bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Lipopolysaccharide Core Capping Leads to Quantitative and Correlated Modifications of Mechanical and Structural Properties in
Pseudomonas aeruginosa
Biofilms
Authors: Lau Peter C. Y. , Lindhout Theresa , Beveridge Terry J. , Dutcher John R. , Lam Joseph S. 
Published: August 2009

ABSTRACT

Bacterial biofilms are responsible for the majority of all microbial infections and have profound impact on industrial and geochemical processes. While many studies documented phenotypic differentiation and gene regulation of biofilms, the importance of their structural and mechanical properties is poorly understood. Here we investigate how changes in lipopolysaccharide (LPS) core capping in
Pseudomonas aeruginosa
affect biofilm structure through modification of adhesive, cohesive, and viscoelastic properties at an early stage of biofilm development. Microbead force spectroscopy and atomic force microscopy were used to characterize
P. aeruginosa
biofilm interactions with either glass substrata or bacterial lawns. Using isogenic
migA
,
wapR
, and
rmlC
mutants with defined LPS characteristics, we observed significant changes in cell mechanical properties among these strains compared to wild-type strain PAO1. Specifically, truncation of core oligosaccharides enhanced both adhesive and cohesive forces by up to 10-fold, whereas changes in instantaneous elasticity were correlated with the presence of O antigen. Using confocal laser scanning microscopy to quantify biofilm structural changes with respect to differences in LPS core capping, we observed that textural parameters varied with adhesion or the inverse of cohesion, while areal and volumetric parameters were linked to adhesion, cohesion, or the balance between them. In conclusion, this report demonstrated for the first time that changes in LPS expression resulted in quantifiable cellular mechanical changes that were correlated with structural changes in bacterial biofilms. Thus, the interplay between architectural and functional properties may be an important contributor to bacterial community survival.
A Novel Insertion Sequence Derepresses Efflux Pump Expression and Preadapts
Pseudomonas putida
S12 for Extreme Solvent Stress
Authors: Sun Xu , Dennis Jonathan J. 
Published: August 2009

ABSTRACT

A multidrug efflux pump, SrpABC, plays a key role in
Pseudomonas putida
S12 tolerance to toxic organic solvents. SrpRS are putative regulators of the SrpABC efflux pump encoded upstream of the
srpABC
structural genes, and previous studies suggest that SrpS is a repressor of SrpABC expression. An S12 isolate able to withstand extreme solvent stress carries a novel insertion sequence, IS
Ppu21
, interrupting
srpS
. This insertion preadapts S12 to extreme solvent conditions through constitutive SrpABC expression.
A Collagen-Binding Adhesin, Acb, and Ten Other Putative MSCRAMM and Pilus Family Proteins of
Streptococcus gallolyticus
subsp.
gallolyticus
(
Streptococcus bovis
Group, Biotype I)
Authors: Sillanpää Jouko , Nallapareddy Sreedhar R. , Qin Xiang , Singh Kavindra V. , Muzny Donna M. , Kovar Christie L. , Nazareth Lynne V. , Gibbs Richard A. , Ferraro Mary J. , Steckelberg James M. , Weinstock George M. , Murray Barbara E. 
Published: August 2009

ABSTRACT

Members of the
Streptococcus bovis
group are important causes of endocarditis. However, factors associated with their pathogenicity, such as adhesins, remain uncharacterized. We recently demonstrated that endocarditis-derived
Streptococcus gallolyticus
subsp.
gallolyticus
isolates frequently adhere to extracellular matrix (ECM) proteins. Here, we generated a draft genome sequence of an ECM protein-adherent
S. gallolyticus
subsp.
gallolyticus
strain and found, by genome-wide analyses, 11 predicted LPXTG-type cell wall-anchored proteins with characteristics of MSCRAMMs, including a modular architecture of domains predicted to adopt immunoglobulin (Ig)-like folding. A recombinant segment of one of these, Acb, showed high-affinity binding to immobilized collagen, and cell surface expression of Acb correlated with the presence of
acb
and collagen adherence of isolates. Three of the 11 proteins have similarities to major pilus subunits and are organized in separate clusters, each including a second Ig-fold-containing MSCRAMM and a class C sortase, suggesting that the sequenced strain encodes three distinct types of pili. Reverse transcription-PCR demonstrated that all three genes of one cluster,
acb
-
sbs7
-
srtC1
, are cotranscribed, consistent with pilus operons of other gram-positive bacteria. Further analysis detected expression of all 11 genes in cells grown to mid to late exponential growth phases. Wide distribution of 9 of the 11 genes was observed among
S. gallolyticus
subsp.
gallolyticus
isolates with fewer genes present in other
S. bovis
group species/subspecies. The high prevalence of genes encoding putative MSCRAMMs and pili, including a collagen-binding MSCRAMM, among
S. gallolyticus
subsp.
gallolyticus
isolates may play an important role in the predominance of this subspecies in
S. bovis
endocarditis.
Mycoplasma pneumoniae
Cytoskeletal Protein HMW2 and the Architecture of the Terminal Organelle
Authors: Bose Stephanie R. , Balish Mitchell F. , Krause Duncan C. 
Published: August 2009

ABSTRACT

The terminal organelle of
Mycoplasma pneumoniae
mediates cytadherence and gliding motility and functions in cell division. The defining feature of this complex membrane-bound cell extension is an electron-dense core of two segmented rods oriented longitudinally and enlarging to form a bulb at the distal end. While the components of the core have not been comprehensively identified, previous evidence suggested that the cytoskeletal protein HMW2 forms parallel bundles oriented lengthwise to yield the major rod of the core. In the present study, we tested predictions emerging from that model by ultrastructural and immunoelectron microscopy analyses of cores from wild-type
M. pneumoniae
and mutants producing HMW2 derivatives. Antibodies specific for the N or C terminus of HMW2 labeled primarily peripheral to the core along its entire length. Furthermore, truncation of HMW2 did not correlate specifically with core length. However, mutant analysis correlated specific HMW2 domains with core assembly, and examination of core-enriched preparations confirmed that HMW2 was a major component of these fractions. Taken together, these findings yielded a revised model for HMW2 in terminal organelle architecture.
A Novel Splice Variant of GLI1 That Promotes Glioblastoma Cell Migration and Invasion
Authors: Lo Hui-Wen , Zhu Hu , Cao Xinyu , Aldrich Amy , Ali-Osman Francis 
Published: August 2009

Abstract
The family of GLI zinc finger transcription factors regulates the expression of genes involved in many important cellular processes, notably embryonal development and cellular differentiation. The glioma-associated oncogene homologue 1 (GLI1) isoform, in particular, has attracted much attention because of its frequent activation in many human cancers and its interactions with other signaling pathways, such as those mediated by K-RAS, transforming growth factor-β, epidermal growth factor receptor, and protein kinase A. Here, we report the identification of a novel truncated GLI1 splice variant, tGLI1, with an in-frame deletion of 123 bases (41 codons) spanning the entire exon 3 and part of exon 4 of the GLI1 gene. Expression of tGLI1 is undetectable in normal cells but is high in glioblastoma multiforme (GBM) and other cancer cells. Although tGLI1 undergoes nuclear translocalization and transactivates GLI1-binding sites similar to GLI1, unlike GLI1, it is associated with increased motility and invasiveness of GBM cells. Using microarray analysis, we showed &gt;100 genes to be differentially expressed in tGLI1-expressing compared with GLI1-expressing GBM cells, although both cell types expressed equal levels of known GLI1-regulated genes, such as PTCH1. We further showed one of the tGLI1 up-regulated genes, CD24, an invasion-associated gene, to be required for the migratory and invasive phenotype of GBM cells. These data provide conclusive evidence for a novel gain-of-function GLI1 splice variant that promotes migration and invasiveness of GBM cells and open up a new research paradigm on the role of the GLI1 pathway in malignancy. [Cancer Res 2009;69(17):6790–8]
Human Papillomavirus 16 E7 Oncoprotein Attenuates DNA Damage Checkpoint Control by Increasing the Proteolytic Turnover of Claspin
Authors: Spardy Nicole , Covella Kathryn , Cha Elliot , Hoskins Elizabeth E. , Wells Susanne I. , Duensing Anette , Duensing Stefan 
Published: August 2009

Abstract
The human papillomavirus (HPV) 16 E7 oncoprotein has been reported previously to stimulate DNA damage and to activate host cell DNA damage checkpoints. How HPV-16 E7 maintains proliferation despite activated DNA damage checkpoints is incompletely understood. Here, we provide evidence that cells expressing the HPV-16 E7 oncoprotein can enter mitosis in the presence of DNA damage. We show that this activity of HPV-16 E7 involves attenuation of DNA damage checkpoint control by accelerating the proteolytic turnover of claspin. Claspin mediates the activation of CHK1 by ATR in response to replication stress, and its degradation plays a critical role in DNA damage checkpoint recovery. Expression of a nondegradable mutant of claspin was shown to inhibit mitotic entry in HPV-16 E7–expressing cells. Multiple components of the SCFβ-TrCP–based claspin degradation machinery were found deregulated in the presence of HPV-16 E7, including cullin 1, β-TrCP, Aurora A, and Polo-like kinase-1 (PLK1). In contrast, no difference in the expression level of the claspin deubiquitinating enzyme USP7 was detected. Levels of Aurora A and PLK1 as well as phosphorylated PLK1 at threonine 210, a prerequisite for DNA damage checkpoint recovery, remained detectable following replication stress in HPV-16 E7–expressing cells but not in control cells. In summary, our results suggest that the HPV-16 E7 oncoprotein alleviates DNA damage checkpoint responses and promotes mitotic entry by accelerating claspin degradation through a mechanism that involves deregulation of components of the SCFβ-TrCP–based claspin degradation machinery. [Cancer Res 2009;69(17):7022–9]
Adjuvant Hormonal Therapy for Breast Cancer and Risk of Hormone Receptor–Specific Subtypes of Contralateral Breast Cancer
Authors: Li Christopher I. , Daling Janet R. , Porter Peggy L. , Tang Mei-Tzu C. , Malone Kathleen E. 
Published: August 2009

Abstract
Compared with the breast cancer risk women in the general population have, breast cancer survivors have a substantially higher risk of developing a second primary contralateral breast cancer. Adjuvant hormonal therapy reduces this risk, but preliminary data indicate that it may also increase risk of hormone receptor–negative contralateral tumors. We conducted a population-based nested case-control study including 367 women diagnosed with both first primary estrogen receptor (ER)–positive invasive breast cancer and second primary contralateral breast cancer and 728 matched control women diagnosed only with a first breast cancer. Data on adjuvant hormonal therapy, other treatments, and breast cancer risk factors were ascertained through telephone interviews and medical record abstractions. Two-sided statistical tests using conditional logistic regression were conducted to quantify associations between adjuvant hormonal therapy and risk of hormone receptor–specific subtypes of contralateral breast cancer (n = 303 ER+ and n = 52 ER− cases). Compared with women not treated with hormonal therapy, users of adjuvant tamoxifen for ≥5 years had a reduced risk of ER+ contralateral breast cancer [odds ratio, 0.4; 95% confidence interval (CI), 0.3–0.7], but a 4.4-fold (95% CI, 1.03–19.0) increased risk of ER− contralateral breast cancer. Tamoxifen use for &lt;5 years was not associated with ER− contralateral breast cancer risk. Although adjuvant hormonal therapy has clear benefits, risk of the relatively uncommon outcome of ER− contralateral breast cancer may now need to be tallied among its risks. This is of clinical concern given the poorer prognosis of ER− compared with ER+ tumors. [Cancer Res 2009;69(17):6865–70]
Multimodal Assessment of Protein Functional Deficiency Supports Pathogenicity of BRCA1 p.V1688del
Authors: De Nicolo Arcangela , Parisini Emilio , Zhong Quan , Dalla Palma Maurizia , Stoeckert Kathryn A. , Domchek Susan M. , Nathanson Katherine L. , Caligo Maria A. , Vidal Marc , Cusick Michael E. , Garber Judy E. 
Published: August 2009

Abstract
Unequivocal discrimination between neutral variants and deleterious mutations is crucial for appropriate counseling of individuals with a BRCA1 or BRCA2 sequence change. An increasing number of variants of uncertain significance (VUS) are being identified, the unclassified biological effect of which poses clinical concerns. A multifactorial likelihood–based approach recently suggested disease causality for BRCA1 p.V1688del, a VUS recurrent in Italian breast/ovarian cancer families. Whether and how this single amino acid deletion in the BRCA1 COOH terminus (BRCT) domain affects the function of the mutant protein (ΔValBRCA1) has not been elucidated. We undertook comprehensive functional characterization of ΔValBRCA1, comprising comparative structural modeling, analysis of protein stability and associations, and analysis of DNA repair function. Our model predicted BRCT domain destabilization and folding disruption caused by BRCA1 p.V1688del. Consistently, the recombinant ΔValBRCA1 was less stable than wild-type BRCA1 and, unlike the latter, failed to associate with BRIP1, CtIP, and Rap80 and to relocalize to sites of DNA damage. Yeast two-hybrid analysis revealed a compromised interaction with FHL2 and KPNA2, which is likely responsible for improper subcellular localization of ΔValBRCA1. In addition, we found four new breast/ovarian cancer families of Italian ancestry who carried this sequence alteration. These results provide the first evidence of the effect of BRCA1 p.V1688del on protein stability and function, supporting the view that it is a deleterious mutation. Multimodal analyses like ours could advance understanding of tumor suppression by BRCA1 and ultimately contribute to developing efficient strategies for screening and characterization of VUS. [Cancer Res 2009;69(17):7030–7]
Preclinical Evaluation of Novel Glutamate-Urea-Lysine Analogues That Target Prostate-Specific Membrane Antigen as Molecular Imaging Pharmaceuticals for Prostate Cancer
Authors: Hillier Shawn M. , Maresca Kevin P. , Femia Frank J. , Marquis John C. , Foss Catherine A. , Nguyen Nghi , Zimmerman Craig N. , Barrett John A. , Eckelman William C. , Pomper Martin G. , Joyal John L. , Babich John W. 
Published: August 2009

Abstract
Prostate-specific membrane antigen (PSMA) is expressed in normal human prostate epithelium and is highly up-regulated in prostate cancer. We previously reported a series of novel small molecule inhibitors targeting PSMA. Two compounds, MIP-1072, (S)-2-(3-((S)-1-carboxy-5-(4-iodobenzylamino)pentyl)ureido)pentanedioic acid, and MIP-1095, (S)-2-(3-((S)-1carboxy-5-(3-(4-iodophenyl)ureido)pentyl)ureido)pentanedioic acid, were selected for further evaluation. MIP-1072 and MIP-1095 potently inhibited the glutamate carboxypeptidase activity of PSMA (Ki = 4.6 ± 1.6 nmol/L and 0.24 ± 0.14 nmol/L, respectively) and, when radiolabeled with 123I, exhibited high affinity for PSMA on human prostate cancer LNCaP cells (Kd = 3.8 ± 1.3 nmol/L and 0.81 ± 0.39 nmol/L, respectively). The association of [123I]MIP-1072 and [123I]MIP-1095 with PSMA was specific; there was no binding to human prostate cancer PC3 cells, which lack PSMA, and binding was abolished by coincubation with a structurally unrelated NAALADase inhibitor, 2-(phosphonomethyl)pentanedioic acid (PMPA). [123I]MIP-1072 and [123I]MIP-1095 internalized into LNCaP cells at 37°C. Tissue distribution studies in mice showed 17.3 ± 6.3% (at 1 hour) and 34.3 ± 12.7% (at 4 hours) injected dose per gram of LNCaP xenograft tissue, for [123I]MIP-1072 and [123I]MIP-1095, respectively. [123I]MIP-1095 exhibited greater tumor uptake but slower washout from blood and nontarget tissues compared with [123I]MIP-1072. Specific binding to PSMA in vivo was shown by competition with PMPA in LNCaP xenografts, and the absence of uptake in PC3 xenografts. The uptake of [123I]MIP-1072 and [123I]MIP-1095 in tumor-bearing mice was corroborated by single-photon emission computed tomography/computed tomography (SPECT/CT) imaging. PSMA-specific radiopharmaceuticals should provide a novel molecular targeting option for the detection and staging of prostate cancer. [Cancer Res 2009;69(17):6932–40]
2009 Biospecimen Research Network Symposium: Advancing Cancer Research through Biospecimen Science
Authors: Moore Helen M. , Compton Carolyn C. , Lim Mark D. , Vaught Jimmie , Christiansen Katerina N. , Alper Joe 
Published: August 2009

Abstract
This report details the proceedings of the 2009 Biospecimen Research Network (BRN) Symposium that took place on March 16 to 18, 2009, the second in a series of annual symposia sponsored by the National Cancer Institute Office of Biorepositories and Biospecimen Research. The BRN Symposium is a public forum addressing the relevance of biospecimen quality to progress in cancer research and the systematic investigation needed to understand how different methods of collection, processing, and storage of human biospecimens affect subsequent molecular research results. More than 300 participants from industry, academia, and government attended the symposium, which featured both formal presentations and a day of workshops aimed at addressing several key issues in biospecimen science. An additional 100 individuals participated via a live webcast (archived at http://brnsymposium.com). The BRN Symposium is part of a larger program designed as a networked, multidisciplinary research approach to increase the knowledge base for biospecimen science. Biospecimens are generally understood to represent an accurate representation of a patient's disease biology, but can instead reflect a combination of disease biology and the biospecimen's response to a wide range of biological stresses. The molecular signatures of disease can thus be confounded by the signatures of biospecimen biological stress, with the potential to affect clinical and research outcomes through incorrect diagnosis of disease, improper use of a given therapy, and irreproducible research results that can lead to misinterpretation of artifacts as biomarkers. Biospecimen research represents the kind of bricks-and-mortar research that provides a solid scientific foundation for future advances that will directly help patients. [Cancer Res 2009;69(17):6770–2]
The Role of Vascular Endothelial Growth Factor Genetic Variability in Cancer
Authors: Schneider Bryan P. , Radovich Milan , Miller Kathy D. 
Published: August 2009

Abstract
Angiogenesis is a hallmark of tumor pathogenesis. Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis and its inhibition has become a successful approach to antitumor therapy across tumor types. The VEGF gene is highly polymorphic with multiple common single nucleotide polymorphisms (SNPs) in the promoter, 5′ untranslated region and 3′ untranslated region. There is evidence that these SNPs in the regulatory regions can affect VEGF expression. In vitro and in vivo data show that genetic variability affects the activity and expression of VEGF. Case-control and cohort studies suggest that genetic variability may affect risk and outcome of a variety of disease states that are tightly regulated by angiogenesis. Recently, genetic variability in VEGF has been studied as a potential predictive biomarker for bevacizumab. The VEGF-1154 AA and -2578 AA genotypes predicted an improved median overall survival, whereas the VEGF-634 CC and -1498 TT genotypes predicted protection from grade 3-4 hypertension in the pivotal trial, E2100. If validated, these finding could help direct which subgroup of patients should receive bevacizumab. (Clin Cancer Res 2009;15(17):5297–302)
Cyclin D1 Splice Variants: Polymorphism, Risk, and Isoform-Specific Regulation in Prostate Cancer
Authors: Comstock Clay E.S. , Augello Michael A. , Benito Ruth Pe , Karch Jason , Tran Thai H. , Utama Fransiscus E. , Tindall Elizabeth A. , Wang Ying , Burd Craig J. , Groh Eric M. , Hoang Hoa N. , Giles Graham G. , Severi Gianluca , Hayes Vanessa M. , Henderson Brian E. , Le Marchand Loic , Kolonel Laurence N. , Haiman Christopher A. , Baffa Raffaele , Gomella Leonard G. , Knudsen Erik S. , Rui Hallgeir , Henshall Susan M. , Sutherland Robert L. , Knudsen Karen E. 
Published: August 2009

Abstract
Purpose: Alternative CCND1 splicing results in cyclin D1b, which has specialized, protumorigenic functions in prostate not shared by the cyclin D1a (full length) isoform. Here, the frequency, tumor relevance, and mechanisms controlling cyclin D1b were challenged.
Experimental Design: First, relative expression of both cyclin D1 isoforms was determined in prostate adenocarcinomas. Second, relevance of the androgen axis was determined. Third, minigenes were created to interrogate the role of the G/A870 polymorphism (within the splice site), and findings were validated in primary tissue. Fourth, the effect of G/A870 on cancer risk was assessed in two large case-control studies.
Results: Cyclin D1b is induced in tumors, and a significant subset expressed this isoform in the absence of detectable cyclin D1a. Accordingly, the isoforms showed noncorrelated expression patterns, and hormone status did not alter splicing. Whereas G/A870 was not independently predictive of cancer risk, A870 predisposed for transcript-b production in cells and in normal prostate. The influence of A870 on overall transcript-b levels was relieved in tumors, indicating that aberrations in tumorigenesis likely alter the influence of the polymorphism.
Conclusions: These studies reveal that cyclin D1b is specifically elevated in prostate tumorigenesis. Cyclin D1b expression patterns are distinct from that observed with cyclin D1a. The A870 allele predisposes for transcript-b production in a context-specific manner. Although A870 does not independently predict cancer risk, tumor cells can bypass the influence of the polymorphism. These findings have major implications for the analyses of D-cyclin function in the prostate and provide the foundation for future studies directed at identifying potential modifiers of the G/A870 polymorphism. (Clin Cancer Res 2009;15(17):5338–49)
Complexity of CEBPA Dysregulation in Human Acute Myeloid Leukemia
Authors: Pabst Thomas , Mueller Beatrice U. 
Published: August 2009

Abstract
The transcription factor CCAAT enhancer binding protein alpha (CEBPA) is crucial for normal development of granulocytes. Various mechanisms have been identified how CEBPA function is dysregulated in patients with acute myeloid leukemia (AML). In particular, dominant-negative mutations located either at the N- or the C terminus of the CEBPA gene are observed in roughly 10% of AML patients, either in the combination on separate alleles or as sole mutation. Clinically significant complexity exists among AML with CEBPA mutations, and patients with double CEBPA mutations seem to have a more favorable course of the disease than patients with a single mutation. In addition, myeloid precursor cells of healthy carriers with a single germ-line CEBPA mutation evolve to overt AML by acquiring a second sporadic CEBPA mutation. This review summarizes recent reports on dysregulation of CEBPA function at various levels in human AML and therapeutic concepts targeting correction of CEBPA activity. The currently available data are persuasive evidence that impaired CEBPA function contributes directly to the development of AML, whereas restoring CEBPA function represents a promising target for novel therapeutic strategies in AML. (Clin Cancer Res 2009;15(17):5303–7)