
Published: January 2011

Emotional responses are triggered by environmental signals and involve profound changes at multiple levels, from molecular to behavior. Much has been learnt about two emotions, fear and anxiety, by studying mammalian models. In particular, neural circuits and the corresponding molecular mechanisms essential for the learning and retention of fear, as well as the activation of anxiety, are well known. In contrast, little is known about how these emotions are terminated. The zebrafish is a newcomer to the world of emotion research. A number of assays for fear and anxiety now exist, but the underlying neural circuitry is largely undefined. Recent experiments, however, appear to provide a hint as to how anxiety is downregulated. In particular, they point to an essential role for a circuit involving the posterior septum, medial habenula, and interpeduncular nucleus. This evolutionarily conserved circuit may fulfill a similar function in mammals. © 2011 Wiley Periodicals, Inc. Develop Neurobiol 72: 395–403, 2012
The role of sensory organs and the forebrain for the development of the craniofacial shape as revealed by Foxg1‐cre‐mediated microRNA loss
Authors: Kersigo Jennifer , D'Angelo Alex , Gray Brian D. , Soukup Garrett A. , Fritzsch Bernd
Published: January 2011

Cranial development is critically influenced by the relative growth of distinct elements. Previous studies have shown that the transcription factor Foxg1 is essential the for development of the telencephalon, olfactory epithelium, parts of the eye and the ear. Here we investigate the effects of a Foxg1‐cre‐mediated conditional deletion of Dicer1 and microRNA (miRNA) depletion on mouse embryos. We report the rapid and complete loss of the telencephalon and cerebellum as well as the severe reduction in the ears and loss of the anterior half of the eyes. These losses result in unexpectedly limited malformations of anterodorsal aspects of the skull. We investigated the progressive disappearance of these initially developing structures and found a specific miRNA of nervous tissue, miR‐124, to disappear before reduction in growth of the specific neurosensory areas. Correlated with the absence of miR‐124, these areas showed numerous apoptotic cells that stained positive for anticleaved caspase 3 and the phosphatidylserine stain PSVue® before the near or complete loss of those brain and sensory areas (forebrain, cerebellum, anterior retina, and ear). We conclude that Foxg1‐cre‐mediated conditional deletion of Dicer1 leads to the absence of functional miRNA followed by complete or nearly complete loss of neurons. Embryonic neurosensory development therefore depends critically on miRNA. Our data further suggest that loss of a given neuronal compartment can be triggered using early deletion of Dicer1 and thus provides a novel means to genetically remove specific neurosensory areas to investigate loss of their function on morphology (this study) or signal processing within the brain. genesis 49:326–341, 2011. © 2011 Wiley‐Liss, Inc.
Nickel–Iron–Selenium Hydrogenases – An Overview
Authors: Baltazar Carla S. A. , Marques Marta C. , Soares Cláudio M. , DeLacey Antonio M. , Pereira Inês A. C. , Matias Pedro M.
Published: January 2011

[NiFeSe] hydrogenases are a subgroup of the large family of [NiFe] hydrogenases in which a selenocysteine ligand coordinates the Ni atom at the active site. As observed for other selenoproteins, the [NiFeSe] hydrogenases display much higher catalytic activities than their Cys‐containing homologues. Here, we review the biochemical, catalytic, spectroscopic and structural properties of known [NiFeSe] hydrogenases, namely from the Hys (group 1 [NiFeSe] hydrogenase), Fru (F420‐reducing [NiFeSe] hydrogenases) and Vhu families (F420‐non‐reducing [NiFeSe] hydrogenases). A survey of new [NiFeSe] hydrogenases present in the databases showed that all enzymes belong to either group 1 periplasmic uptake hydrogenases (Hys) or to group 3 cytoplasmic hydrogenases (Fru and Vhu) and are present in either sulfate‐reducing or methanogenic microorganisms. In both kinds of organisms, the [NiFeSe] hydrogenases are preferred over their Cys‐containing homologues if selenium is available. Since no structural information is available for the Vhu and Fru enzymes, we have modelled the large subunit of these enzymes and analyzed the area surrounding the active site. Three[NiFeSe] hydrogenases of the Hys and Vhu types were identified in which the selenocysteine residue is found in a different location in the sequence, which could result in a different coordination to the Ni atom. The high activity and fast reactivation, together with a degree of oxygen tolerance for the H2‐production activity, make the Hys hydrogenases attractive catalysts for technological applications.
An initial study on the formation of 3‐MCPD esters during oil refining
Authors: Hrncirik Karel , van Duijn Gerrit
Published: January 2011

Oil refining is essential for ensuring quality and safety of oils and fats. However, during the deodorization step of the refining process, the oil is exposed to high temperatures and changes in the lipid matrix may occur leading to the formation of 3‐chloropropane‐1,2‐diol (3‐MCPD) esters and possibly other processing by‐products. This study was initiated to address the limited understanding on the formation of 3‐MCPD ester in oil refining. The impact of refining conditions, both at pilot‐plant and industrial scale, were investigated by subjecting palm and rapeseed oils to different refining treatments. The experiments showed that 3‐MCPD esters and glycidyl esters were formed during the deodorization of palm oil, but not rapeseed oil. The level of 3‐MCPD esters in the refined palm oils (3.5–4.9 mg/kg) was independent of the deodorization conditions. No correlation was found between the level of 3‐MCPD esters formed and the content of the potential precursors, partial acylglycerols and chlorides. In contrast, the formation of glycidyl esters was affected by the deodorization conditions (both temperature and residence time). Higher levels of glycidyl esters (up to 3.8 mg/kg) were found in palm oil deodorized at temperatures above 230°C.
The volatile and semi‐volatile constituents of agarwood, the infected heartwood of Aquilaria species: a review
Authors: Naef Regula
Published: January 2011

A compilation of the volatile and semi‐volatile constituents of agarwood, the infected fragrant heartwood of some Aquilaria species, mainly A. malaccensis, A. sinensis and A. crassna, is presented. This high‐priced wood has a long tradition in religious ceremonies as incense and its essential oil is well appreciated in fine perfumery. More than 150 compounds have been identified so far, mostly sesquiterpenoids, chromones and volatile aromatic compounds. The scarce knowledge of their organoleptic properties is summarized. Studies on the chemistry of agarwood smoke are discussed. Emphasis is given to structural and analytical aspects. Copyright © 2011 John Wiley & Sons, Ltd.
Alternative lengthening of telomeres—An enhanced chromosomal instability in aggressive non‐MYCN amplified and telomere elongated neuroblastomas
Authors: Lundberg Gisela , Sehic Daniel , Länsberg John‐Kalle , Øra Ingrid , Frigyesi Attila , Castel Victoria , Navarro Samuel , Piqueras Marta , Martinsson Tommy , Noguera Rosa , Gisselsson David
Published: January 2011

Telomere length alterations are known to cause genomic instability and influence clinical course in several tumor types, but have been little investigated in neuroblastoma (NB), one of the most common childhood tumors. In the present study, telomere‐dependent chromosomal instability and telomere length were determined in six NB cell lines and fifty tumor biopsies. The alternative lengthening of telomeres (ALT) pathway was assayed by scoring ALT‐associated promyelocytic leukemia (PML) bodies (APBs). We found a reduced probability of overall survival for tumors with increased telomere length compared to cases with reduced or unchanged telomere length. In non‐MYCN amplified tumors, a reduced or unchanged telomere length was associated with 100% overall survival. Tumor cells with increased telomere length had an elevated frequency of APBs, consistent with activation of the ALT pathway. The vast majority of tumor biopsies and cell lines exhibited an elevated rate of anaphase bridges, suggesting telomere‐dependent chromosomal instability. This was more pronounced in tumors with increased telomere length. In cell lines, there was a close correlation between lack of telomere‐protective TTAGGG‐repeats, anaphase bridging, and remodeling of oncogene sequences. Thus, telomere‐dependent chromosomal instability is highly prevalent in NB, and may contribute to the complexity of genomic alterations as well as therapy resistance in the absence of MYCN amplification and in this tumor type. © 2011 Wiley‐Liss, Inc.
Comparative analysis of various tumor-associated antigen-specific t-cell responses in patients with hepatocellular carcinoma
Authors: Mizukoshi Eishiro , Nakamoto Yasunari , Arai Kuniaki , Yamashita Tatsuya , Sakai Akito , Sakai Yoshio , Kagaya Takashi , Yamashita Taro , Honda Masao , Kaneko Shuichi
Published: January 2011

Many tumor-associated antigens (TAAs) recognized by cytotoxic T cells (CTLs) have been identified during the last two decades and some of them have been used in clinical trials. However, there are very few in the field of immunotherapy for hepatocellular carcinoma (HCC) because there have not been comparative data regarding CTL responses to various TAAs. In the present study, using 27 peptides derived from 14 different TAAs, we performed comparative analysis of various TAA-specific T-cell responses in 31 HCC patients to select useful antigens for immunotherapy and examined the factors that affect the immune responses to determine a strategy for more effective therapy. Twenty-four of 31 (77.4%) HCC patients showed positive responses to at least one TAA-derived peptide in enzyme-linked immunospot assay. The TAAs consisting of cyclophilin B, squamous cell carcinoma antigen recognized by T cells (SART) 2, SART3, p53, multidrug resistance-associated protein (MRP) 3, alpha-fetoprotein (AFP) and human telomerase reverse transcriptase (hTERT) were frequently recognized by T cells and these TAA-derived peptides were capable of generating peptide-specific CTLs in HCC patients, which suggested that these TAAs are immunogenic. HCC treatments enhanced TAA-specific immune responses with an increased number of memory T cells and induced

de novo

T-cell responses to lymphocyte-specific protein tyrosine kinase, human epidermal growth factor receptor type 2, p53, and hTERT. Blocking cytotoxic T-lymphocyte antigen-4 (CTLA-4) resulted in unmasking of TAA-specific immune responses by changing cytokine and chemokine profiles of peripheral blood mononuclear cells stimulated by TAA-derived peptides.

Conclusion:

Cyclophilin B, SART2, SART3, p53, MRP3, AFP, and hTERT were immunogenic targets for HCC immunotherapy. TAA-specific immunotherapy combined with HCC treatments and anti-CTLA-4 antibody has the possibility to produce stronger tumor-specific immune responses. (HEPATOLOGY 2011;)
In vitro steroid resistance correlates with outcome in severe alcoholic hepatitis
Authors: di Mambro A. J. , Parker R. , McCune A. , Gordon F. , Dayan C. M. , Collins P.
Published: January 2011

Steroids improve the outcome in alcoholic hepatitis (AH), but up to 40% of patients fail to respond adequately. Interleukin-2 (IL-2) exacerbates steroid resistance

in vitro

. We performed a prospective study to determine if intrinsic steroid sensitivity correlates with response to steroids in individuals with severe AH and if IL-2 receptor blockade can reverse this. Peripheral blood mononuclear cells (PBMCs) were isolated from 20 patients with AH and a Maddrey's score >32. Patients were treated with oral prednisolone plus full supportive measures. Clinical resistance to oral steroid treatment was defined as a drop in serum bilirubin of <25% within 7 days or death within 6 months.

In vitro

steroid resistance was measured in PBMC using the dexamethasone suppression of lymphocyte proliferation assay and repeated after the addition of the anti-IL-2 receptor (anti-CD25) monoclonal antibody, basiliximab. Suppression of lymphocyte proliferation <60% was considered to indicate steroid resistance. In all, 82% (9/11) of

in vitro

steroid-resistant patients were dead at 6 months as compared to 21% (2/9) of steroid-sensitive patients (

P

= 0.03). Similarly, 91% (10/11) of

in vitro

steroid-resistant patients failed to show a significant fall in bilirubin at day 7 as compared to 44% (4/9) of steroid-sensitive patients (

P

< 0.05). Basiliximab improved the maximal proliferation count in 91% (10/11) of

in vitro

steroid-resistant patients (

P

= 0.003).

Conclusion:

Clinical outcome of steroid therapy in this patient cohort correlated with

in vitro

steroid resistance. IL-2 blockade improved

in vitro

steroid sensitivity. This suggests that intrinsic lack of steroid sensitivity may contribute to poor clinical response to steroids in severe AH. IL-2 receptor blockade represents a possible mechanism to overcome this. (HEPATOLOGY 2011;)
Occludin is regulated by epidermal growth factor receptor activation in brain endothelial cells and brains of mice with acute liver failure
Authors: Chen Feng , Hori Tomohide , Ohashi Norifumi , Baine Ann-Marie , Eckman Christopher B. , Nguyen Justin H.
Published: January 2011

Mechanisms of brain edema in acute liver failure (ALF) are not completely understood. We recently demonstrated that matrix metalloproteinase 9 (MMP-9) induces significant alterations to occludin in brain endothelial cells

in vitro

and in brains of mice with experimental ALF (Hepatology 2009;50:1914). In this study we show that MMP-9-induced transactivation of epidermal growth factor receptor (EGFR) and p38 MAPK/NFκB (mitogen-activated protein kinase/nuclear factor-kappa B) signals participate in regulating brain endothelial occludin level. Mouse brain endothelial bEnd3 cells were exposed to MMP-9 or p38 MAPK up-regulation in the presence and absence of EGFR inhibitor, p38 MAPK inhibitor, NFκB inhibitor, and/or appropriate small interfering RNA. Reverse-transcription polymerase chain reaction (RT-PCR) and western blotting were used for messenger RNA and protein expression analyses. Immunohistochemical staining and confocal microscopy were used to demonstrate cellular EGFR activation. Intraperitoneal azoxymethane was use to induce ALF in mice. Brains of comatose ALF mice were processed for histological and biochemical analyses. When bEnd3 cells were exposed to MMP-9, EGFR was significantly transactivated, followed by p38 MAPK activation, I-kappa B alpha (IκBα) degradation, NFκB activation, and suppression of occludin synthesis and expression. Similar EGFR activation and p38 MAPK/NFκB activation were found in the brains of ALF mice, and these changes were attenuated with GM6001 treatment.

Conclusion:

EGFR activation with p38 MAPK/NFκB signaling contributes to the regulation of tight junction integrity in ALF. EGFR activation may thus play an important role in vasogenic brain edema in ALF. (HEPATOLOGY 2011;)
Proteins ZNF198 and SUZ12 are down-regulated in hepatitis B virus (HBV) X protein-mediated hepatocyte transformation and in HBV replication
Authors: Wang Wen-Horng , Studach Leo L. , Andrisani Ourania M.
Published: January 2011

Chronic hepatitis B virus (HBV) infection is a major etiologic factor in hepatocellular carcinoma (HCC) pathogenesis, involving effects of chronic liver inflammation and of the weakly oncogenic HBV X protein (pX). pX-mediated hepatocyte transformation requires Polo-like kinase1 (Plk1) activity, but the mechanism is not fully understood. We identified by a genome-wide short hairpin RNA (shRNA) library screen the genes zinc finger, MYM-type 2 (ZNF198) and suppressor of zeste 12 homolog (

Drosophila)

(SUZ12) whose protein depletion rescues pX-expressing cells from DNA damage-induced apoptosis. ZNF198 and SUZ12 are components of chromatin remodeling complexes and associate with promyelocytic leukemia (PML) nuclear bodies. Knockdown of ZNF198 and SUZ12 by small interfering RNA (siRNA) reduced p53 stability and DNA repair, rescued pX-expressing hepatocytes from DNA damage-induced apoptosis, and increased pX-induced polyploidy and oncogenic transformation, suggesting ZNF198 and SUZ12 have a role in pX-mediated transformation. Interestingly, during pX-mediated transformation the protein but not messenger RNA (mRNA) levels of ZNF198 and SUZ12 progressively decreased, whereas Plk1 levels increased. Inhibition of Plk1 activity restored protein levels of ZNF198 and SUZ12. In addition, transfected Polo-box-domain (PBD) of Plk1 coimmunoprecipitated with ZNF198 and SUZ12, suggesting that these proteins are Plk1 substrates. Elevated Plk1 and reduced protein levels of ZNF198 and SUZ12 were also observed in human liver cancer cell lines derived from HBV-related tumors and in the presence of HBV replication. Importantly, knockdown by siRNA of ZNF198 and SUZ12 enhanced HBV replication.

Conclusion:

Reduced protein levels of ZNF198 and SUZ12 and elevated Plk1 occur during pX-mediated hepatocyte transformation in human liver cancer cell lines, as well as during HBV replication, underscoring the significance of these genes both in HBV-mediated HCC pathogenesis and HBV replication. We propose Plk1 activity down-regulates ZNF198 and SUZ12, thereby enhancing both HBV replication and pX-mediated oncogenic transformation. (HEPATOLOGY 2011)
Transcription factor Fra-1 induces cholangitis and liver fibrosis
Authors: Kireva Trayana , Erhardt Annette , Tiegs Gisa , Tilg Herbert , Denk Helmut , Haybaeck Johannes , Aigner Elmar , Moschen Alexander , Distler Jörg H. , Schett Georg , Zwerina Jochen
Published: January 2011

Chronic diseases of the biliary system are common and may cause fibrosis and eventually progression to liver cirrhosis. The aim was to define a new mouse model of a cholangiopathy leading to liver fibrosis in

fra-1tg

mice. Liver pathology of

fra-1tg

mice was analyzed in detail by histology and flow cytometry. Transcript levels of fibrosis-related genes and matrix metalloproteinase (MMP) activities were quantified and immunohistochemical analysis additionally applied. The role of the immune system in this model was analyzed by crossing

fra-1tg

mice with

rag2

-/- mice. Furthermore, expression of Fra-1 in corresponding human liver diseases was investigated on transcription level and histologically.

Fra-1tg

mice spontaneously develop biliary fibrosis preceded by ductular proliferation and infiltration of inflammatory cells.

Fra-1

protein is present in cholangiocytes and inflammatory cells within the liver. These findings were replicated in human biopsies of patients with advanced liver fibrosis. The inflammatory infiltrate showed a strong increase in activated T cells and decreased natural killer (NK), natural killer T cells (NKT), and B cells in

fra-1tg

mice as compared to wildtype mice. Moreover,

fra-1tg

mice develop biliary fibrosis with a time-dependent increase in hepatic collagen content and increase in relative messenger RNA (mRNA) expression of profibrotic genes. Attenuation but not complete prevention of collagen accumulation in liver was observed in the

fra-1tg

×

rag2-/-

mice. However, transplantation of

fra-1tg

bone marrow cells into wildtype mice could not induce disease.

Conclusion:

Fra-1tg

mice spontaneously develop a progressive biliary disease. These mice are an attractive model for the investigation of cholangiopathies and their interaction with the immune system. (HEPATOLOGY 2011;)
Virological response is associated with decline in hemoglobin concentration during pegylated interferon and ribavirin therapy in hepatitis C virus genotype 1
Authors: Sievert William , Dore Gregory J. , McCaughan Geoffrey W. , Yoshihara Motoko , Crawford Darrell H. , Cheng Wendy , Weltman Martin , Rawlinson William , Rizkalla Bishoy , DePamphilis Jean K. , Roberts Stuart K.
Published: January 2011

Anemia may increase the likelihood of achieving a sustained virological response (SVR) during pegylated interferon and ribavirin treatment of hepatitis C virus (HCV) infection. To determine whether hemoglobin decline is associated with SVR, we retrospectively evaluated the CHARIOT study of 871 treatment-naïve HCV genotype 1 patients. Anemia (serum hemoglobin <100 g/L) occurred in 137 (16%) patients, of whom only 14 (10%) received erythropoietin. Hemoglobin decline >30g/L from baseline occurred in 76% of patients overall, including 526 patients who did not become anemic. Virological responses were higher in anemic patients compared with those who did not develop anemia (end of treatment, 80% versus 65%,

P

= 0.003; SVR, 61% versus 50%,

P

= 0.02); these differences remained significant when patients receiving erythropoietin were excluded from analysis. SVR was also higher in patients with hemoglobin decline >30 g/L compared with patients without a similar decline. In multiple logistic regression analyses with treatment group and baseline characteristics, the odds ratio for SVR was 1.97 (95% confidence interval, 1.08-3.62) for anemia and 2.17 (95% confidence interval, 1.31-3.62) for hemoglobin decline >30 g/L. Patients who first developed a hemoglobin decline >30 g/L during weeks 5-12 and 13-48 were more likely to achieve SVR than those who first developed such changes in weeks 0-4 or who never experienced them.

Conclusion:

Patients with HCV genotype 1 infection who develop anemia or experience a hemoglobin decline >30 g/L during weeks 5-48 of therapy achieve higher virological responses to pegylated interferon and ribavirin therapy that are unrelated to erythropoietin use. (HEPATOLOGY 2011;)
Acting within the boundaries of work systems development
Authors: Béguin Pascal
Published: January 2011

This article proposes a model for analyzing and acting on the relationship between design and ergonomics. In applying their knowledge and methods in design processes, ergonomists encounter constraints that frame, orient, and limit their professional practices. It is argued that these constraints stem from the organizational boundaries of the design process. One of the challenges of ergonomics is to act on these boundaries to define constraints that contribute to or facilitate the promotion of workers' health and productive efficiency. This analytical model is applied to work systems development. Three types of organizational boundary (namely, “goal‐oriented boundaries,” “time boundaries,” and “collective boundaries”) and their constraints are identified, and proposals to act on those boundaries are discussed. © 2011 Wiley Periodicals, Inc.
Medial and lateral perforant path evoked potentials are selectively modulated by pairing with glutamatergic activation of locus coeruleus in the dentate gyrus of the anesthetized rat
Authors: Edison Hilary T. , Harley Carolyn W.
Published: January 2011

Norepinephrine (NE) in vitro produces long‐lasting potentiation of medial perforant path input and depression of lateral perforant path input to dentate gyrus in the rat. Similar, but highly transient, effects have been reported in vivo using paragigantocellular stimulation to release NE. The present study uses alternate stimulation of the medial perforant path and lateral olfactory tract (eliciting a lateral perforant path‐evoked potential) to examine the effects of glutamatergic activation of locus coeruleus (LC) on the two pathways for up to 3 h post‐LC activation. In the first experiment, the expected potentiation of the medial perforant path population spike in dentate gyrus was observed, but without accompanying depression of the lateral perforant path‐mediated evoked potential (lateral olfactory tract stimulation, 60 s ISI). In a second experiment, with more frequent pairing of input with NE release (10 s ISI), significant potentiation of lateral perforant path‐mediated input to dentate gyrus occurred, but potentiation of medial perforant path input was not seen. A third experiment with a 30 s ISI again produced potentiation of lateral perforant path‐mediated input without potentiation of the medial perforant path population spike. The size of effects with the 30 s ISI was intermediate between that seen with 10 s and 60 s ISI. Potentiation of lateral perforant path over medial perforant path input has previously been reported with acute nicotinic activation of the LC. This outcome also resembles heterosynaptic modulation previously reported with tetanic potentiation. The data argue for a competitive relationship between medial and lateral perforant path inputs to dentate gyrus and suggest pairing with increased NE produces a bias favoring one or the other pathway depending on parameters such as strength and frequency. NE potentiating effects on lateral perforant path input here may also have occurred in entorhinal cortex (EC) given the system‐wide NE release with LC activation. © 2011 Wiley Periodicals, Inc.
Antitumour activity of oral E7080, a novel inhibitor of multiple tyrosine kinases, in human sarcoma xenografts
Authors: Bruheim Skjalg , Kristian Alexandr , Uenaka Toshimitsu , Suo Zhenhe , Tsuruoka Akihiko , Nesland Jahn M. , Fodstad Øystein
Published: January 2011

E7080 is an inhibitor of multiple tyrosine kinases, several of which have pro‐angiogenic properties, including receptors for VEGF, FGF, SCF and PDGF. We undertook our study to evaluate the preclinical activity of E7080 in human sarcomas. The antitumour activity of orally administered E7080 was tested in ten human tumour xenografts representing different sarcoma histotypes. Concomitant changes in microvessel density were assayed by immunohistochemistry to CD31. Immunohistochemistry was also used to assess the expression of kinases that E7080 is known to inhibit. The MTS assay was applied to determine effects on tumour cell viability in vitro. At the Q1D5 × 2 schedule, E7080 (30 mg/kg) was active (T/C<40%) in 7/10 xenografts. The effects were accompanied by marked decrease in microvessel densities. Given at the Q1D5 × 4 schedule, E7080 (30, 10, 3 mg/kg) showed antitumour activity in a dose dependent manner in two different xenografts. E7080 growth inhibition did not correlate with the expression of VEGFR1‐3, PDGFRA, PDGFRB, FGFR1 or KIT on tumour cells but was significantly correlated with expression of VEGFR2 on tumour microvessels. In vitro E7080 did not show potent effects on tumour cell viability in four different sarcoma cell lines, with IC50 values ≥10 μM. In conclusion, E7080 showed broad in vivo antitumour activity in sarcoma, mainly attributable to angiogenesis inhibition. E7080 was also active in xenografts resistant to one or more clinically relevant reference drugs given at MTD (doxorubicin, cisplatin or ifosfamide). The present results encourage further investigation of a potential role of E7080 in sarcoma therapy in the clinic.
MiR‐9 downregulates CDX2 expression in gastric cancer cells
Authors: Rotkrua Pichayanoot , Akiyama Yoshimitsu , Hashimoto Yutaka , Otsubo Takeshi , Yuasa Yasuhito
Published: January 2011

Ectopic expression of CDX2, a caudal‐related homeobox protein, is known to be associated with the development of intestinal metaplasia in the stomach and gastric carcinogenesis. Previously, we reported that DNA methylation was partly responsible for CDX2 silencing in gastric cancer (GC). However, the mechanism underlying the aberrant expression of CDX2 during malignant transformation remained unclear. MicroRNAs (miRNAs) are small non‐coding RNAs that function as post‐transcriptional regulators. To elucidate the role of miRNAs in CDX2 downregulation in GC cells, putative miRNAs, such as miR‐9, were computationally predicted. After exogenous pre‐miR‐9 precursor transfection, the luciferase activity of a reporter vector containing a part of the 3′‐UTR of CDX2 was downregulated in HEK‐293T cells. The inverse correlation between the miR‐9 and CDX2 protein levels was demonstrated in GC cell lines. By means of miR‐9 overexpression and knockdown techniques, the expression levels of the CDX2 protein and downstream target genes (p21, MUC2 and TFF3) were responsively altered in MKN45 and NUGC‐3 cells. Transfection of an anti‐miR‐9 molecule significantly inhibited cell growth by promoting G1 cell cycle arrest in MKN45 cells similarly to the effect of CDX2 overexpression. Moreover, examination of the miR‐9 levels in primary GC tissues revealed that the amounts of miR‐9 in the CDX2‐negative group were significantly higher than those in the CDX2‐positive group (p = 0.004). Therefore, miR‐9 might repress CDX2 expression via the binding site in the 3′‐UTR, resulting in the promotion of cell proliferation in GCs.
MED29, a component of the mediator complex, possesses both oncogenic and tumor suppressive characteristics in pancreatic cancer
Authors: Kuuselo Riina , Savinainen Kimmo , Sandström Saana , Autio Reija , Kallioniemi Anne
Published: January 2011

Mediator complex subunit 29 (MED29) is part of a large multiprotein coactivator complex that mediates regulatory signals from gene‐specific activators to general transcription machinery in RNA polymerase II mediated transcription. We previously found thatMED29is amplified and overexpressed in pancreatic cancer and thatMED29silencing leads to decreased cell survival in PANC‐1 pancreatic cancer cells with highMED29expression. Here we further demonstrate decreased migration, invasion and colony formation in PANC‐1 cells afterMED29silencing. Unexpectedly, lentiviral‐based overexpression of MED29 led to decreased proliferation of NIH/3T3 cells as well as MIAPaCa‐2 pancreatic cancer cells with low endogenous expression. More importantly, subcutaneous inoculation of the MED29‐transduced pancreatic cancer cells into immuno‐compromised mice resulted in dramatic tumor suppression. The mock‐control mice developed large tumors, whereas the animals with MED29‐xenografts showed both decreased tumor incidence and a major reduction in tumor size. Gene expression analysis in the MED29‐transduced pancreatic cancer cells revealed differential expression of genes involved in control of cell cycle and cell division. The observed gene expression changes are expected to modulate the cell cycle in a way that leads to reduced cell growth, explaining thein vivotumor suppressive phenotype. Taken together, these data implicate MED29 as an important regulator of key cellular functions in pancreatic cancer with both oncogenic and tumor suppressive characteristics. Such a dualistic role appears to be more common than previously thought and is likely to depend on the genetic background of the cancer cells and their surrounding environment.
Epstein‐Barr virus‐associated gastric carcinoma among patients with pernicious anemia
Authors: Boysen Trine , Friborg Jeppe , Stribolt Katrine , Hamilton‐Dutoit Stephen , Goertz Sanne , Wohlfahrt Jan , Melbye Mads
Published: January 2011

Approximately 9% of gastric carcinomas worldwide are associated with Epstein‐Barr virus (EBV), making it the most frequent EBV‐associated malignancy. Pernicious anemia, a condition with chronic gastritis and achlorhydria, is strongly associated with gastric carcinoma. Both chronic inflammation and the lack of stomach acid may influence the likelihood of EBV infection of the neoplastic gastric epithelium, but the prevalence of EBV‐associated gastric carcinoma among patients with pernicious anemia is unknown. Therefore, we conducted a Danish nationwide case–control study comparing gastric carcinoma patients with pernicious anemia (PA‐GC) with those without pernicious anemia (nonPA‐GC), frequency matched 1:2. Tumor tissues were reclassified by expert histopathologists blinded to pernicious anemia and EBV status. In total, 186 samples (55 PA‐GC and 131 nonPA‐GC) were identified. EBV‐associated gastric carcinoma (EBV‐GC) was more common among PA‐GC compared with nonPA‐GC, adjusted odds ratio (OR) = 2.53 (CI: 0.88; 7.14), p = 0.08, with further adjustment for lymphocytic infiltrate OR = 2.94 (0.99–8.67), p = 0.05. Gastric carcinomas with signet‐ring cell morphology were significantly less common in patients with PA‐GC compared with nonPA‐GC (OR = 0.05, CI 0.01; 0.24). Although these conditions are rare, we found suggestive evidence that EBV‐associated gastric carcinomas are more common among gastric carcinoma patients with pernicious anemia compared with those without.
Maternal smoking during pregnancy and childhood lymphoma: A meta‐analysis
Authors: Antonopoulos C.N. , Sergentanis T.N. , Papadopoulou C. , Andrie E. , Dessypris N. , Panagopoulou P. , Polychronopoulou S. , Pourtsidis A. , Athanasiadou‐Piperopoulou F. , Kalmanti M. , Sidi V. , Moschovi M. , Petridou E.T.
Published: January 2011

Results from epidemiological studies exploring the association between childhood lymphoma and maternal smoking during pregnancy have been contradictory. This meta‐analysis included all published cohort (n = 2) and case–control (n = 10) articles; among the latter, the data of the Greek Nationwide Registry for Childhood Hematological Malignancies study were updated to include all recently available cases (‐2008). Odds ratios (ORs), relative risks and hazard ratios were appropriately pooled in three separate analyses concerning non‐Hodgkin lymphoma (NHL, n = 1,072 cases), Hodgkin lymphoma (HL, n = 538 cases) and any lymphoma (n = 1,591 cases), according to data availability in the included studies. An additional metaregression analysis was conducted to explore dose–response relationships. A statistically significant association between maternal smoking (any vs. no) during pregnancy and risk for childhood NHL was observed (OR = 1.22, 95% confidence interval, CI: 1.03–1.45, fixed effects model), whereas the risk for childhood HL was not statistically significant (OR = 0.90, 95% CI: 0.66–1.21, fixed effects model). The analysis on any lymphoma did not reach statistical significance (OR = 1.10, 95% CI = 0.96–1.27, fixed effects model), possibly because of the case‐mix of NHL to HL. No dose–response association was revealed in the metaregression analysis. In conclusion, this meta‐analysis points to a modest increase in the risk for childhood NHL, but not HL, among children born by mothers smoking during pregnancy. Further investigation of dose–response phenomena in the NHL association, however, warrants accumulation of additional data.
Regulation of p53 and cell proliferation by resveratrol and its derivatives in breast cancer cells: An in silico and biochemical approach targeting integrin αvβ3
Authors: Hsieh Tze‐Chen , Wong Christina , John Bennett Dylan , Wu Joseph M.
Published: January 2011

Resveratrol is a grape polyphenol with cancer preventative activities in tissue culture and animal model studies. Potential of resveratrol as a broad‐based chemopreventive agent have been questioned by its limited bioavailability. The bioefficacy of resveratrol was compared with its derivatives, triacetyl‐resveratrol (trans‐3,5,4′‐triacetylstilbene) and trimethoxy‐resveratrol (trans‐3,5,4′‐trimethoxystilbene) in both estrogen receptor‐α (ERα)‐positive MCF‐7 and ERα‐negative MDA‐MB‐231 breast cancer cells. Binding to integrin αvβ3 and control of cell proliferation and p53 were chosen as targets for comparative analysis using an in silico and biochemical approach. Resveratrol and triacetyl‐resveratrol interacted avidly and specifically with integrin αvβ3 through binding at the site targeted by the high affinity cyclic Arg‐Gly‐Asp (RGD) peptide. In contrast, binding of trimethoxy‐resveratrol to this site was substantially less robust. Moreover, the different stilbenes also elicited diverse cellular and signaling responses in MCF‐7 and MDA‐MB‐231 cells, as evidenced by analysis of colony formation, cell proliferation, cell cycle phase transition, the extent of phosphorylation of p53 at Ser15 and p53‐inducible proteins, p21 and p53R2, respectively. Further, stilbene‐elicited signaling cascade leading to p53 activation was examined in MCF‐7 cells and results showed that resveratrol and triacetyl‐resveratrol induced both ERK and p38 phosphorylation, whereas only marginal changes in state of phosphorylation in these two kinases were observed in trimethoxy‐resveratrol‐treated cells. Taken together, these results support that resveratrol and triacetyl‐resveratrol regulate proliferation and gene expression in breast cancer cells by utilizing largely similar signaling molecules and pathways and cellular events, which appear quite distinct from those targeted by trimethoxy‐resveratrol.
Characterization of bionanocomposite scaffolds comprised of amine‐functionalized single‐walled carbon nanotubes crosslinked to an acellular porcine tendon
Authors: Deeken Corey R. , Cozad Matthew J. , Bachman Sharon L. , Ramshaw Bruce J. , Grant Sheila A.
Published: January 2011

Carbon nanotubes (CNT) possess many unique electrical and mechanical properties that make them useful for a variety of industrial and biomedical applications. They are especially attractive materials for biomedical applications since their dimensions are similar to components of the extracellular matrix. In this study, amine‐functionalized single‐walled carbon nanotubes were crosslinked to an acellular porcine diaphragm tendon. The resulting bionanocomposite scaffolds were subjected to a number of materials characterization techniques including a collagenase assay, uniaxial tensile testing, modulated differential scanning calorimetry, and attenuated total reflectance Fourier transform infrared (ATR‐FTIR) spectroscopy to determine whether the properties of the original extracellular matrix were altered by the treatment processes. A variety of SWCNT concentrations were investigated. While none of the conditions investigated resulted in bionanocomposites with significantly improved physicochemical properties, no detrimental effects were observed due to any of the processing steps. Future studies should be performed to determine if carbon nanotubes can influence cellular adhesion and function in order to promote rapid integration and remodeling. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A:, 2011.
Incidental sonographic detection of mucosa‐associated lymphoid tissue lymphoma of the urinary bladder found in a very young woman: Report of a case
Authors: Szopiński Tomasz R. , Sudoł‐Szopińska Iwona , Dzik Tomasz , Borówka Andrzej , Dembowska‐Bagińska Bożenna , Perek Danuta
Published: January 2011

We report a rare case of a mucosa‐associated lymphoid tissue (MALT)‐type lymphoma of the bladder, incidentally found on sonography in a 17‐year‐old girl during the workup of arterial hypertension. The diagnosis was established by a transurethral biopsy. Treatment consisted of transurethral resection of the bladder tumor and subsequent chemotherapy. To the best of our knowledge, this is the youngest patient with asymptomatic MALT‐type lymphoma of the urinary bladder. © 2011 Wiley Periodicals, Inc. J Clin Ultrasound, 2011
Engaging hospitalists in antimicrobial stewardship: The CDC perspective
Authors: Srinivasan Arjun
Published: January 2011

There has never been a more important time to promote efforts to improve the use of antibiotics in hospitals. The growing challenges of C. difficile infections and antimicrobial resistance can both be addressed, at least in part, through so called “antimicrobial stewardship” efforts. Data suggest that when the right antibiotics are prescribed at the right dose for the right durations patient outcomes are improved and healthcare dollars are saved. That improving antibiotic use is a win‐win‐win is not in question; what remains to be determined is how best to ensure that these efforts are implemented in all hospitals. I believe that hospitalists must play an important role in advancing antimicrobial stewardship. Journal of Hospital Medicine 2011;6:S31‐S33.