bluuebunny/crossref_metadata_2025_split huggingface dataset:
Leishmania-Infected Macrophages Are Targets of NK Cell-Derived Cytokines but Not of NK Cell Cytotoxicity
Authors: Prajeeth Chittappen K. , Haeberlein Simone , Sebald Heidi , Schleicher Ulrike , Bogdan Christian 
Published: April 2011

ABSTRACTNatural killer (NK) cells are important components of a protective immune response against intracellular pathogens such asLeishmaniaparasites, which reside within myeloid cells. Previousin vivostudies in murine cutaneous or visceral leishmaniasis showed that NK cells are activated by conventional dendritic cells in a Toll-like receptor 9-, interleukin-12 (IL-12)-, and IL-18-dependent manner during the early phase of infection and help to restrict the tissue parasite burden by unknown mechanisms. Here, we tested whether NK cells contribute to the control ofLeishmaniainfections by lysing or by activating infected host cells. Coculture experiments revealed that activated NK cells from poly(I:C)-treated mice readily killed tumor target cells, whereasLeishmania infantum- orL. major-infected macrophages or dendritic cells remained viable. Infection withLeishmaniadid not significantly alter the expression of NK cell-activating molecules (retinoic acid early transcript alpha [Rae-1α], mouse UL16-binding protein-like transcript 1 [MULT-1], CD48) or inhibitory molecules (major histocompatibility complex [MHC] class I, nonclassical MHC class 1b molecule Qa-1) on the surface of myeloid cells, which offers an explanation for their protection from NK cell cytotoxicity. Consistent with thesein vitrodata,in vivocytotoxicity assays revealed poor cytolytic activity of NK cells against adoptively transferred infected wild-type macrophages, whereas MHC class I-deficient macrophages were efficiently eliminated. NK cells activated by IL-12 and IL-18 stimulated macrophages to kill intracellularLeishmaniain a cell contact-independent but gamma interferon-, tumor necrosis factor-, and inducible nitric oxide synthase-dependent manner. We conclude thatLeishmaniaparasites, unlike viruses, do not render infected myeloid cells susceptible to the cytotoxicity of NK cells. Instead, soluble products of NK cells trigger the leishmanicidal activity of macrophages.
Role of Src Kinases in Mobilization of Glycosylphosphatidylinositol-Anchored Decay-Accelerating Factor by Dr Fimbria-Positive Adhering Bacteria
Authors: Queval Christophe J. , Nicolas Valérie , Beau Isabelle 
Published: April 2011

ABSTRACTAfa/Dr fimbriae constitute the major virulence factor of diffusely adheringEscherichia coli(Afa/Dr DAEC). After recognizing membrane-bound signaling receptors, they trigger cell responses. One of these receptors is the human decay-accelerating factor (hDAF). It has previously been reported that the binding of Afa/Dr fimbriae to hDAF quickly induces recruitment of hDAF around adhering bacteria. The aim of our study is to analyze the role of Src kinases in the Dr fimbria-induced recruitment of hDAF. Using biochemical methods and confocal microscopy followed by 3-dimensional (3D) analysis, we have shown that the activation and cell membrane targeting of Src kinases are necessary for the recruitment and organization of hDAF around adhering bacteria. We identified c-Src to be the specific kinase involved in this process. Using a set of Src-green fluorescent protein mutants, we showed that the catalytic activity and the Src homology 2 (SH2) and SH3 domains of the Src kinases are necessary for Dr fimbria-induced hDAF mobilization to occur. In addition, using mutated Dr fimbriae and a set of mutated hDAFs in which each of the complement control protein (CCP) domains had successively been deleted, we found that the aspartic acids at position 54 in the Dr fimbriae and in CCP domain 4 of hDAF played pivotal roles in the mobilization of the Src kinases and hDAF, respectively.
Toll-Like Receptors Participate in Macrophage Activation and Intracellular Control of Leishmania (Viannia) panamensis
Authors: Gallego Carolina , Golenbock Douglas , Gomez Maria Adelaida , Saravia Nancy Gore 
Published: April 2011

ABSTRACTToll-like receptors (TLRs) play a central role in macrophage activation and control of parasitic infections. Their contribution to the outcome ofLeishmaniainfection is just beginning to be deciphered. We examined the interaction ofLeishmania panamensiswith TLRs in the activation of host macrophages.L. panamensisinfection resulted in upregulation of TLR1, TLR2, TLR3, and TLR4 expression and induced tumor necrosis factor alpha (TNF-α) secretion by human primary macrophages at comparable levels and kinetics to those of specific TLR ligands. The TLR dependence of the host cell response was substantiated by the absence of TNF-α production in MyD88/TRIF−/−murine bone marrow-derived macrophages and mouse macrophage cell lines in response to promastigotes and amastigotes. Systematic screening of TLR-deficient macrophages revealed that TNF-α production was completely abrogated in TLR4−/−macrophages, consistent with the increased intracellular parasite survival at early time points of infection. TNF-α secretion was significantly reduced in macrophages lacking endosomal TLRs but was unaltered by a lack of TLR2 or MD-2. Together, these findings support the participation of TLR4 and endosomal TLRs in the activation of host macrophages byL. panamensisand in the early control of infection.
Nearshore articulate crinoid from the Albian of Alberta, Canada (Early Cretaceous, Echinodermata)
Authors: Ausich William I. , Buckley Robin A. , Plint A. Guy 
Published: April 2011

During the middle Albian, a southward incursion of the Boreal Ocean flooded northern Alberta and adjacent British Columbia, forming a large embayment known as the Hulcross Sea. Marine mudstones of the Hulcross Formation and Harmon Member of the Peace River Formation record transgression, whereas sandstones of the Cadotte Member of the Peace River Formation record shoreline regression to the north. Abundant hummocky and swaley lamination in the Cadotte sandstone attest to the influence of storms on a shallow shelf. The Cadotte sandstone undergoes a lateral facies change from mud-free shoreface sandstone in the south to heterolithic offshore facies in the north. An articulated crinoid was found within a hummocky sandstone bed about 15 km seaward (north) of the shoreface-shelf facies transition. The articulated state of the crinoid indicates that it was buried very rapidly, and never exhumed. The arms through 20 mm of the column are preserved, but because the details of the aboral cup are not well preserved, this specimen must be left in open nomenclature. The elliptical columnals with a concave latus in the distal portion of the preserved column ally this specimen to the Bourgueticrinida, although with details of the aboral cup lacking and other characters atypical for Mesozoic bourgueticrinids, the Canadian specimen is placed in Bathycrinidae indeterminate. The oldest previously recorded bathycrinids were from the Upper Cretaceous (Maastrichtian), thus this report extends their range to the Lower Cretaceous (Albian).
The consequences of short-term cortisol elevation on individual physiology and growth rate in wild largemouth bass (Micropterus salmoides)
Authors: O’Connor Constance M. , Gilmour Kathleen M. , Arlinghaus Robert , Matsumura Shuichi , Suski Cory D. , Philipp David P. , Cooke Steven J. 
Published: April 2011

In this study, we explored the growth, survival, and potential population-level effects of short-term experimentally induced stress in largemouth bass ( Micropterus salmoides ). Cortisol implants [50 mg·(kg body mass)–1] were used to increase circulating stress hormones in a group of wild fish in a research lake for ∼6 d in June 2007. Through mark-and-recapture, we compared survival, growth, and plasma biochemistry of cortisol-treated, sham-treated, and control fish at liberty until October 2007. Cortisol-treated fish displayed persistent growth rate depression compared with other groups. However, neither plasma biochemistry nor mortality rates differed among treatments. In a complementary study, we found that the standard metabolic rates (SMR) of cortisol-treated fish were higher than control fish ∼56 h following treatment. Bioenergetics modelling revealed that a transient elevation in SMR alone was insufficient to explain the observed growth depression. Finally, we constructed a simple population model to explore the potential consequences of growth depression. We found that a 10% reduction in population growth rate is conceivable when 39% of the population experiences a stress causing the growth rate depression documented in this study. Our study is novel in highlighting that individual and potentially population-level growth depression can result from a single stress event of short duration.
Do juvenile Atlantic salmon (Salmo salar) use chemosensory cues to detect and avoid risky habitats in the wild?
Authors: Kim Jae-Woo , Grant James W.A. , Brown Grant E. 
Published: April 2011

We examined whether juvenile Atlantic salmon ( Salmo salar ) in the wild adjust their behaviour in response to chemical cues of predator activity during a 4-week period after emergence from gravel nests. In each of seven 75 m2 sites in Catamaran Brook, New Brunswick, Canada, we established three contiguous sections differing in perceived predator activity by releasing stream water in control sections, conspecific alarm cues in risky sections, and nothing in buffer sections in both 2006 and 2007. As predicted, the density of young-of-the-year (YOY) salmon tended to decrease in alarm cue sections, while it increased in control and buffer sections. After the 2-week manipulation in 2006, we switched treatments so that buffer sections became alarm cue sections and alarm cue sections became buffer sections for an additional 2-week period. After the switch, the number of YOY increased least in the new alarm cue sections and most in control and new buffer sections. In contrast with YOY, the density of age 1+ parr was not affected by the experimental treatments. Our results suggest that YOY salmon can use chemical alarm cues to assess the predator activity of habitats in the wild.
Targeted Methylation of Two Tumor Suppressor Genes Is Sufficient to Transform Mesenchymal Stem Cells into Cancer Stem/Initiating Cells
Authors: Teng I-Wen , Hou Pei-Chi , Lee Kuan-Der , Chu Pei-Yi , Yeh Kun-Tu , Jin Victor X. , Tseng Min-Jen , Tsai Shaw-Jenq , Chang Yu-Sun , Wu Chi-Sheng , Sun H. Sunny , Tsai Kuen-daw , Jeng Long-Bin , Nephew Kenneth P. , Huang Tim H.-M. , Hsiao Shu-Huei , Leu Yu-Wei 
Published: April 2011

Abstract
Although DNA hypermethylation within promoter CpG islands is highly correlated with tumorigenesis, it has not been established whether DNA hypermethylation within a specific tumor suppressor gene (TSG) is sufficient to fully transform a somatic stem cell. In this study, we addressed this question using a novel targeted DNA methylation technique to methylate the promoters of HIC1 and RassF1A, two well-established TSGs, along with a two-component reporter system to visualize successful targeting of human bone marrow–derived mesenchymal stem cells (MSC) as a model cell system. MSCs harboring targeted promoter methylations of HIC1/RassF1A displayed several features of cancer stem/initiating cells including loss of anchorage dependence, increased colony formation capability, drug resistance, and pluripotency. Notably, inoculation of immunodeficient mice with low numbers of targeted MSC resulted in tumor formation, and subsequent serial xenotransplantation and immunohistochemistry confirmed the presence of stem cell markers and MSC lineage in tumor xenografts. Consistent with the expected mechanism of TSG hypermethylation, treatment of the targeted MSC with a DNA methyltransferase inhibitor reversed their tumorigenic phenotype. To our knowledge, this is the first direct demonstration that aberrant TSG hypermethylation is sufficient to transform a somatic stem cell into a fully malignant cell with cancer stem/initiating properties. Cancer Res; 71(13); 4653–63. ©2011 AACR.
HER2 Overexpression Elicits a Proinflammatory IL-6 Autocrine Signaling Loop That Is Critical for Tumorigenesis
Authors: Hartman Zachary C. , Yang Xiao-Yi , Glass Oliver , Lei Gangjun , Osada Takuya , Dave Sandeep S. , Morse Michael A. , Clay Timothy M. , Lyerly Herbert K. 
Published: April 2011

Abstract
HER2 overexpression occurs in approximately 25% of breast cancers, where it correlates with poor prognosis. Likewise, systemic inflammation in breast cancer correlates with poor prognosis, although the process is not understood. In this study, we explored the relationship between HER2 and inflammation, comparing the effects of overexpressing wild-type or mutated inactive forms of HER2 in primary human breast cells. Wild-type HER2 elicited a profound transcriptional inflammatory profile, including marked elevation of interleukin-6 (IL-6) expression, which we established to be a critical determinant of HER2 oncogenesis. Mechanistic investigations revealed that IL-6 secretion induced by HER2 overexpression activated Stat3 and altered gene expression, enforcing an autocrine loop of IL-6/Stat3 expression. Both mouse and human in vivo models of HER2-amplified breast carcinoma relied critically on this HER2–IL-6–Stat3 signaling pathway. Our studies offer the first direct evidence linking HER2 to a systemic inflammatory mechanism that orchestrates HER2-mediated tumor growth. We suggest that the HER2–IL-6–STAT3 signaling axis we have defined in breast cancer could prompt new therapeutic or prevention strategies for treatment of HER2-amplified cancers. Cancer Res; 71(13); 4380–91. ©2011 AACR.
Targeted Nanogels: A Versatile Platform for Drug Delivery to Tumors
Authors: Murphy Eric A. , Majeti Bharat K. , Mukthavaram Rajesh , Acevedo Lisette M. , Barnes Leo A. , Cheresh David A. 
Published: April 2011

Abstract
Although nanoparticle-based drug delivery formulations can improve the effectiveness and safety of certain anticancer drugs, many drugs, due to their chemical composition, are unsuitable for nanoparticle loading. Here, we describe a targeted nanogel drug delivery platform that can (i) encapsulate a wide range of drug chemotypes, including biological, small molecule, and cytotoxic agents; (ii) display targeting ligands and polymeric coatings on the surface; (iii) enhance drug retention within the nanogel core after photo-cross-linking; and (iv) retain therapeutic activity after lyophilization allowing for long-term storage. For therapeutic studies, we used integrin αvβ3–targeted lipid-coated nanogels with cross-linked human serum albumin in the core for carrying therapeutic cargoes. These particles exhibited potent activity in tumor cell viability assays with drugs of distinct chemotype, including paclitaxel, docetaxel, bortezomib, 17-AAG, sorafenib, sunitinib, bosutinib, and dasatinib. Treatment of orthotopic breast and pancreas tumors in mice with taxane-loaded nanogels produced a 15-fold improvement in antitumor activity relative to Abraxane by blocking both primary tumor growth and spontaneous metastasis. With a modifiable surface and core, the lipid-coated nanogel represents a platform technology that can be easily adapted for specific drug delivery applications to treat a wide range of malignant diseases. Mol Cancer Ther; 10(6); 972–82. ©2011 AACR.
ATM and p53 Regulate FOXM1 Expression via E2F in Breast Cancer Epirubicin Treatment and Resistance
Authors: Millour Julie , de Olano Natalia , Horimoto Yoshiya , Monteiro Lara J. , Langer Julia K. , Aligue Rosa , Hajji Nabil , Lam Eric W.-F. 
Published: April 2011

Abstract
In this report, we investigated the role and regulation of forkhead box M1 (FOXM1) in breast cancer and epirubicin resistance. We generated epirubicin-resistant MCF-7 breast carcinoma (MCF-7-EPIR) cells and found FOXM1 protein levels to be higher in MCF-7-EPIR than in MCF-7 cells and that FOXM1 expression is downregulated by epirubicin in MCF-7 but not in MCF-7-EPIR cells. We also established that there is a loss of p53 function in MCF-7-EPIR cells and that epirubicin represses FOXM1 expression at transcription and gene promoter levels through activation of p53 and repression of E2F activity in MCF-7 cells. Using p53−/− mouse embryo fibroblasts, we showed that p53 is important for epirubicin sensitivity. Moreover, transient promoter transfection assays showed that epirubicin and its cellular effectors p53 and E2F1 modulate FOXM1 transcription through an E2F-binding site located within the proximal promoter region. Chromatin immunoprecipitation analysis also revealed that epirubicin treatment increases pRB (retinoblastoma protein) and decreases E2F1 recruitment to the FOXM1 promoter region containing the E2F site. We also found ataxia-telangiectasia mutated (ATM) protein and mRNA to be overexpressed in the resistant MCF-7-EPIR cells compared with MCF-7 cells and that epirubicin could activate ATM to promote E2F activity and FOXM1 expression. Furthermore, inhibition of ATM in U2OS cells with caffeine or depletion of ATM in MCF-7-EPIR with short interfering RNAs can resensitize these resistant cells to epirubicin, resulting in downregulation of E2F1 and FOXM1 expression and cell death. In summary, our data show that ATM and p53 coordinately regulate FOXM1 via E2F to modulate epirubicin response and resistance in breast cancer. Mol Cancer Ther; 10(6); 1046–58. ©2011 AACR.
B7-H3 Silencing Increases Paclitaxel Sensitivity by Abrogating Jak2/Stat3 Phosphorylation
Authors: Liu Hao , Tekle Christina , Chen Yih-Wen , Kristian Alexandr , Zhao Yuhua , Zhou Ming , Liu Zixing , Ding Yan , Wang Bin , Mælandsmo Gunhild Mari , Nesland Jahn Marthin , Fodstad Oystein , Tan Ming 
Published: April 2011

Abstract
In many types of cancer, the expression of the immunoregulatory protein B7-H3 has been associated with poor prognosis. Previously, we observed a link between B7-H3 and tumor cell migration and invasion, and in present study, we have investigated the role of B7-H3 in chemoresistance in breast cancer. We observed that silencing of B7-H3, via stable short hairpin RNA or transient short interfering RNA transfection, increased the sensitivity of multiple human breast cancer cell lines to paclitaxel as a result of enhanced drug-induced apoptosis. Overexpression of B7-H3 made the cancer cells more resistant to the drug. Next, we investigated the mechanisms behind B7-H3–mediated paclitaxel resistance and found that the level of Stat3 Tyr705 phosphorylation was decreased in B7-H3 knockdown cells along with the expression of its direct downstream targets Mcl-1 and survivin. The phosphorylation of Janus kinase 2 (Jak2), an upstream molecule of Stat3, was also significantly decreased. In contrast, reexpression of B7-H3 in B7-H3 knockdown and low B7-H3 expressing cells increased the phosphorylation of Jak2 and Stat3. In vivo animal experiments showed that B7-H3 knockdown tumors displayed a slower growth rate than the control xenografts. Importantly, paclitaxel treatment showed a strong antitumor activity in the mice with B7-H3 knockdown tumors, but only a marginal effect in the control group. Taken together, our data show that in breast cancer cells, B7-H3 induces paclitaxel resistance, at least partially by interfering with Jak2/Stat3 pathway. These results provide novel insight into the function of B7-H3 and encourage the design and testing of approaches targeting this protein and its partners. Mol Cancer Ther; 10(6); 960–71. ©2011 AACR.
Glutathione Peroxidase-3 Deficiency Promotes Platelet-Dependent Thrombosis In Vivo
Authors: Jin Richard C. , Mahoney Christopher E. , (Coleman) Anderson Laura , Ottaviano Filomena , Croce Kevin , Leopold Jane A. , Zhang Ying-Yi , Tang Shiow-Shih , Handy Diane E. , Loscalzo Joseph 
Published: April 2011

Background—
Glutathione peroxidase-3 (GPx-3) is a selenocysteine-containing plasma protein that scavenges reactive oxygen species in the extracellular compartment. A deficiency of this enzyme has been associated with platelet-dependent thrombosis, and a promoter haplotype with reduced function has been associated with stroke risk.

Methods and Results—

We recently developed a genetic mouse model to assess platelet function and thrombosis in the setting of GPx-3 deficiency. The GPx-3
(−/−)
mice showed an attenuated bleeding time and an enhanced aggregation response to the agonist ADP compared with wild-type mice. GPx-3
(−/−)
mice displayed increased plasma levels of soluble P-selectin and decreased plasma cyclic cGMP compared with wild-type mice. ADP infusion-induced platelet aggregation in the pulmonary vasculature produced a more robust platelet activation response in the GPx-3
(−/−)
than wild-type mice; histological sections from the pulmonary vasculature of GPx-3
(−/−)
compared with wild-type mice showed increased platelet-rich thrombi and a higher percentage of occluded vessels. Cremaster muscle preparations revealed endothelial dysfunction in the GPx-3
(−/−)
compared with wild-type mice. With a no-flow ischemia-reperfusion stroke model, GPx-3
(−/−)
mice had significantly larger cerebral infarctions compared with wild-type mice and platelet-dependent strokes. To assess the neuroprotective role of antioxidants in this model, we found that manganese(III) meso-tetrakis(4-benzoic acid)porphyrin treatment reduced stroke size in GPx-3
(−/−)
mice compared with vehicle-treated controls.

Conclusions—
These findings demonstrate that GPx-3 deficiency results in a prothrombotic state and vascular dysfunction that promotes platelet-dependent arterial thrombosis. These data illustrate the importance of this plasma antioxidant enzyme in regulating platelet activity, endothelial function, platelet-dependent thrombosis, and vascular thrombotic propensity.
Lapaquistat Acetate
Authors: Stein Evan A. , Bays Harold , O'Brien Dennis , Pedicano Jim , Piper Edward , Spezzi Andrea 
Published: April 2011

Background—
Lapaquistat acetate is a squalene synthase inhibitor investigated for the treatment of hypercholesterolemia.

Methods and Results—
This report summarizes the phase 2 and 3 results from the lapaquistat clinical program, which was halted at an advanced stage as a result of potential hepatic safety issues. Efficacy and safety data were pooled from 12 studies (n=6151). These were 6- to 96-week randomized, double-blind, parallel, placebo- or active-controlled trials with lapaquistat monotherapy or coadministration with other lipid-altering drugs in dyslipidemic patients, including a large (n=2121) 96-week safety study. All studies included lapaquistat 100 mg daily; 5 included 50 mg; and 1 included 25 mg. The main outcome measures were the percent change in low-density lipoprotein cholesterol, secondary lipid/metabolic parameters, and overall safety. Lapaquistat 100 mg significantly decreased low-density lipoprotein cholesterol by 21.6% in monotherapy and by 18.0% in combination with a statin. It also reduced other cardiovascular risk markers, such as C-reactive protein. Total adverse events were higher for lapaquistat than placebo, although individual events were generally similar. At 100 mg, there was an increase in alanine aminotransferase value ≥3 times the upper limit of normal on ≥2 consecutive visits (2.0% versus 0.3% for placebo in the pooled efficacy studies; 2.7% versus 0.7% for low-dose atorvastatin in the long-term study). Two patients receiving lapaquistat 100 mg met the Hy Law criteria of alanine aminotransferase elevation plus increased total bilirubin.

Conclusions—
Squalene synthase inhibition with lapaquistat acetate, alone or in combination with statins, effectively lowered low-density lipoprotein cholesterol in a dose-dependent manner. Elevations in alanine aminotransferase, combined with a rare increase in bilirubin, presented potential hepatic safety issues, resulting in termination of development. The lapaquistat experience illustrates the current challenges in lipid-altering drug development.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifiers: NCT00487994, NCT00143663, NCT00143676, NCT00864643, NCT00263081, NCT00286481, NCT00249899, NCT00249912, NCT00813527, NCT00256178, NCT00268697, and NCT00251680.