bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Chemokine CCL2 Is Required for Control of Murine GastricSalmonella entericaInfection
Authors: DePaolo R. William , Lathan Rashida , Rollins Barrett J. , Karpus William J. 
Published: September 2005

ABSTRACTSalmonella entericais a gram-negative intracellular pathogen that can cause a variety of diseases ranging from gastroenteritis to typhoid fever. The Typhimurium serotype causes gastroenteritis in humans; however, infection of mice results in an enteric fever that resembles human typhoid fever and has been used as a model for typhoid fever. The present study examined the role of the chemokine CCL2 in the control ofSalmonellainfection. Upon infection with salmonellae, mucosal expression of CCL2 is rapidly up-regulated, followed by systemic expression in the spleen. CCL2−/−mice became moribund earlier and had a higher rate of mortality compared to wild-type C57BL/6 mice. Moreover, CCL2−/−mice had significantly higher levels of bacteria in the liver compared to wild-type controls. Mucosal and serum interleukin-6 and tumor necrosis factor alpha levels were elevated in CCL2−/−mice compared to wild-type mice. In vitro analysis demonstrated that CCL2−/−macrophages infected with salmonellae resulted in dysregulated cytokine production compared to macrophages derived from wild-type mice. These data are the first to directly demonstrate CCL2 as a critical factor for immune responses and survival followingS. entericainfection.
Disruption of a Locus Encoding a Nucleolar Zinc Finger Protein Decreases Tachyzoite-to-Bradyzoite Differentiation in
Toxoplasma gondii
Authors: Vanchinathan Padmini , Brewer Jeremy L. , Harb Omar S. , Boothroyd John C. , Singh Upinder 
Published: September 2005

ABSTRACT

During its life cycle in intermediate hosts,
Toxoplasma gondii
exists in two interconverting developmental stages: tachyzoites and bradyzoites. This interconversion is essential for the survival and pathogenicity of the parasite, but little is known about the genetic mechanisms that control this process. We have previously generated tachyzoite-to-bradyzoite differentiation (Tbd
−
) mutants using chemical mutagenesis and a green fluorescent protein-based selection strategy. The genetic loci responsible for the Tbd
−
phenotype, however, could not be identified. We have now used an insertional mutagenesis strategy to generate two differentiation mutants: TBD-5 and TBD-6 that switch to bradyzoites at 10 and 50% of wild-type levels, respectively. In TBD-6 there is a single insertion of the mutagenesis vector 164 bp upstream of the transcription start site of a gene encoding a zinc finger protein (
ZFP
1). Disruption of this locus in wild-type parasites reproduces the decreased stage conversion phenotype. ZFP1 is targeted to the parasite nucleolus by CCHC motifs and significantly altered expression levels are toxic to the parasites. This represents the first identification of a gene necessary for efficient conversion of tachyzoites to bradyzoites.
Comparative Transcriptional Profiling ofBorrelia burgdorferiClinical Isolates Differing in Capacities for Hematogenous Dissemination
Authors: Ojaimi Caroline , Mulay Vishwaroop , Liveris Dionysios , Iyer Radha , Schwartz Ira 
Published: September 2005

ABSTRACTBorrelia burgdorferi, the etiologic agent of Lyme disease, is genetically heterogeneous. Previous studies have shown a significant association between the frequency of hematogenous dissemination in Lyme disease patients and the genotype of the infectingB. burgdorferistrain. Comparative transcriptional profiling of two representative clinical isolates with distinct genotypes (BL206 and B356) was undertaken. A total of 78 open reading frames (ORFs) had expression levels that differed significantly between the two isolates. A number of genes with potential involvement in nutrient uptake (BB0603, BBA74, BB0329, BB0330, and BBB29) have significantly higher expression levels in isolate B356. Moreover, nearly 25% of the differentially expressed genes are predicted to be localized on the cell surface, implying that these two isolates have cell surface properties that differ considerably. One of these genes, BBA74, encodes a protein of 257 amino acid residues that has been shown to possess porin activity. BBA74 transcript level was >20-fold higher in B356 than in BL206, and strain B356 contained three- to fivefold more BBA74 protein. BBA74 was disrupted by the insertion of a kanamycin resistance cassette into the coding region. The growth rates of both wild-type and mutant strains were essentially identical, and cultures reached the same final cell densities. However, the mutant strains consistently showed prolonged lags of 2 to 5 days prior to the induction of log-phase growth compared to wild-type strains. It is tempting to speculate that the absence of BBA74 interferes with the enhanced nutrient uptake that may be required for the entry of cells into log-phase growth. These studies demonstrate the value of comparative transcriptional profiling for identifying differences in the transcriptomes ofB. burgdorfericlinical isolates that may provide clues to pathogenesis. The 78 ORFs identified here are a good starting point for the investigation of factors involved in the hematogenous dissemination ofB. burgdorferi.
Nasal Colonization with
Streptococcus pneumoniae
Includes Subpopulations of Surface and Invasive Pneumococci
Authors: Briles David E. , Novak Lea , Hotomi Muneki , van Ginkel Frederik W. , King Janice 
Published: September 2005

ABSTRACT

We demonstrated that during colonization with
Streptococcus pneumoniae
the nasal mucosal tissues of mice support two populations of pneumococci. Transparent-phase pneumococci can be readily washed from the outer surface, while a second population composed of primarily opaque-phase pneumococci is released only by homogenization of the nasal tissue. The fact that the opaque phase has previously been associated with invasion and the fact that opaque-phase pneumococci were released by homogenization of previously washed nasal tissue suggest that the opaque-phase pneumococci may have invaded the nasal tissue. Consistent with this hypothesis was our observation that there was inflammation in portions of the nasal mucosa of the colonized mice but not in the mucosa of noncolonized mice, but this observation did not prove the hypothesis. If the opaque-phase pneumococci released from the nasal tissue were from within the tissue and/or if resistance of the opaque-phase subpopulation to antibody, complement, and phagocytes is essential for long-term carriage, it seems likely that the virulence factors of
S. pneumoniae
that are necessary for killing humans exist to facilitate carriage. Although this speculation is unproven, the observation that there are separate populations of pneumococci during colonization may help guide future attempts to understand the biology of nasal colonization by this pathogen.
Expression of Matrix Metalloproteinases Subsequent to UrogenitalChlamydia muridarumInfection of Mice
Authors: Ramsey K.H. , Sigar I.M. , Schripsema J. H. , Shaba N. , Cohoon K. P. 
Published: September 2005

ABSTRACTThe central hypothesis of this study was that matrix metalloproteinases (MMPs) would be enhanced following murine chlamydial infection and that their expression would vary in mouse strains that differ in their susceptibility to chronic chlamydia-induced disease. To address this hypothesis, female C3H/HeN and C57BL/6 mice were infected intravaginally withChlamydia muridarum. Uterine and oviduct tissues were assessed for transcription of MMP genes and their tissue inhibitors. An increased activity of MMP genes relative to preinfection tissues was observed in the C3H/HeN mice when compared to C57BL/6 mice. Using gelatin zymography, we detected constitutive MMP-2 activity in both strains of mice but an increase in MMP-9. Casein zymography indicated the presence of two elastase-like activities consistent with MMP-12 and possibly MMP-7. Western blotting and antigen capture enzyme-linked immunoassay also confirmed an increase in MMP-9 but constitutive MMP-2 expression subsequent to the infection in both strains of mice. In C57BL/6 mice, MMP-9 was present in monomer and dimer form throughout the 56-day monitoring period. C3H/HeN mice produced dimeric MMP-9, but increases in the monomer form were also observed through day 14. Post-translational modification of MMP-9 between the two strains also differed. Immunohistochemistry revealed neutrophils as a prominent source for MMP-9 in both strains of mice. We conclude that differences in the relative expression and activity of MMPs, particularly MMP-9, occur in mice differing in their susceptibility to the development of chronic chlamydial disease. These differences may account for disparate outcomes with regard to chronic sequelae of the disease.
Toll-Like Receptor 2 Regulates Interleukin-1β-Dependent Cardiomyocyte Hypertrophy Triggered by
Trypanosoma cruzi
Authors: Petersen Christine A. , Krumholz Katherine A. , Burleigh Barbara A. 
Published: September 2005

ABSTRACT

Trypanosoma cruzi
, the intracellular protozoan parasite that causes Chagasic cardiomyopathy, elicits a robust hypertrophic response in isolated cardiomyocytes. Previous studies established that
T. cruzi
-elicited cardiomyocyte hypertrophy is mediated by interleukin-1β produced by infected cardiomyocyte cultures. Here, we define key upstream signaling events leading to cardiomyocyte hypertrophy in response to
T. cruzi
infection, to be dependent on Toll-like receptor 2 and NF-κB. Furthermore, we demonstrate that cardiomyocyte hypertrophy, which is initiated by live infective
T. cruzi
trypomastigotes or stimulation of isolated myocytes with secreted/released trypomastigote molecules, is a common outcome of the cardiomyocyte recognition of pathogen-associated molecular patterns by intrinsic Toll-like receptors. This study is the first to link pathogen recognition by intrinsic Toll-like receptors to cardiomyocyte hypertrophy.
Combined 5-Fluorouracil/Systemic Interferon-β Gene Therapy Results in Long-Term Survival in Mice with Established Colorectal Liver Metastases
Authors: Choi Eugene A. , Lei Hanqin , Maron David J. , Mick Rosemarie , Barsoum James , Yu Qian-chun , Fraker Douglas L. , Wilson James M. , Spitz Francis R. 
Published: September 2005

Abstract
Preclinical in vitro and in vivo studies have demonstrated synergistic interactions between 5-fluorouracil (5-FU) and type I and II IFNs against human colorectal cancer cells. Despite these activities, randomized human trials have failed to identify a clinical benefit for this combination treatment. These limited clinical results may be secondary to the short half-life of recombinant IFN protein and the increased systemic toxicities of 5-FU/IFN combinations. We have previously reported an adenoviral-mediated IFN-β gene therapy strategy, which may circumvent the pitfalls of recombinant IFN therapy. However, a dose-dependent toxicity and acute inflammatory response to systemically administered adenovirus vectors may limit the clinical application of this therapy. The combination of adenoviral-mediated IFN-β gene therapy and 5-FU resulted in tumor regression, apoptosis, and improved survival in an established liver metastases model. These therapeutic effects were observed at a significantly lower vector dose than we had previously reported and with limited toxicity. This approach may allow for an effective clinical application of this therapy and warrants additional investigation.
Clinical Significance of Immunocytochemical Detection of Tumor Cells Using Digital Microscopy in Peripheral Blood and Bone Marrow of Breast Cancer Patients
Authors: Pierga Jean-Yves , Bonneton Charlyne , Vincent-Salomon Anne , de Cremoux Patricia , Nos Claude , Blin Nathalie , Pouillart Pierre , Thiery Jean-Paul , Magdelénat Henri 
Published: September 2005

Abstract
Purpose: The presence of tumor cells in bone marrow has been reported to represent an important prognostic indicator in breast cancer, but the clinical significance of circulating cells in peripheral blood is less well known. The aim of this study was to evaluate the feasibility of identifying cytokeratin (CK)-expressing cells in peripheral blood with an automat-assisted immunohistochemical detection system and to compare it with detection of tumor cells in bone marrow samples.
Experimental Design: Cytospun Ficoll fractions of peripheral blood and bone marrow were obtained simultaneously in 114 breast cancer patients at different stages of the disease (I to IV) before treatment with chemotherapy. The pancytokeratin (CK) monoclonal antibody A45-B/B3 (anti-CKs 8, 18, and 19) was used for epithelial cell detection. Immunostained cells were detected by an automated cellular imaging system (ChromaVision Medical System).
Results: CK+ cells were detected in 28 (24.5%) patients in blood and in 67 (59%) patients in bone marrow. Twenty-six (93%) patients with CK-positive cells in blood also had positive bone marrow (P &lt; 0.001). Positive cells were detected in peripheral blood in 3/39 (7.5%) operable breast cancers (stage I/II), 9 of 36 (25%) locally advanced breast cancers (stage III), and 16 of 39 (41%) patients with metastatic disease (stage IV; P = 0.017). In the subgroup of nonmetastatic patients (n = 75), prognostic factors for poor disease-free survival were: absence of estrogen receptor; presence of CK+ cells in bone marrow (P = 0.012); clinical nodal involvement; large tumor size (T4); and presence of tumor emboli. Presence of circulating CK+ cells in the peripheral blood was not statistically correlated with disease-free survival. On multivariate analysis, independent indicators for disease-free survival were: absence of estrogen receptor (P = 0.043) and presence of CK+ cells in bone marrow (P = 0.076).
Conclusions: The clinical relevance of circulating epithelial cells as a prognostic factor is not supported by the present data, especially in comparison with tumor cells in the bone marrow. However, this method of detection may be useful to monitor the efficacy of treatment in advanced or metastatic breast cancer.
Prognostic Value of CD40 in Adult Soft Tissue Sarcomas
Authors: Ottaiano Alessandro , De Chiara Anna , Perrone Francesco , Botti Gerardo , Fazioli Flavio , De Rosa Vincenzo , Mozzillo Nicola , Ravo Vincenzo , Morrica Brunello , Gallo Ciro , Pisano Carmela , Napolitano Maria , Ascierto Paolo Antonio , Iaffaioli Rosario Vincenzo , Apice Gaetano 
Published: September 2005

Abstract
Purpose: The purpose is to evaluate the expression of CD40, a membrane protein predominantly expressed on B cells, dendritic cells, and macrophages, in a series of adult soft tissue sarcomas and to test its possible prognostic value.
Experimental Design: CD40 expression was studied by immunohistochemistry. Correlations with other baseline characteristics of patients and tumors were analyzed with χ2 test. The prognostic value was studied with univariable and multivariable analysis adjusted by age, sex, tumor size, grade, location, and distant metastases.
Results: Eighty-two patients, between January 1994 and May 2001, were analyzed. Membrane or cytoplasmic staining for CD40 protein was absent in 30% of the tumors but present in &lt;10% of cells in 22 (27%), in 10% to 50% in 23 (28%), and in &gt;50% of cells in 12 (15%) tumors. There was no correlation between CD40 expression and age, sex, size, grade, and location of the primary tumor and distant metastases. With 61 patients (74.4%) progressed and 31 (37.8%) dead, CD40 expression was a significant prognostic factor for disease-free and overall survival at univariable and multivariable analysis. Patients with tumors expressing CD40 in &gt;50% of cells had a dramatically unfavorable prognosis with median disease-free and overall survival of 7 and 17 months, respectively, and hazard ratios of relapse and death as compared with patients with CD40-negative tumors of 2.89 (95% confidence interval: 1.26–6.60) and 6.92 (95% confidence interval: 2.18–22.0), respectively.
Conclusions: These data suggest that expression of CD40 protein in &gt;50% of cells might indicate an unfavorable prognosis in adult soft tissue sarcomas.
Quantitative
TP73
Transcript Analysis in Hepatocellular Carcinomas
Authors: Stiewe Thorsten , Tuve Sebastian , Peter Martin , Tannapfel Andrea , Elmaagacli Ahmet H. , Pützer Brigitte M. 
Published: September 2005

Abstract
Purpose: The p53 family member p73 displays significant homology to p53, but data from primary tumors demonstrating increased expression levels of p73 in the absence of any gene mutations argue against a classical tumor suppressor function. A detailed analysis of the p73 protein in tumor tissues has revealed expression of two classes of p73 isoforms. Whereas the proapoptotic, full-length, transactivation-competent p73 protein (TA-p73) has a putative tumor suppressor activity similar to p53, the antiapoptotic, NH2-terminally truncated, transactivation-deficient p73 protein (ΔTA-p73) has been shown to possess oncogenic activity. The oncogenic proteins can be generated by the following two different mechanisms: (a) aberrant splicing (p73Δex2, p73Δex2/3, ΔN′-p73) and (b) alternative promoter usage of a second intronic promoter (ΔN-p73). The purpose of our study was to elucidate the origin of ΔTA-p73 isoforms in hepatocellular carcinomas.
Experimental Design: We analyzed the underlying mechanisms of p73 overexpression in cancer cells by quantification of p73 transcripts from 10 hepatocellular carcinoma patients using isoform-specific real-time reverse transcription-PCR.
Results: Our data demonstrate that only aberrantly spliced ΔTA-p73 transcripts from the TA promoter show significantly increased expression levels in the tumor whereas the ΔN-p73 transcript generated from the second promoter is not significantly up-regulated.
Conclusions: Although we only analyzed 10 patient samples the results strongly suggest that the elevated activity of the first promoter (TA promoter) accounts for high-level expression of both full-length TA-p73 and aberrantly spliced ΔTA-p73 isoforms in hepatocellular carcinoma tissues.
Phase I and Pharmacokinetic Study of the Polyamine Synthesis Inhibitor SAM486A in Combination with 5-Fluorouracil/ Leucovorin in Metastatic Colorectal Cancer
Authors: van Zuylen Lia , Bridgewater John , Sparreboom Alex , Eskens Ferry A. L. M. , de Bruijn Peter , Sklenar Ivo , Planting Andre S. T. , Choi Les , Bootle Douglas , Mueller Christian , Ledermann Jonathan A. , Verweij Jaap 
Published: September 2005

AbstractPurpose: The purpose of our study was to determine the maximum-tolerated dose, dose-limiting toxicity, safety profile, and pharmacokinetics of the polyamine synthesis inhibitor SAM486A given in combination with 5-fluorouracil/leucovorin (5-FU/LV) in cancer patients.Experimental Design: Patients with advanced colorectal cancer were treated with 5-FU [bolus (400 mg/m2) followed by a 22-h infusion (600 mg/m2)] and LV (200 mg/m2) and escalating doses of SAM486A, 1–3-h infusion daily for 3 days. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of the combinationResults: Twenty-seven patients with metastatic colorectal cancer and 1 with pseudomyxoma peritonei were treated. Twenty-six patients received SAM486A in the combination at doses ranging from 25 to 150 mg/m2/day. Dose-limiting toxicity consisting of fatigue grade 3 was seen at 150 mg/m2/day. Other adverse events included neutropenia, hand and foot syndrome, nausea, vomiting, diarrhea, and constipation. Fifteen of 26 patients evaluable for best response according to the Southwest Oncology Group criteria achieved a partial response [8 (30%) of 26] or stable disease [9 (35%) of 26]. SAM486A did not influence the pharmacokinetics of 5-FU, and SAM486A clearance was similar to that when used as a single agent.Conclusions: The novel molecular agent SAM486A is tolerable and safe in combination with a standard 5-FU regimen in patients with advanced colorectal cancer. The dose of SAM486A recommended for additional studies with this combination is 125 mg/m2/day. A disease-directed evaluation of SAM486A using this regimen is warranted.
Expression of Trypsinogen-1, Trypsinogen-2, and Tumor-Associated Trypsin Inhibitor in Ovarian Cancer
Authors: Paju Annukka , Vartiainen Juhani , Haglund Caj , Itkonen Outi , von Boguslawski Kristina , Leminen Arto , Wahlström Torsten , Stenman Ulf-Håkan 
Published: September 2005

Abstract
Purpose: The purpose is to study the prognostic significance of tissue expression of trypsinogen-1, trypsinogen-2, and tumor-associated trypsin inhibitor (TATI) and serum concentration of trypsinogen-2, trypsin-2-API (complex of trypsin-2 with α-1-proteinase inhibitor), and TATI in epithelial ovarian cancer.
Experimental Design: Expression of trypsinogen-1, trypsinogen-2, and TATI was determined by immunohistochemistry with monoclonal antibodies in tissue sections of tumors from 119 patients with untreated primary epithelial ovarian cancer. Preoperative serum concentrations of trypsinogen-2, trypsin-2-API and TATI were analyzed using specific immunoassays.
Results: Fifty-four percent of the tumors expressed trypsinogen-1, 45% expressed trypsinogen-2, and 30% expressed TATI. In patients with stage III and IV disease, TATI tissue expression (P = 0.002) and elevated TATI concentration in serum (P = 0.048) were associated with adverse cancer-specific and progression-free survival in univariate analysis. In multivariate analysis, TATI tissue expression (P = 0.005), tumor grade (P = 0.0001), histological type (P = 0.02), and stage (P = 0.0005) were independent prognostic factors for adverse cancer-specific survival and TATI tissue expression (P = 0.006) and grade (P = 0.0003) for progression-free survival. In multivariate analysis of all patients and those with advanced disease, serum trypsin-2-API concentration was an adverse prognostic factor for cancer-specific and progression-free survival, and it was independent of stage and histological type of the tumor (P ≤ 0.01).
Conclusions: Tissue expression of TATI and an elevated preoperative serum concentration of trypsin-2-API are strong independent prognostic factors in advanced epithelial ovarian cancer. These results suggest that trypsin expression plays a role in the progression of ovarian cancer. TATI and trypsin-2-API are of potential use as an aid for stratification of randomized studies and for selecting treatment strategies.