bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevention of
Escherichia coli
K1 Penetration of the Blood-Brain Barrier by Counteracting the Host Cell Receptor and Signaling Molecule Involved in
E. coli
Invasion of Human Brain Microvascular Endothelial Cells
Authors: Zhu Longkun , Pearce Donna , Kim Kwang Sik 
Published: June 2010

ABSTRACT

Escherichia coli
meningitis is an important cause of mortality and morbidity, and a key contributing factor is our incomplete understanding of the pathogenesis of
E. coli
meningitis. We have shown that
E. coli
penetration into the brain requires
E. coli
invasion of human brain microvascular endothelial cells (HBMEC), which constitute the blood-brain barrier.
E. coli
invasion of HBMEC involves its interaction with HBMEC receptors, such as
E. coli
cytotoxic necrotizing factor 1 (CNF1) interaction with its receptor, the 67-kDa laminin receptor (67LR), and host signaling molecules including cytosolic phospholipase A
2
α (cPLA
2
α). In the present study, we showed that treatment with etoposide resulted in decreased expression of 67LR on HBMEC and inhibited
E. coli
invasion of HBMEC. Pharmacological inhibition of cysteinyl leukotrienes, lipoxygenated products of arachidonic acid released by cPLA
2
α, using montelukast (an antagonist of the type 1 cysteinyl leukotriene receptor) also inhibited
E. coli
invasion of HBMEC.
E. coli
penetration into the brain was significantly decreased by etoposide as well as by montelukast, and a combination of etoposide and montelukast was significantly more effective in inhibiting
E. coli
K1 invasion of HBMEC than single agents alone. These findings demonstrate for the first time that counteracting the HBMEC receptor and signaling molecule involved in
E. coli
invasion of HBMEC provides a novel approach for prevention of
E. coli
penetration into the brain, the essential step required for development of
E. coli
meningitis.
Yersinia enterocoliticaPromotes Robust Mucosal Inflammatory T-Cell Immunity in Murine Neonates
Authors: Echeverry Andrea , Saijo Shinobu , Schesser Kurt , Adkins Becky 
Published: June 2010

ABSTRACTMucosal immunity to gastrointestinal pathogens in early life has been studied only slightly. Recently, we developed an infection model in murine neonates using the gastroenteric pathogenYersinia enterocolitica. Here, we report that oral infection of neonatal mice with low doses of virulentY. enterocoliticaleads to vigorous intestinal and systemic adaptive immunity.Y. enterocoliticainfection promoted the development of anti-LcrV memory serum IgG1 and IgG2a responses of comparable affinity and magnitude to adult responses. Strikingly, neonatal mesenteric lymph node CD4+T cells producedYersinia-specific gamma interferon (IFN-γ) and interleukin-17A (IL-17A), exceeding adult levels. The robust T- and B-cell responses elicited in neonates exposed toY. enterocoliticawere associated with long-term protection against mucosal challenge with this pathogen. Using genetically deficient mice, we found that IFN-γ and CD4+cells, but not B cells, are critical for protection of neonates during primaryY. enterocoliticainfection. In contrast, adults infected with low bacterial doses did not require either cell population for protection. CD4-deficient neonatal mice adoptively transferred with CD4+cells from wild-type, IFN-γ-deficient, or IL-17AF-deficient mice were equally protected from infection. These data demonstrate that inflammatory CD4+T cells are required for protection of neonatal mice and that this protection may not require CD4-derived IFN-γ, IL-17A, or IL-17F. Overall, these studies support the idea thatY. enterocoliticapromotes the development of highly inflammatory mucosal responses in neonates and that intestinal T-cell function may be a key immune component in protection from gastrointestinal pathogens in early life.
The biostratigraphic importance of conchostracans in the continental Triassic of the northern hemisphere
Authors: Kozur Heinz W. , Weems Robert E. 
Published: June 2010

Abstract

Conchostracans or clam shrimp (order Conchostraca Sars) are arthropods with a carapace consisting of two chitinous lateral valves. Triassic conchostracans range in size from 2 to 12.5 mm long and are common in deposits that formed in fresh water lakes, isolated ponds and brackish areas. Their dessication- and freeze-resistant eggs can be dispersed by wind over long distances. Therefore many conchostracan species are distributed throughout the entire northern hemisphere. In the Late Permian to Middle Triassic interval, several of these forms are also found in Gondwana. Many wide-ranging conchostracan species have short stratigraphic ranges, making them excellent guide forms for subdivision of Triassic time and for long-range correlations. The stratigraphic resolution that can be achieved with conchostracan zones is often as high as for ammonoid and conodont zones found in pelagic marine deposits. This makes conchostracans the most useful group available for biostratigraphic subdivision and correlation in continental lake deposits. Upper Triassic Gondwanan conchostracan faunas are different from conchostracan faunas of the northern hemisphere. In the Norian, some slight provincialism can be observed even within the northern hemisphere. For example, the Sevatian
Redondestheria
seems to be restricted to North America and
Acadiestheriella
n. gen. so far has been found only in the Sevatian deposits from the Fundy Basin of southeastern Canada. Here we establish a conchostracan zonation for the Changhsingian (Late Permian) to Hettangian (Early Jurassic) of the northern hemisphere that, for the most part, is very well correlated with the marine scale. This zonation is especially robust for the Changhsingian to early Anisian, late Ladinian to Cordevolian and Rhaetian to Hettangian intervals. For most of the Middle and Upper Triassic, this zonation is still preliminary. Five new genera, six new species and a new subspecies of conchostracans are described that are stratigraphically important.
The Triassic chronostratigraphic scale: history and status
Authors: Lucas Spencer G. 
Published: June 2010

Abstract
The Triassic chronostratigraphic scale is a hierarchy of three series, seven stages and 15 substages developed during nearly two centuries of research. The first geological studies of Triassic rocks began in Germany in the late 1700s and culminated in 1834 when Friedrich August von Alberti coined the term ‘Trias’ for the Bunten Sandsteins, Muschelkalk and Keuper, a thick succession of strata between the Zechstein and the Lias. Recognition of the Trias outside of Germany soon followed, and by the 1860s Austrian geologist Edmund von Mojsisovics began constructing a detailed Triassic chronostratigraphy based on ammonoid biostratigraphy. In 1895, Mojsisovics and his principal collaborators, Wilhelm Waagen and Carl Diener, published a Triassic timescale that contains most of the stage and substage names still used today. In 1934, Leonard Spath proposed a Triassic ammonoid-based biochronological timescale that differed little from that of Mojsisovics and his collaborators. In the 1960s, E. Timothy Tozer proposed a Triassic ammonoid-based timescale based on North American standards, and his timescale included proposal of four Lower Triassic stages (Griesbachian, Dienerian, Smithian and Spathian). The work of the Subcommission on Triassic Stratigraphy began in the 1970s and resulted in current recognition of seven Triassic stages in three series: Lower Triassic–Induan, Olenekian; Middle Triassic–Anisian, Ladinian; Upper Triassic–Carnian, Norian and Rhaetian. The 1990s saw the rise of Triassic conodont biostratigraphy so that four intervals that have agreed on Triassic GSSPs use conodont occurrences as defining features: bases of Induan, Olenekian, Anisian and Rhaetian. The bases of the Ladinian and Carnian are defined by ammonoid events. The base of the Norian remains undefined, but will most likely be defined by conodonts.
Except for the Rhaetian, the Middle and Upper Triassic stages and substages have been fairly stable for decades, but there has been much less agreement on Lower Triassic chronostratigraphic subdivisions. Issues in the development of a Triassic chronostratigraphic scale include those of: stability and priority of nomenclature and concepts; disagreement over and changing taxonomy; the use of ammonoid v. conodont biostratigraphy; differences in the perceived significance of biotic events for chronostratigraphic classification; disagreements about the utility of relatively short stages; correlation problems between the Tethyan and Boreal realms (provinces); and competing standards from the Old and New worlds. Most of these issues have been resolved in the recognition of three Triassic series and seven stages. Further development of the Triassic chronostratigraphic scale needs to focus on definition and characterization of the 15 Triassic substages as these will provide a much more detailed basis for subdivision of Triassic time than do the seven stages.
Comprehensive Analysis of Missense Variations in the BRCT Domain of BRCA1 by Structural and Functional Assays
Authors: Lee Megan S. , Green Ruth , Marsillac Sylvia M. , Coquelle Nicolas , Williams R. Scott , Yeung Telford , Foo Desmond , Hau D. Duong , Hui Ben , Monteiro Alvaro N.A. , Glover J.N. Mark 
Published: June 2010

Abstract
Genetic screening of the breast and ovarian cancer susceptibility gene BRCA1 has uncovered a large number of variants of uncertain clinical significance. Here, we use biochemical and cell-based transcriptional assays to assess the structural and functional defects associated with a large set of 117 distinct BRCA1 missense variants within the essential BRCT domain of the BRCA1 protein that have been documented in individuals with a family history of breast or ovarian cancer. In the first method, we used limited proteolysis to assess the protein folding stability of each of the mutants compared with the wild-type. In the second method, we used a phosphopeptide pull-down assay to assess the ability of each of the variants to specifically interact with a peptide containing a pSer-X-X-Phe motif, a known functional target of the BRCA1 BRCT domain. Finally, we used transcriptional assays to assess the ability of each BRCT variant to act as a transcriptional activation domain in human cells. Through a correlation of the assay results with available family history and clinical data, we define limits to predict the disease risk associated with each variant. Forty-two of the variants show little effect on function and are likely to represent variants with little or no clinical significance; 50 display a clear functional effect and are likely to represent pathogenic variants; and the remaining 25 variants display intermediate activities. The excellent agreement between the structure/function effects of these mutations and available clinical data supports the notion that functional and structure information can be useful in the development of models to assess cancer risk. Cancer Res; 70(12); 4880–90. ©2010 AACR.
Regulation of Vascular Endothelial Growth Factor Receptors by Rb and E2F1: Role of Acetylation
Authors: Pillai Smitha , Kovacs Michelle , Chellappan Srikumar 
Published: June 2010

Abstract
E2F transcription factors regulate a variety of cellular processes, but their role in angiogenesis is not clear. We find that many genes involved in angiogenesis such as FLT-1, KDR, and angiopoietin 2 have potential E2F1 binding sites in their promoter. Chromatin immunoprecipitation (ChIP) assays showed that E2F1 can associate with these promoters and the recruitment of E2F1 was enhanced upon vascular endothelial growth factor (VEGF) stimulation with concomitant dissociation of Rb, leading to the transcriptional activation of these promoters. Transient transfection experiments showed that these promoters were induced by E2F1 and repressed by Rb, whereas depletion of E2F1 decreased their expression. The increased binding of E2F1 to these promoters upon VEGF stimulation correlated with the acetylation of histones and E2F1; this required VEGF receptor function, as seen in ChIP-re-ChIP experiments. This suggests the existence of a positive feedback loop regulating E2F1 acetylation and VEGF receptor expression. Acetylation associated with VEGF signaling seems to be predominantly mediated by P300/CBP-associated factor, and the depletion of histone acetyl transferases disrupted the formation of angiogenic tubules. These results suggest a novel role for E2F1 and acetylation in the angiogenic process. Cancer Res; 70(12); 4931–40. ©2010 AACR.
Myc-Induced MicroRNAs Integrate Myc-Mediated Cell Proliferation and Cell Fate
Authors: Kim Jong Wook , Mori Seiichi , Nevins Joseph R. 
Published: June 2010

Abstract
The Myc pathway, often deregulated in cancer, is critical in determining cell fate by coordinating a gene expression program that links the control of cell proliferation with cell fate decisions. As such, precise control of the Myc pathway activity must be achieved to ensure faithful execution of appropriate cellular response and to prevent progressing toward a malignant state. With recent highlighted roles of microRNAs (miRNA) as critical components of gene control, we sought to evaluate the extent to which miRNAs may contribute in the execution of Myc function. Combined analysis of mRNA and miRNA expression profiles reveals an integration whereby the Myc-mediated induction of miRNAs leads to the repression of various mRNAs encoding tumor suppressors that block cell proliferation including p21, p27, and Rb. In addition, the proapoptotic PTEN tumor suppressor gene is also repressed by Myc-induced miRNAs, suggesting that Myc-induced miRNAs contribute to the precise control of a transcriptional program that coordinates the balance of cell proliferation and cell death. Cancer Res; 70(12); 4820–8. ©2010 AACR.
Potent Antitumor Activity in Experimental Hepatocellular Carcinoma by Adenovirus-Mediated Coexpression of TRAIL and shRNA against COX-2
Authors: Chen Qing , Lou Wenjia , Shen Junjie , Ma Leina , Yang Zhi , Liu Li , Luo Jingjing , Qian Cheng 
Published: June 2010

Abstract
Purpose: Recent studies have indicated that short hairpin RNA (shRNA) driven by RNA polymerase (Pol) II promoters can be transcribed into precursor mRNAs together with transgenes. It remains unclear, however, whether coexpression of shRNA and transgene from a single promoter is feasible for cancer therapy.
Experimental Design: In this study, we generated novel adenoviral vectors that permitted coexpression of shRNA against cyclooxygenase-2 (COX-2) and the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapeutic gene from a cytomegalovirus promoter to evaluate whether silencing of COX-2 could increase the sensitivity of hepatocellular carcinoma to TRAIL.
Results: Our data showed that adenovirus vector Ad-TM, in which the shRNA was inserted into the 3′ untranslated region of the TRAIL gene, not only significantly suppressed COX-2 expression, but also expressed a high level of TRAIL. Moreover, infection with Ad-TM resulted in significant cytotoxicity in hepatocellular carcinoma cell lines. In contrast, it had no effect on normal liver cell line. Impressively, treatment of the established hepatocellular carcinoma tumors with Ad-TM resulted in complete tumor regression. This potent antitumor activity induced by Ad-TM was due to strong inhibition of COX-2 and high expression of TRAIL. Furthermore, using the shRNA and transgene coexpression adenovirus system, we showed that silencing of COX-2 increased the sensitivity of hepatocellular carcinoma to TRAIL through inhibition of Bcl-2 and Bcl-w.
Conclusion: This study indicated that adenovirus carrying shRNA and transgene expressed from a single promoter represented a potent approach for cancer therapy. Clin Cancer Res; 16(14); 3696–705. ©2010 AACR.
Effect of Pazopanib on Tumor Microenvironment and Liposome Delivery
Authors: Tailor Tina D. , Hanna Gabi , Yarmolenko Pavel S. , Dreher Matthew R. , Betof Allison S. , Nixon Andrew B. , Spasojevic Ivan , Dewhirst Mark W. 
Published: June 2010

Abstract
Pathologic angiogenesis creates an abnormal microenvironment in solid tumors, characterized by elevated interstitial fluid pressure (IFP) and hypoxia. Emerging theories suggest that judicious downregulation of proangiogenic signaling pathways may transiently “normalize” the vascular bed, making it more suitable for drug delivery and radiotherapy. In this work, we investigate the role of pazopanib, a small-molecule inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, on tumor IFP, angiogenesis, hypoxia, and liposomal drug delivery. Nude mice bearing A549 human non–small cell lung cancer xenografts were treated with 100 mg/kg pazopanib (n = 20) or vehicle (n = 20) through oral gavage for 8 days, followed by a one-time intravenous dose of 10 mg/kg Doxil (liposomal doxorubicin). Pazopanib treatment resulted in significant reduction of tumor IFP and decreased vessel density, assessed by CD31 staining. Despite these trends toward normalization, high-performance liquid chromatography revealed no differences in doxorubicin concentration between pazopanib-treated and control tumors, with Doxil penetration from microvessels being significantly reduced in the pazopanib group. Additionally, tumor hypoxia, evaluated by CA-IX immunostaining and confirmed in a second study by EF5 expression (n = 4, 100 mg/kg pazopanib; n = 4, vehicle), was increased in pazopanib-treated tumors. Our results suggest that the classic definition of tumor “normalization” may undermine the crucial role of vessel permeability and oncotic pressure gradients in liposomal drug delivery, and that functional measures of normalization, such as reduced IFP and hypoxia, may not occur in parallel temporal windows. Mol Cancer Ther; 9(6); 1798–808. ©2010 AACR.
ARC Synergizes with ABT-737 to Induce Apoptosis in Human Cancer Cells
Authors: Bhat Uppoor G. , Pandit Bulbul , Gartel Andrei L. 
Published: June 2010

AbstractPreviously, we reported that the nucleoside analogue/transcriptional inhibitor ARC (4-amino-6-hydrazino-7-β-d-ribofuranosyl-7H-pyrrolo(2,3-d)-pyrimidine-5-carboxamide) was able to induce p53-independent apoptosis in multiple cancer cell lines of different origins. This occurred, at least in part, by the suppression of short-lived, prosurvival member of the Bcl-2 family, Mcl-1. In contrast, we show here that treatment of human cancer cells with the pan-Bcl-2 inhibitor ABT-737 alone led to upregulation of Mcl-1 protein expression. Combination of subapoptotic concentrations of ABT-737 and ARC induced mitochondrial injury and potent caspase-3/caspase-9–dependent apoptosis in a wide variety of human cancer cell lines. These data suggest that the ABT-737/ARC combination, which simultaneously targets Bcl-2 and Mcl-1, may be efficient against human cancer. Mol Cancer Ther; 9(6); 1688–96. ©2010 AACR.
Role of the 18:1 Lysophosphatidic Acid–Ovarian Cancer Immunoreactive Antigen Domain Containing 1 (OCIAD1)–Integrin Axis in Generating Late-Stage Ovarian Cancer
Authors: Wang Chunyan , Michener Chad M. , Belinson Jerome L. , Vaziri Susan , Ganapathi Ram , Sengupta Saubhik 
Published: June 2010

AbstractChemotherapy resistance in ovarian cancer remains an unsolved problem in caring for women with this disease. We now show that ovarian cancer immunoreactive antigen domain containing 1 (OCIAD1) has higher expression in chemoresistant compared with chemosensitive ovarian cancer cell lines. We have designed a novel secondary cell homing assay (SCHA) to test the ability of cells to withstand chemotherapy and form secondary colonies that could form recurrent disease. OCIAD1 upregulated cells had significantly higher secondary colony-forming ability than had OCIAD1 downregulated cells following treatment with paclitaxel. Additionally, 18:1 lysophosphatidic acid (LPA) increases OCIAD1 expression in a time- and dose-dependent manner. LPA stimulates OCIAD1 serine phosphorylation within two hours of stimulation. Transfection of MKK6 increases OCIAD1 expression but nuclear translocation is inhibited. Inhibition of p38 mitogen-activated protein kinase blocks LPA-induced OCIAD1 expression. Cycloheximide treatment of MKK6-transfected cells does not inhibit OCIAD1 expression, suggesting that MKK6 upregulation is not translationally controlled. OCIAD1 downregulation knocks down LPA-induced cell adhesion to collagen I and laminin 10/11 and specifically inhibits cell attachment to α2, α5, αV, and β1 integrins. Proteomic studies indicate that OCIAD1 is physically attached to α actin 4 and β actin. Thus, OCIAD1 may play a role in cytoskeletal function which can alter sensitivity to paclitaxel. This is the first study to indicate that OCIAD1 is a key player in generating ovarian cancer recurrence; it is functionally controlled by LPA and MKK6 signaling, and inhibition of OCIAD1 could be an important strategy in the management of recurrent ovarian cancer. Mol Cancer Ther; 9(6); 1709–18. ©2010 AACR.
Antitumor Activity and Immune Response Induction of a Dual Agonist of Toll-Like Receptors 7 and 8
Authors: Wang Daqing , Precopio Melissa , Lan Tao , Yu Dong , Tang Jimmy X. , Kandimalla Ekambar R. , Agrawal Sudhir 
Published: June 2010

AbstractViral and synthetic single-stranded RNAs are the ligands for Toll-like receptors 7 and 8 (TLR7 and TLR8). We have reported a novel class of synthetic oligoribonucleotides, referred to as stabilized immune-modulatory RNA compounds, which act as agonists of TLR7, TLR8, or both TLR7 and TLR8 depending on the sequence composition and the presence of specific chemical modifications. In the present study, we evaluated the antitumor activity of a dual TLR7/8 agonist in tumor-bearing mice with peritoneal disseminated CT26.CL25 colon and 3LL-C75 lung carcinomas. Peritoneal administration of dual TLR7/8 agonist in mice bearing CT26.CL25 colon carcinomas had potent dose-dependent antitumor activity, which was associated with a marked decrease in CD4+CD25+Foxp3+ T regulatory cells and a significant increase in tumor antigen–specific IFN-γ–secreting effector cell responses in splenocytes and local tumor-infiltrating cells. In 3LL-C75 lung carcinoma, dual TLR7/8 agonist induced strong immune responses and antitumor effects in C57BL/6 and TLR9−/− mice, but not in TLR7−/− and MyD88−/− mice, indicating that the agonist induces immune responses via TLR7 and through the MyD88-dependent signaling pathway. TLR8 is not functional in mice. Additionally, s.c. administration of TLR7/8 agonist effectively prevented lung metastasis of tumors in the CT26.CL25 pulmonary metastasis model. These studies show that the dual TLR7/8 agonist induced Th1-type immune responses and potent antitumor activity in mice via TLR7 and through the MyD88-dependent pathway. Mol Cancer Ther; 9(6); 1788–97. ©2010 AACR.