bluuebunny/crossref_metadata_2025_split huggingface dataset:
Local Treatment of Experimental
Pseudomonas aeruginosa
Osteomyelitis with a Biodegradable Dilactide Polymer Releasing Ciprofloxacin
Authors: Kanellakopoulou Kyriaki , Thivaios George C. , Kolia Maria , Dontas Ismini , Nakopoulou Lydia , Dounis Eleftherios , Giamarellos-Bourboulis Evangelos J. , Andreopoulos Andreas , Karagiannakos Panayotis , Giamarellou Helen 
Published: April 2008

ABSTRACT

A biodegradable system of poly-
d
,
l
-dilactide releasing ciprofloxacin was assessed in a
Pseudomonas aeruginosa
osteomyelitis model after inoculation of the test pathogen into the left tibia of 76 New Zealand White rabbits; 31 were controls (group A), and 45 were implanted with the polymer at the infection site (group B). The rabbits were killed on a weekly basis, and cancellous bone was harvested for histopathology and for estimation of bacterial growth and the concentrations of ciprofloxacin. Tibial X ray was performed immediately before the animals were killed. The total number of fistulas with purulent discharge that developed after inoculation of the pathogen was counted, and fistulas with purulent discharge were found in 16 animals in group A (51.6%) and 3 animals in group B (6.7%) (
P
< 0.0001). The animals in group A had a profound loss of body weight compared to the animals in group B. The main radiological finding was the presence of sequestra in 25 animals (80.6%) in group A and 6 animals in group B (13.3%) (
P
< 0.0001). The bacterial load in group B was significantly reduced compared to that in group A, possibly due to the prolonged local antibiotic release at concentrations exceeding even 80 times the MIC for the test pathogen. The histology of animals killed after week 49 revealed a mild inflammatory reaction accompanied by diffuse fibrosis and new bone formation in group A animals and the presence of small polymer particles in group B animals. It is concluded that the system described achieved eradication of the pathogen, accompanied by clinical and radiologically confirmed benefits, so this treatment may be a candidate for the management of difficult orthopedic infections.
Whole-Genome Pyrosequencing of an Epidemic Multidrug-Resistant
Acinetobacter baumannii
Strain Belonging to the European Clone II Group
Authors: Iacono Michele , Villa Laura , Fortini Daniela , Bordoni Roberta , Imperi Francesco , Bonnal Raoul J. P. , Sicheritz-Ponten Thomas , De Bellis Gianluca , Visca Paolo , Cassone Antonio , Carattoli Alessandra 
Published: April 2008

ABSTRACT

The whole-genome sequence of an epidemic, multidrug-resistant
Acinetobacter baumannii
strain (strain ACICU) belonging to the European clone II group and carrying the plasmid-mediated
bla
OXA
-
58
carbapenem resistance gene was determined. The
A. baumannii
ACICU genome was compared with the genomes of
A. baumannii
ATCC 17978 and
Acinetobacter baylyi
ADP1, with the aim of identifying novel genes related to virulence and drug resistance.
A. baumannii
ACICU has a single chromosome of 3,904,116 bp (which is predicted to contain 3,758 genes) and two plasmids, pACICU1 and pACICU2, of 28,279 and 64,366 bp, respectively. Genome comparison showed 86.4% synteny with
A. baumannii
ATCC 17978 and 14.8% synteny with
A. baylyi
ADP1. A conspicuous number of transporters belonging to different superfamilies was predicted for
A. baumannii
ACICU. The relative number of transporters was much higher in ACICU than in ATCC 17978 and ADP1 (76.2, 57.2, and 62.5 transporters per Mb of genome, respectively). An antibiotic resistance island, AbaR2, was identified in ACICU and had plausibly evolved by reductive evolution from the AbaR1 island previously described in multiresistant strain
A. baumannii
AYE. Moreover, 36 putative alien islands (pAs) were detected in the ACICU genome; 24 of these had previously been described in the ATCC 17978 genome, 4 are proposed here for the first time and are present in both ATCC 17978 and ACICU, and 8 are unique to the ACICU genome. Fifteen of the pAs in the ACICU genome encode genes related to drug resistance, including membrane transporters and ex novo acquired resistance genes. These findings provide novel insight into the genetic basis of
A. baumannii
resistance.
Utilization of an Intracellular Bacterial Community Pathway inKlebsiella pneumoniaeUrinary Tract Infection and the Effects of FimK on Type 1 Pilus Expression
Authors: Rosen David A. , Pinkner Jerome S. , Jones Jennifer M. , Walker Jennifer N. , Clegg Steven , Hultgren Scott J. 
Published: April 2008

ABSTRACTKlebsiella pneumoniaeis an important cause of urinary tract infection (UTI), but little is known about its pathogenesis in vivo. The pathogenesis of theK. pneumoniaecystitis isolate TOP52 was compared to that of the uropathogenicEscherichia coli(UPEC) isolate UTI89 in a murine cystitis model. Bladder and kidney titers of TOP52 were lower than those of UTI89 at early time points but similar at later time points. TOP52, like UTI89, formed biofilm-like intracellular bacterial communities (IBCs) within the murine bladder, albeit at significantly lower levels than UTI89. Additionally, filamentation of TOP52 was observed, a process critical for UTI89 evasion of neutrophil phagocytosis and persistence in the bladder. Thus, the IBC pathway is not specific to UPEC alone. We investigated if differences in type 1 pilus expression may explain TOP52's early defect in vivo. The type 1 pilus operon is controlled by recombinase-mediated (fimE,fimB, andfimX) phase variation of an invertible promoter element. We found thatK. pneumoniaecarries an extra gene of unknown function at the 3′ end of its type 1 operon,fimK, and the genome lacks the recombinasefimX. A deletion mutant offimKwas constructed, and TOP52 ΔfimKhad higher titers and formed more IBCs in the murine cystitis model than wild type. The loss offimKor expression ofE. coli fimXfrom a plasmid in TOP52 resulted in a larger phase-ON population and higher expression levels of type 1 pili and gave TOP52 the ability to form type 1-dependent biofilms. Complementation with pfimKdecreased type 1 pilus expression and biofilm formation of TOP52 ΔfimKand decreased UTI89 biofilm formation. Thus,K. pneumoniaeappears programmed for minimal expression of type 1 pili, which may explain, in part, whyK. pneumoniaeis a less prevalent etiologic agent of UTI than UPEC.
gp96 Is a Human Colonocyte Plasma Membrane Binding Protein for
Clostridium difficile
Toxin A
Authors: Na Xi , Kim Ho , Moyer Mary P. , Pothoulakis Charalabos , LaMont J. Thomas 
Published: April 2008

ABSTRACT

Clostridium difficile
toxin A (TxA), a key mediator of antibiotic-associated colitis, requires binding to a cell surface receptor prior to internalization. Our aim was to identify novel plasma membrane TxA binding proteins on human colonocytes. TxA was coupled with biotin and cross-linked to the surface of HT29 human colonic epithelial cells. The main colonocyte binding protein for TxA was identified as glycoprotein 96 (gp96) by coimmunoprecipitation and mass spectrum analysis. gp96 is a member of the heat shock protein family, which is expressed on human colonocyte apical membranes as well as in the cytoplasm. TxA binding to gp96 was confirmed by fluorescence immunostaining and in vitro coimmunoprecipitation. Following TxA binding, the TxA-gp96 complex was translocated from the cell membrane to the cytoplasm. Pretreatment with gp96 antibody decreased TxA binding to colonocytes and inhibited TxA-induced cell rounding. Small interfering RNA directed against gp96 reduced gp96 expression and cytotoxicity in colonocytes. TxA-induced inflammatory signaling via p38 and apoptosis as measured by activation of BAK (Bcl-2 homologous antagonist/killer) and DNA fragmentation were decreased in gp96-deficient B cells. We conclude that human colonocyte gp96 serves as a plasma membrane binding protein that enhances cellular entry of TxA, participates in cellular signaling events in the inflammatory cascade, and facilitates cytotoxicity.
Perceived anxiety and plasma cortisol concentrations following rock climbing with differing safety rope protocols
Authors: Hodgson C I , Draper N , McMorris T , Jones G , Fryer S , Coleman I 
Published: April 2008

Objectives:To examine how different safety rope protocols impact on subjective anxiety and self-confidence levels and plasma cortisol concentrations and the relationship between subjective states and cortisol during rock climbing.Methods:Participants (n = 12) were tested in three climbing conditions that were designed to invoke low, moderate and high physical and mental stress. Plasma cortisol concentrations were collected before and after climbing and participants reported subjective anxiety and self-confidence states for each climb.Results:Repeated measures analysis of variance showed significant differences between conditions for somatic anxiety (F2, 22 = 7.74, p = 0.009), self-confidence (F2, 22 = 9.52, p = 0.001) and change in plasma cortisol concentration (F2, 22 = 3.71, p = 0.041). Preplanned polynomial comparisons showed that these were linear effects; somatic anxiety was higher in the higher stress conditions whilst self-confidence was lower. Plasma cortisol concentration change was also linear. Regression analyses showed cubic relationships between plasma cortisol concentration and cognitive anxiety (R2 = 0.452), self-confidence (R2 = 0.281) and somatic anxiety (R2 = 0.268).Conclusions:There is a relationship between plasma cortisol concentration and subjective anxiety and self-confidence states during rock climbing. Changes in the way the safety rope is organised can impact on anxiety, cortisol concentration and self-confidence during rock climbing.
Modeling the CD8+ T Effector to Memory Transition in Adoptive T-Cell Antitumor Immunotherapy
Authors: Rolle Cleo E. , Carrio Roberto , Malek Thomas R. 
Published: April 2008

AbstractAdoptive T-cell therapy with CD8+ CTLs is often characterized by poor persistence of the transferred T cells and limited effector responses. Improved persistence and therapeutic efficacy have been noted when antigen-activated CD8+ T cells express properties of memory cells. The current study was undertaken to more precisely characterize the development of memory-like CD8+ T cells from short-term CTLs in vitro and upon transfer in vivo, including their antitumor activity. Ovalbumin (OVA)–specific OT-I CTLs acquired phenotypic and functional properties of memory cells 2 to 3 days later either by lowering the concentration of antigen to a level that does not support primary responses and providing a survival signal through transgenic Bcl-2 in vitro or simply by transferring early day 3 CTLs to antigen-free lymphoid-replete mice. In lymphoid-replete mice, established OVA-expressing E.G7 tumor was rejected by short-term CTLs that simultaneously acquired memory-like properties in secondary lymphoid tissues, where tumor antigen level remained low. Collectively, these data indicate that CTLs readily converted to memory-like cells upon lowering antigen to a concentration that selectively supports memory responses and suggest that such conversion predicts successful adoptive immunotherapy. [Cancer Res 2008;68(8):2984–92]
NVP-AUY922: A Novel Heat Shock Protein 90 Inhibitor Active against Xenograft Tumor Growth, Angiogenesis, and Metastasis
Authors: Eccles Suzanne A. , Massey Andy , Raynaud Florence I. , Sharp Swee Y. , Box Gary , Valenti Melanie , Patterson Lisa , de Haven Brandon Alexis , Gowan Sharon , Boxall Frances , Aherne Wynne , Rowlands Martin , Hayes Angela , Martins Vanessa , Urban Frederique , Boxall Kathy , Prodromou Chrisostomos , Pearl Laurence , James Karen , Matthews Thomas P. , Cheung Kwai-Ming , Kalusa Andrew , Jones Keith , McDonald Edward , Barril Xavier , Brough Paul A. , Cansfield Julie E. , Dymock Brian , Drysdale Martin J. , Finch Harry , Howes Rob , Hubbard Roderick E. , Surgenor Alan , Webb Paul , Wood Mike , Wright Lisa , Workman Paul 
Published: April 2008

Abstract
We describe the biological properties of NVP-AUY922, a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. NVP-AUY922 potently inhibits HSP90 (Kd = 1.7 nmol/L) and proliferation of human tumor cells with GI50 values of approximately 2 to 40 nmol/L, inducing G1-G2 arrest and apoptosis. Activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. NVP-AUY922 was glucuronidated less than previously described isoxazoles, yielding higher drug levels in human cancer cells and xenografts. Daily dosing of NVP-AUY922 (50 mg/kg i.p. or i.v.) to athymic mice generated peak tumor levels at least 100-fold above cellular GI50. This produced statistically significant growth inhibition and/or regressions in human tumor xenografts with diverse oncogenic profiles: BT474 breast tumor treated/control, 21%; A2780 ovarian, 11%; U87MG glioblastoma, 7%; PC3 prostate, 37%; and WM266.4 melanoma, 31%. Therapeutic effects were concordant with changes in pharmacodynamic markers, including induction of HSP72 and depletion of ERBB2, CRAF, cyclin-dependent kinase 4, phospho-AKT/total AKT, and hypoxia-inducible factor-1α, determined by Western blot, electrochemiluminescent immunoassay, or immunohistochemistry. NVP-AUY922 also significantly inhibited tumor cell chemotaxis/invasion in vitro, WM266.4 melanoma lung metastases, and lymphatic metastases from orthotopically implanted PC3LN3 prostate carcinoma. NVP-AUY922 inhibited proliferation, chemomigration, and tubular differentiation of human endothelial cells and antiangiogenic activity was reflected in reduced microvessel density in tumor xenografts. Collectively, the data show that NVP-AUY922 is a potent, novel inhibitor of HSP90, acting via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. NVP-AUY922 has entered phase I clinical trials. [Cancer Res 2008;68(8):2850–60]
The Regulatory T Cell–Associated Transcription Factor FoxP3 Is Expressed by Tumor Cells
Authors: Ebert Lisa M. , Tan Bee Shin , Browning Judy , Svobodova Suzanne , Russell Sarah E. , Kirkpatrick Naomi , Gedye Craig , Moss Denis , Ng Sweet Ping , MacGregor Duncan , Davis Ian D. , Cebon Jonathan , Chen Weisan 
Published: April 2008

Abstract
FoxP3 is a member of the forkhead family of transcription factors critically involved in the development and function of CD25+ regulatory T cells (Treg). Until recently, FoxP3 expression was thought to be restricted to the T-cell lineage. However, using immunohistochemistry and flow cytometric analysis of human melanoma tissue, we detected FoxP3 expression not only in the tumor infiltrating Treg but also in the melanoma cells themselves. FoxP3 is also widely expressed by established human melanoma cell lines (as determined by flow cytometry, PCR, and Western blot), as well as cell lines derived from other solid tumors. Normal B cells do not express FoxP3; however, expression could be induced after transformation with EBV in vitro and in vivo, suggesting that malignant transformation of healthy cells can induce FoxP3. In addition, a FOXP3 mRNA variant lacking exons 3 and 4 was identified in tumor cell lines but was absent from Treg. Interestingly, this alternative splicing event introduces a translation frame-shift that is predicted to encode a novel protein. Together, our results show that FoxP3, a key regulator of immune suppression, is not only expressed by Treg but also by melanoma cells, EBV-transformed B cells, and a wide variety of tumor cell lines. [Cancer Res 2008;68(8):3001–9]
Apoptotic Activity and Mechanism of 2-Cyano-3,12-Dioxoolean-1,9-Dien-28-Oic-Acid and Related Synthetic Triterpenoids in Prostate Cancer
Authors: Hyer Marc L. , Shi Ranxin , Krajewska Maryla , Meyer Colin , Lebedeva Irina V. , Fisher Paul B. , Reed John C. 
Published: April 2008

Abstract
Synthetic triterpenoids 2-cyano-3, 12-dioxooleana-1, 9-(11)-dien-28-oic acid (CDDO) and CDDO-Me (CDDO-methyl ester) have entered clinical trials for cancer. We determined that CDDO analogues at submicromolar concentrations induce apoptosis of cultured prostate cancer cell lines, LNCaP, ALVA31, Du145, PC3, and PPC1, with lethal dose 50% ∼1 μmol/L for CDDO-Me and an imidazole analogue (CDDO-Im). These compounds induced apoptosis of prostate cancer cells as characterized by cleavage of caspase-3, caspase-7, caspase-8, caspase-9, caspase-10, BID, and poly(ADP)ribose polymerase and by dependence on caspase activity. Moreover, triterpenoid-induced cell death was abolished by caspase-8–targeting small interfering (si) RNA. To explore the mechanism(s) involved in caspase-8 activation, we examined cell surface expression of death receptor (DR)4 and DR5 after triterpenoid treatment. Cell surface DR4 and DR5 expression was significantly up-regulated by CDDO or CDDO-Im but not by CDDO-Me. DR4 and DR5 knockdown with siRNA significantly inhibited apoptosis induced by CDDO and CDDO-Im but had no effect on CDDO-Me–induced killing, suggesting that CDDO and CDDO-Im induce apoptosis by a different mechanism than CDDO-Me. In addition to activating the caspase-8–dependent extrinsic apoptosis pathway, we observed that Bcl-XL overexpression inhibited triterpenoid-mediated killing of prostate cancer cell line Du145, suggesting that the intrinsic pathway (via mitochondria) also participates in triterpenoid-mediated killing. In vivo antitumor activity of CDDO-Me was shown using a Du145 tumor xenograft model in nude rats. Altogether, these findings suggest CDDO and related synthetic triterpenoids should be further evaluated as potential novel therapeutics for hormone refractory prostate cancers. [Cancer Res 2008;68(8):2927–33]
Genetic Variation in the Inhibin Pathway and Risk of Testicular Germ Cell Tumors
Authors: Purdue Mark P. , Graubard Barry I. , Chanock Stephen J. , Rubertone Mark V. , Erickson Ralph L. , McGlynn Katherine A. 
Published: April 2008

Abstract
Gene-knockout studies in mice suggest that INHA, encoding a subunit of gonadotropin-regulating proteins known as inhibins, is a tumor suppressor for testicular stromal cell tumors. It is not known whether genetic variation in the inhibin pathway also influences susceptibility to testicular germ cell tumors (TGCT), the most common testicular cancer in young men. To address this question, we conducted a case-control analysis (577 cases; 707 controls) of single-nucleotide polymorphisms (SNP) in genes in the inhibin pathway among participants in the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study. Thirty-eight tagging SNPs in six genes (INHA, INHBA, INHBB, INHBC, INHBE, and SMAD4) were genotyped. Odds ratios (OR) and 95% confidence intervals (CI) relating variant genotypes to TGCT risk were calculated using unconditional logistic regression. Among White subjects, an elevated risk of TGCT was observed for carriers of the T allele of the INHA variant rs2059693 (CT genotype: OR, 1.33; 95% CI, 1.04–1.71; TT: OR, 1.60; 95% CI, 1.01–2.52; Ptrend = 0.008). The association with rs2059693 was stronger for nonseminomas, and for teratomas and teratocarcinomas in particular (N = 58; CT: OR, 1.63; 95% CI, 0.89–2.99; TT: OR, 4.54; 95% CI 2.00–10.3; Ptrend = 0.0008). We found no evidence of association with variants in the other investigated genes. These findings suggest that genetic variation in the INHA locus influences TGCT development. [Cancer Res 2008;68(8):3043–8]
Broad Overexpression of Ribonucleotide Reductase Genes in Mice Specifically Induces Lung Neoplasms
Authors: Xu Xia , Page Jennifer L. , Surtees Jennifer A. , Liu Houchun , Lagedrost Sarah , Lu Young , Bronson Roderick , Alani Eric , Nikitin Alexander Yu. , Weiss Robert S. 
Published: April 2008

Abstract
Ribonucleotide reductase (RNR) catalyzes the rate-limiting step in nucleotide biosynthesis and plays a central role in genome maintenance. Although a number of regulatory mechanisms govern RNR activity, the physiologic effect of RNR deregulation had not previously been examined in an animal model. We show here that overexpression of the small RNR subunit potently and selectively induces lung neoplasms in transgenic mice and is mutagenic in cultured cells. Combining RNR deregulation with defects in DNA mismatch repair, the cellular mutation correction system, synergistically increased RNR-induced mutagenesis and carcinogenesis. Moreover, the proto-oncogene K-ras was identified as a frequent mutational target in RNR-induced lung neoplasms. Together, these results show that RNR deregulation promotes lung carcinogenesis through a mutagenic mechanism and establish a new oncogenic activity for a key regulator of nucleotide metabolism. Importantly, RNR-induced lung neoplasms histopathologically resemble human papillary adenocarcinomas and arise stochastically via a mutagenic mechanism, making RNR transgenic mice a valuable model for lung cancer. [Cancer Res 2008;68(8):2652–60]
Androgen Receptor Overexpression in Prostate Cancer Linked to Purα Loss from a Novel Repressor Complex
Authors: Wang Longgui G. , Johnson Edward M. , Kinoshita Yayoi , Babb James S. , Buckley Michael T. , Liebes Leonard F. , Melamed Jonathan , Liu Xiao-Mei , Kurek Ralf , Ossowski Liliana , Ferrari Anna C. 
Published: April 2008

Abstract
Increased androgen receptor (AR) expression and activity are pivotal for androgen-independent (AI) prostate cancer (PC) progression and resistance to androgen-deprivation therapy. We show that a novel transcriptional repressor complex that binds a specific sequence (repressor element) in the AR gene 5′-untranslated region contains Purα and hnRNP-K. Purα expression, its nuclear localization, and its AR promoter association, as determined by chromatin immunoprecipitation analysis, were found to be significantly diminished in AI-LNCaP cells and in hormone-refractory human PCs. Transfection of AI cells with a plasmid that restored Purα expression reduced AR at the transcription and protein levels. Purα knockdown in androgen-dependent cells yielded higher AR and reduced p21, a gene previously shown to be under negative control of AR. These changes were linked to increased proliferation in androgen-depleted conditions. Treatment of AI cells with histone deacetylase and DNA methylation inhibitors restored Purα protein and binding to the AR repressor element. This correlated with decreased AR mRNA and protein levels and inhibition of cell growth. Purα is therefore a key repressor of AR transcription and its loss from the transcriptional repressor complex is a determinant of AR overexpression and AI progression of PC. The success in restoring Purα and the repressor complex function by pharmacologic intervention opens a promising new therapeutic approach for advanced PC. [Cancer Res 2008;68(8):2678–88]
Down-regulation of Caspase-2 by Rottlerin via Protein Kinase C-δ–Independent Pathway
Authors: Basu Alakananda , Adkins Brett , Basu Chandreyi 
Published: April 2008

Abstract
Protein kinase C-δ (PKCδ) plays an important role in DNA damage–induced apoptosis. We have previously shown that the PKCδ inhibitor rottlerin protects against cisplatin-induced apoptosis acting upstream of caspase-9. In the present study, we have investigated if rottlerin regulates caspase-2 activation. Knockdown of caspase-2 by siRNA inhibited processing of apical caspase-9 and caspase-8, whereas depletion of caspase-9 had little effect on caspase-2 processing. Rottlerin inhibited activation and processing of caspase-9 and caspase-8 and cleavage of poly(ADP)ribose polymerase. We made a novel observation that rottlerin induced down-regulation of caspase-2 but not of caspase-3, caspase-7, caspase-8, or caspase-9. Pharmacologic inhibitors of PKC, such as Gö 6983 and bisindolylmaleimide, or depletion of PKCδ by siRNA had no effect on the down-regulation of caspase-2 by rottlerin. The proteasome inhibitor MG132 reversed caspase-2 down-regulation by rottlerin, whereas calpain inhibitor had no effect. These results suggest that rottlerin induces down-regulation of caspase-2 via PKCδ-independent but ubiquitin proteasome–mediated pathway. Furthermore, down-regulation of caspase-2 by rottlerin can explain its antiapoptotic function during DNA damage–induced apoptosis. [Cancer Res 2008;68(8):2795–802]