bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of the Binding Domain of
Streptococcus oralis
Glyceraldehyde-3-Phosphate Dehydrogenase for
Porphyromonas gingivalis
Major Fimbriae
Authors: Nagata Hideki , Iwasaki Mio , Maeda Kazuhiko , Kuboniwa Masae , Hashino Ei , Toe Masahiro , Minamino Naoto , Kuwahara Hiromiki , Shizukuishi Satoshi 
Published: September 2009

ABSTRACT

Porphyromonas gingivalis
forms communities with antecedent oral biofilm constituent streptococci.
P. gingivalis
major fimbriae bind to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) present on the streptococcal surface, and this interaction plays an important role in
P. gingivalis
colonization. This study identified the binding domain of
Streptococcus oralis
GAPDH for
P. gingivalis
fimbriae.
S. oralis
recombinant GAPDH (rGAPDH) was digested with lysyl endopeptidase. Cleaved fragments of rGAPDH were applied to a reverse-phase high-pressure liquid chromatograph equipped with a C
18
column. Each peak was collected; the binding activity toward
P. gingivalis
recombinant fimbrillin (rFimA) was analyzed with a biomolecular interaction analysis system. The fragment displaying the strongest binding activity was further digested with various proteinases, after which the binding activity of each fragment was measured. The amino acid sequence of each fragment was determined by direct sequencing, mass spectrometric analysis, and amino acid analysis. Amino acid residues 166 to 183 of
S. oralis
GAPDH exhibited the strongest binding activity toward rFimA; confocal laser scanning microscopy revealed that the synthetic peptide corresponding to amino acid residues 166 to 183 of
S. oralis
GAPDH (pep166-183, DNFGVVEGLMTTIHAYTG) inhibits
S. oralis
-
P. gingivalis
biofilm formation in a dose-dependent manner. Moreover, pep166-183 inhibited interbacterial biofilm formation by several oral streptococci and
P. gingivalis
strains with different types of FimA. These results indicate that the binding domain of
S. oralis
GAPDH for
P. gingivalis
fimbriae exists within the region encompassing amino acid residues 166 to 183 of GAPDH and that pep166-183 may be a potent inhibitor of
P. gingivalis
colonization in the oral cavity.
Antibody-Mediated Protection against Infection withHelicobacter pyloriin a Suckling Mouse Model of Passive Immunity
Authors: Gorrell Rebecca J. , Robins-Browne Roy M. 
Published: September 2009

ABSTRACTStudies of active immunization againstHelicobacter pyloriindicate that antibodies play a minor role in immunity. There is also evidence, however, that the translocation of antibodies in the stomach may be insufficient to achieve functional antibody levels in the gastric lumen. We have used a suckling mouse model of passive immunity to determine if perorally delivered antibodies can protect against infection withH. pylori. Female C57BL/6 mice were immunized parenterally with formalin-fixed cells of three clinical isolates ofH. pylori(3HP) or the mouse-adaptedH. pyloristrain SS1 before mating. Their pups were challenged with the SS1 strain at 4 days of age and left to suckle before determination of bacterial loads 14 days later. Compared to age-matched controls, pups suckled by 3HP-vaccinated dams were significantly protected against infection (>95% reduction in median bacterial load;P< 0.0001). Pups suckled by SS1-vaccinated dams were also significantly protected in terms of both median bacterial load (>99.5% reduction;P< 0.0001) and the number of culture-negative pups (28% versus 2% for immune and nonimmune cohorts, respectively;P< 0.0001). Similar results were obtained with pups suckled by dams immunized with a urease-deficient mutant of SS1. Fostering experiments demonstrated that protection was entirely attributable to suckling from an immunized dam, and antibody isotype analysis suggested that protection was mediated by the immunoglobulin G fraction of immune milk. Analysis of the bacterial loads in pups sampled before and after weaning confirmed that infection had been prevented in culture-negative animals. These data indicate that antibodies can prevent colonization byH. pyloriand suppress the bacterial loads in animals that are colonized.
CD46 Transgenic Mouse Model of Necrotizing Fasciitis Caused by
Streptococcus pyogenes
Infection
Authors: Matsui Hidenori , Sekiya Yukie , Nakamura Masahiko , Murayama Somay Yamagata , Yoshida Haruno , Takahashi Tetsufumi , Imanishi Ken'ichi , Tsuchimoto Kanji , Uchiyama Takehiko , Sunakawa Keisuke , Ubukata Kimiko 
Published: September 2009

ABSTRACT

We developed a human CD46-expressing transgenic (Tg) mouse model of subcutaneous (s.c.) infection into both hind footpads with clinically isolated 11 group A streptococcus (GAS) serotype M1 strains. When the severity levels of foot lesions at 72 h and the mortality rates by 336 h were compared after s.c. infection with 1 × 10
7
CFU of each GAS strain, the GAS472 strain, isolated from the blood of a patient suffering from streptococcal toxic shock syndrome (STSS), induced the highest severity levels and mortality rates. GAS472 led to a 100% mortality rate in CD46 Tg mice after only 168 h postinfection through the supervention of severe necrotizing fasciitis (NF) of the feet. In contrast, GAS472 led to a 10% mortality rate in non-Tg mice through the supervention of partial necrotizing cutaneous lesions of the feet. The footpad skin sections of CD46 Tg mice showed hemorrhaging and necrotic striated muscle layers in the dermis, along with the exfoliation of epidermis with intracellular edema until 48 h after s.c. infection with GAS472. Thereafter, the bacteria proliferated, reaching a 90-fold or 7-fold increase in the livers of CD46 Tg mice or non-Tg mice, respectively, for 24 h between 48 and 72 h after s.c. infection with GAS472. As a result, the infected CD46 Tg mice appeared to suffer severe liver injuries. These findings suggest that human CD46 enhanced the progression of NF in the feet and the exponential growth of bacteria in deep tissues, leading to death.
Kinetics of the Immune Response Profile in Guinea Pigs after Vaccination withMycobacterium bovisBCG and Infection withMycobacterium tuberculosis
Authors: Grover Ajay , Taylor Jennifer , Troudt JoLynn , Keyser Andrew , Arnett Kimberly , Izzo Linda , Rholl Drew , Izzo Angelo 
Published: September 2009

ABSTRACTThe guinea pig model of tuberculosis is used extensively in assessing novel vaccines, sinceMycobacterium bovisBCG vaccination effectively prolongs survival after low-dose aerosol infection with virulentM. tuberculosis. To better understand how BCG extends time to death after pulmonary infection withM. tuberculosis, we examined cytokine responses postvaccination and recruitment of activated T cells and cytokine response postinfection. At 10 weeks postvaccination, splenic gamma interferon (IFN-γ) mRNA was significantly elevated compared to the levels at 5 weeks in ex vivo stimulation assays. At 15, 40, 60, and 120 days postinfection, T-cell activation (CD4+CD62Llowand CD8+CD62Llow) and mRNA expression of IFN-γ, tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), IL-10, IL-12, and eomesodermin were assessed. Our data show that at day 40, BCG-vaccinated guinea pigs had significantly increased levels of IFN-γ mRNA expression but decreased TNF-α mRNA expression in their lungs compared to the levels in nonvaccinated animals. At day 120, a time when nonvaccinated guinea pigs succumbed to infection, low levels of IFN-γ mRNA were observed even though there were increasing levels of IL-1, IL-12, and IL-10, and the numbers of activated T cells did not differ from those in BCG-vaccinated animals. BCG vaccination conferred the advantage of recruiting greater numbers of CD4+CD62LlowT cells at day 40, although the numbers of CD8+CD62LlowT cells were not elevated compared to the numbers in nonvaccinated animals. Our data suggest that day 40 postinfection may be a pivotal time point in determining vaccine efficacy and prolonged survival and that BCG promotes the capacity of T cells in the lungs to respond to infection.
The
Mycoplasma pneumoniae
MPN490 and
Mycoplasma genitalium
MG339 Genes Encode RecA Homologs That Promote Homologous DNA Strand Exchange
Authors: Sluijter Marcel , Spuesens Emiel B. M. , Hartwig Nico G. , van Rossum Annemarie M. C. , Vink Cornelis 
Published: September 2009

ABSTRACT

The P1, P40, and P90 proteins of
Mycoplasma pneumoniae
and the MgPa and P110 proteins of
Mycoplasma genitalium
are immunogenic adhesion proteins that display sequence variation. Consequently, these proteins are thought to play eminent roles in immune evasive strategies. For each of the five proteins, a similar underlying molecular mechanism for sequence variation was hypothesized, i.e., modification of the DNA sequences of their respective genes. This modification is thought to result from homologous recombination of parts of these genes with repeat elements (RepMp and MgPar elements in
M. pneumoniae
and
M. genitalium
, respectively) that are dispersed throughout the bacterial genome. Proteins that are potentially involved in homologous DNA recombination have been suggested to be implicated in recombination between these repeat elements and thereby in antigenic variation. To investigate this notion, we set out to study the function of the RecA homologs that are encoded by the
M. pneumoniae
MPN490 and
M. genitalium
MG339 genes. Both proteins, which are 79% identical on the amino acid level, were found to promote recombination between homologous DNA substrates in an ATP-dependent fashion. The recombinational activities of both proteins were Mg
2+
and pH dependent and were strongly supported by the presence of single-stranded DNA binding protein, either from
M. pneumoniae
or from
Escherichia coli
. We conclude that the MPN490- and MG339-encoded proteins are RecA homologs that have the capacity to recombine homologous DNA substrates. Thus, they may play a central role in recombination between repetitive elements in both
M. pneumoniae
and
M. genitalium
.
Bacillus anthracis
Capsule Activates Caspase-1 and Induces Interleukin-1β Release from Differentiated THP-1 and Human Monocyte-Derived Dendritic Cells
Authors: Cho Min-Hee , Ahn Hae-Jeong , Ha Hyun-Joon , Park Jungchan , Chun Jeong-Hoon , Kim Bong-Su , Oh Hee-Bok , Rhie Gi-eun 
Published: September 2009

ABSTRACT

The poly-γ-
d
-glutamic acid (PGA) capsule is one of the major virulence factors of
Bacillus anthracis
, which causes a highly lethal infection. The antiphagocytic PGA capsule disguises the bacilli from immune surveillance and allows unimpeded growth of bacilli in the host. Recently, efforts have been made to include PGA as a component of anthrax vaccine; however, the innate immune response of PGA itself has been poorly investigated. In this study, we characterized the innate immune response elicited by PGA in the human monocytic cell line THP-1, which was differentiated into macrophages with phorbol 12-myristate 13-acetate (PMA) and human monocyte-derived dendritic cells (hMoDCs). PGA capsules were isolated from the culture supernatant of either the pXO1-cured strain of
B. anthracis
H9401 or
B. licheniformis
ATCC 9945a. PGA treatment of differentiated THP-1 cells and hMoDCs led to the specific extracellular release of interleukin-1β (IL-1β) in a dose-dependent manner. Evaluation of IL-1β processing by Western blotting revealed that cleaved IL-1β increased in THP-1 cells and hMoDCs after PGA treatment. Enhanced processing of IL-1β directly correlated with increased activation of its upstream regulator, caspase-1, also known as IL-1β-converting enzyme (ICE). The extracellular release of IL-1β in response to PGA was ICE dependent, since the administration of an ICE inhibitor prior to PGA treatment blocked induction of IL-1β. These results demonstrate that
B. anthracis
PGA elicits IL-1β production through activation of ICE in PMA-differentiated THP-1 cells and hMoDCs, suggesting the potential for PGA as a therapeutic target for anthrax.
Inhibition of Tumor Growth Progression by Antiandrogens and mTOR Inhibitor in aPten-Deficient Mouse Model of Prostate Cancer
Authors: Zhang Weisheng , Zhu Joe , Efferson Clay L. , Ware Chris , Tammam Jennifer , Angagaw Minilik , Laskey Jason , Bettano Kimberly A. , Kasibhatla Shailaja , Reilly John F. , Sur Cyrille , Majumder Pradip K. 
Published: September 2009

AbstractAndrogen receptors have been shown to play a critical role in prostate cancer. We used ultrasound imaging techniques to track tumor response to antiandrogen and rapamycin treatment in a prostate-specific Pten-deleted mouse model of cancer. Depletion of androgens by either surgical or chemical castration significantly inhibited tumor growth progression without altering the activation of Akt and mammalian target of rapamycin (mTOR). We also showed for the first time that targeting mTOR along with antiandrogen treatment exhibited additive antitumor effects in vivo when compared with single agents. Our preclinical data suggest that combination of antiandrogens with mTOR inhibitors might be more effective in treating androgen-dependent prostate cancer patients. [Cancer Res 2009;69(18):7466–72]
Pomalidomide and Lenalidomide Induce p21WAF-1 Expression in Both Lymphoma and Multiple Myeloma through a LSD1-Mediated Epigenetic Mechanism
Authors: Escoubet-Lozach Laure , Lin I-Lin , Jensen-Pergakes Kristen , Brady Helen A. , Gandhi Anita K. , Schafer Peter H. , Muller George W. , Worland Peter J. , Chan Kyle W.H. , Verhelle Dominique 
Published: September 2009

AbstractLenalidomide and pomalidomide have both been evaluated clinically for their properties as anticancer agents, with lenalidomide being available commercially. We previously reported that both compounds cause cell cycle arrest in Burkitt's lymphoma and multiple myeloma cell lines by increasing the level of p21WAF-1 expression. In the present study, we unravel the molecular mechanism responsible for p21WAF-1 up-regulation using Namalwa cells as a human lymphoma model. We show that the increase of p21WAF-1 expression is regulated at the transcriptional level through a mechanism independent of p53. Using a combination of approaches, we show that several GC-rich binding transcription factors are involved in pomalidomide-mediated up-regulation of p21WAF-1. Furthermore, we report that p21WAF-1 up-regulation is associated with a switch from methylated to acetylated histone H3 on p21WAF-1 promoter. Interestingly, lysine-specific demethylase-1 (LSD1) silencing reduced both pomalidomide and lenalidomide up-regulation of p21WAF-1, suggesting that this histone demethylase is involved in the priming of the p21WAF-1 promoter. Based on our findings, we propose a model in which pomalidomide and lenalidomide modify the chromatin structure of the p21WAF-1 promoter through demethylation and acetylation of H3K9. This effect, mediated via LSD1, provides GC-rich binding transcription factors better access to DNA, followed by recruitment of RNA polymerase II and transcription activation. Taken together, our results provide new insights on the mechanism of action of pomalidomide and lenalidomide in the regulation of gene transcription, imply possible efficacy in p53 mutated and deleted cancer, and suggest new potential clinical uses as an epigenetic therapy. [Cancer Res 2009;69(18):7347–56]
Role of Cyclic AMP Response Element–Binding Protein in Insulin-like Growth Factor-I Receptor Up-regulation by Sex Steroids in Prostate Cancer Cells
Authors: Genua Marco , Pandini Giuseppe , Sisci Diego , Castoria Gabriella , Maggiolini Marcello , Vigneri Riccardo , Belfiore Antonino 
Published: September 2009

Abstract
Insulin-like growth factor-I receptor (IGF-IR) overexpression may play a role in prostate cancer progression. We found previously that, in prostate cancer cells, IGF-IR is up-regulated by both androgens and estrogens via a nongenotropic pathway. We now show that, in prostate cancer cells, stimulation with either androgens or estrogens up-regulates IGF-IR by inducing cyclic AMP response element–binding protein (CREB) activation. Both sex steroids phosphorylated CREB at Ser133 in a dose-dependent manner in androgen receptor (AR)–positive LNCaP cells, whereas only estrogens phosphorylated CREB in AR-negative PC3 cells. CREB phosphorylation involved c-Src–dependent extracellular signal-regulated kinase 1/2 activation, but not protein kinase A, protein kinase C, or calmodulin-dependent kinase II, and occurred also in cells transfected with AR or estrogen receptor mutants that do not localize into the nucleus. CREB silencing abrogated IGF-IR up-regulation and promoter activation. We also showed that CREB binds to IGF-IR promoter region and identified the relevant CREB-binding site at the 5′-untranslated region fragment of IGF-IR promoter. In conclusion, we describe a novel mechanism of IGF-IR up-regulation and promoter activity by CREB activation, induced by sex steroids, through a nongenotropic signaling. [Cancer Res 2009;69(18):7270–7]
NEDD9 Promotes Oncogenic Signaling in Mammary Tumor Development
Authors: Izumchenko Eugene , Singh Mahendra K. , Plotnikova Olga V. , Tikhmyanova Nadezhda , Little Joy L. , Serebriiskii Ilya G. , Seo Sachiko , Kurokawa Mineo , Egleston Brian L. , Klein-Szanto Andres , Pugacheva Elena N. , Hardy Richard R. , Wolfson Marina , Connolly Denise C. , Golemis Erica A. 
Published: September 2009

Abstract
In the past 3 years, altered expression of the HEF1/CAS-L/NEDD9 scaffolding protein has emerged as contributing to cancer metastasis in multiple cancer types. However, whereas some studies have identified elevated NEDD9 expression as prometastatic, other work has suggested a negative role in tumor progression. We here show that the Nedd9-null genetic background significantly limits mammary tumor initiation in the MMTV-polyoma virus middle T genetic model. Action of NEDD9 is tumor cell intrinsic, with immune cell infiltration, stroma, and angiogenesis unaffected. The majority of the late-appearing mammary tumors of MMTV-polyoma virus middle T;Nedd9−/− mice are characterized by depressed activation of proteins including AKT, Src, FAK, and extracellular signal-regulated kinase, emphasizing an important role of NEDD9 as a scaffolding protein for these prooncogenic proteins. Analysis of cells derived from primary Nedd9+/+ and Nedd9−/− tumors showed persistently reduced FAK activation, attachment, and migration, consistent with a role for NEDD9 activation of FAK in promoting tumor aggressiveness. This study provides the first in vivo evidence of a role for NEDD9 in breast cancer progression and suggests that NEDD9 expression may provide a biomarker for tumor aggressiveness. [Cancer Res 2009;69(18):7198–206]
Anticancer Activity of CX-3543: A Direct Inhibitor of rRNA Biogenesis
Authors: Drygin Denis , Siddiqui-Jain Adam , O'Brien Sean , Schwaebe Michael , Lin Amy , Bliesath Josh , Ho Caroline B. , Proffitt Chris , Trent Katy , Whitten Jeffrey P. , Lim John K. C. , Von Hoff Daniel , Anderes Kenna , Rice William G. 
Published: September 2009

AbstractHallmark deregulated signaling in cancer cells drives excessive ribosome biogenesis within the nucleolus, which elicits unbridled cell growth and proliferation. The rate-limiting step of ribosome biogenesis is synthesis of rRNA (building blocks of ribosomes) by RNA Polymerase I (Pol I). Numerous kinase pathways and products of proto-oncogenes can up-regulate Pol I, whereas tumor suppressor proteins can inhibit rRNA synthesis. In tumorigenesis, activating mutations in certain cancer-associated kinases and loss-of-function mutations in tumor suppressors lead to deregulated signaling that stimulates Pol I transcription with resultant increases in ribosome biogenesis, protein synthesis, cell growth, and proliferation. Certain anticancer therapeutics, such as cisplatin and 5-fluorouracil, reportedly exert, at least partially, their activity through disruption of ribosome biogenesis, yet many prime targets for anticancer drugs within the ribosome synthetic machinery of the nucleolus remain largely unexploited. Herein, we describe CX-3543, a small molecule nucleolus-targeting agent that selectively disrupts nucleolin/rDNA G-quadruplex complexes in the nucleolus, thereby inhibiting Pol I transcription and inducing apoptosis in cancer cells. CX-3543 is the first G-quadruplex interactive agent to enter human clinical trials, and it is currently under evaluation against carcinoid/neuroendocrine tumors in a phase II clinical trial. [Cancer Res 2009;69(19):7653–61]
miR-21: An Androgen Receptor–Regulated MicroRNA that Promotes Hormone-Dependent and Hormone-Independent Prostate Cancer Growth
Authors: Ribas Judit , Ni Xiaohua , Haffner Michael , Wentzel Erik A. , Salmasi Amirali Hassanzadeh , Chowdhury Wasim H. , Kudrolli Tarana A. , Yegnasubramanian Srinivasan , Luo Jun , Rodriguez Ron , Mendell Joshua T. , Lupold Shawn E. 
Published: September 2009

Abstract
Androgen receptor (AR)–mediated oncogenic pathways have not been fully elucidated. In this study, we used high-throughput microarray analysis on two AR-positive prostate cancer (CaP) cell lines to identify 16 AR-responsive microRNAs (miRNA). We focused on miR-21 because of its previously reported oncogenic activity in other cancers. We show androgen-induced AR binding to the defined miR-21 promoter, miPPR-21, suggesting direct transcriptional regulation. Inhibition of miR-21 diminished androgen-induced CaP cell proliferation, providing new evidence that miRNAs can contribute to androgen-driven cell growth. Elevated expression of miR-21 enhanced CaP tumor growth in vivo and, surprisingly, was sufficient for androgen-dependent tumors to overcome castration-mediated growth arrest. Thus, elevated miR-21 expression alone is sufficient to impart castration resistance. Moreover, quantitative reverse transcription-PCR analysis revealed elevated miR-21 expression in CaP when compared with adjacent normal tissue. These results suggest that miR-21 may contribute to CaP pathogenesis. [Cancer Res 2009;69(18):7165–9]
Antitumor Immunity Can Be Uncoupled from Autoimmunity following Heat Shock Protein 70–Mediated Inflammatory Killing of Normal Pancreas
Authors: Kottke Timothy , Pulido Jose , Thompson Jill , Sanchez-Perez Luis , Chong Heung , Calderwood Stuart K. , Selby Peter , Harrington Kevin , Strome Scott E. , Melcher Alan , Vile Richard G. 
Published: September 2009

Abstract
We have a long-term interest in the connectivity between autoimmunity and tumor rejection. However, outside of the melanocyte/melanoma paradigm, little is known about whether autoimmune responses to normal tissue can induce rejection of tumors of the same histologic type. Here, we induced direct, pathogen-like cytotoxicity to the normal pancreas in association with the immune adjuvant heat shock protein 70. In sharp contrast to our studies with a similar approach for the treatment of prostate cancer, inflammatory killing of the normal pancreas induced a Th1-like, anti-self-response to pancreatic antigens, which was rapidly suppressed by a concomitant suppressive regulatory T cell (Treg) response. Interestingly, even when Treg cells were depleted, the Th1-like response was insufficient to induce significant ongoing autoimmunity. However, the Th1-like response to antigens expressed in the pancreas at the time of damage was sufficient to induce rejection of tumors expressing either a foreign (ova) antigen or fully syngeneic tumor antigens (on Panc02 tumor cells), provided that Treg were depleted before inflammatory killing of the normal pancreas. Taken together, these data indicate that profound differences exist between the immunoprotective mechanisms in place between different tissues (pancreas and prostate) in their response to pathogen-like damage. Moreover, they also show that, although multiple layers of immunologic safeguards are in place to prevent the development of severe autoimmune consequences in the pancreas (in contrast to the prostate), tumor rejection responses can still be decoupled from pathologic autoimmune responses in vivo, which may provide novel insights into the immunotherapeutic treatment of pancreatic cancer. [Cancer Res 2009;69(19):7767–74]