bluuebunny/crossref_metadata_2025_split huggingface dataset:
PhoPQ-Mediated Regulation Produces a More Robust Permeability Barrier in the Outer Membrane ofSalmonella entericaSerovar Typhimurium
Authors: Murata Takeshi , Tseng Will , Guina Tina , Miller Samuel I. , Nikaido Hiroshi 
Published: August 2007

ABSTRACTThe PhoPQ two-component system ofSalmonella entericaserovar Typhimurium produces a remodeling of the lipid A domain of the lipopolysaccharide, including the PagP-catalyzed addition of palmitoyl residue, the PmrAB-regulated addition of the cationic sugar 4-aminoarabinose and phosphoethanolamine, and the LpxO-catalyzed addition of a 2-OH group onto one of the fatty acids. By using the diffusion rates of the dyes ethidium, Nile red, and eosin Y across the outer membrane, as well as the susceptibility of cells to large, lipophilic agents, we evaluated the function of this membrane as a permeability barrier. We found that the remodeling process in PhoP-constitutive strains produces an outer membrane that serves as a very effective permeability barrier in an environment that is poor in divalent cations or that contains cationic peptides, whereas its absence inphoPnull mutants produces an outer membrane severely compromised in its barrier function under these conditions. Removing combinations of the lipid A-remodeling functions from a PhoP-constitutive strain showed that the known modification reactions explain a major part of the PhoPQ-regulated changes in permeability. We believe that the increased barrier property of the remodeled bilayer is important in making the pathogen more resistant to the stresses that it encounters in the host, including attack by the cationic antimicrobial peptides. On the other hand, drug-induced killing assays suggest that the outer membrane containing unmodified lipid A may serve as a better barrier in the presence of high concentrations (e.g., 5 mM) of Mg2+.
Osmolality, Temperature, and Membrane Lipid Composition Modulate the Activity of Betaine Transporter BetP in
Corynebacterium glutamicum
Authors: Özcan Nuran , Ejsing Christer S. , Shevchenko Andrej , Lipski Andrej , Morbach Susanne , Krämer Reinhard 
Published: August 2007

ABSTRACT

The gram-positive soil bacterium
Corynebacterium glutamicum
, a major amino acid-producing microorganism in biotechnology, is equipped with several osmoregulated uptake systems for compatible solutes, which is relevant for the physiological response to osmotic stress. The most significant carrier, BetP, is instantly activated in response to an increasing cytoplasmic K
+
concentration. Importantly, it is also activated by chill stress independent of osmotic stress. We show that the activation of BetP by both osmotic stress and chill stress is altered in
C. glutamicum
cells grown at and adapted to low temperatures. BetP from cold-adapted cells is less sensitive to osmotic stress. In order to become susceptible for chill activation, cold-adapted cells in addition needed a certain amount of osmotic stimulation, indicating that there is cross talk of these two types of stimuli at the level of BetP activity. We further correlated the change in BetP regulation properties in cells grown at different temperatures to changes in the lipid composition of the plasma membrane. For this purpose, the glycerophospholipidome of
C. glutamicum
grown at different temperatures was analyzed by mass spectrometry using quantitative multiple precursor ion scanning. The molecular composition of glycerophospholipids was strongly affected by the growth temperature. The modulating influence of membrane lipid composition on BetP function was further corroborated by studying the influence of artificial modulation of membrane dynamics by local anesthetics and the lack of a possible influence of internally accumulated betaine on BetP activity.
Cj0011c, a Periplasmic Single- and Double-Stranded DNA-Binding Protein, Contributes to Natural Transformation in
Campylobacter jejuni
Authors: Jeon Byeonghwa , Zhang Qijing 
Published: August 2007

ABSTRACT

Campylobacter jejuni
is an important bacterial pathogen causing gastroenteritis in humans.
C. jejuni
is capable of natural transformation, which is considered a major mechanism mediating horizontal gene transfer and generating genetic diversity. Despite recent efforts to elucidate the transformation mechanisms of
C. jejuni
, the process of DNA binding and uptake in this organism is still not well understood. In this study, we report a previously unrecognized DNA-binding protein (Cj0011c) in
C. jejuni
that contributes to natural transformation. Cj0011c is a small protein (79 amino acids) with a partial sequence homology to the C-terminal region of ComEA in
Bacillus subtilis
. Cj0011c bound to both single- and double-stranded DNA. The DNA-binding activity of Cj0011c was demonstrated with a variety of DNAs prepared from
C. jejuni
or
Escherichia coli
, suggesting that the DNA binding of Cj0011c is not sequence dependent. Deletion of the cj0011c gene from
C. jejuni
resulted in 10- to 50-fold reductions in the natural transformation frequency. Different from the
B. subtilis
ComEA, which is an integral membrane protein, Cj0011c is localized in the periplasmic space of
C. jejuni
. These results indicate that Cj0011c functions as a periplasmic DNA receptor contributing to the natural transformation of
C. jejuni
.
Frequent nuclear expression of β-catenin protein but rareβ-cateninmutation in pulmonary sclerosing haemangioma
Authors: Chiang P-M , Yuan R-H , Hsu H-C , Mao T-L , Hu R-H , Lai P-L , Jeng Y-M 
Published: August 2007

Background:Pulmonary sclerosing haemangioma (PSH) is an uncommon tumour that is composed of glandular/papillary lining cells and polygonal cells. The biological behaviour of this tumour has been investigated; however, the molecular pathogenesis of PSH remains unknown.Aims:To characterise the role of the Wnt/β-catenin pathway in the genesis of PSH.Methods:37 PSH samples were investigated immunohistochemically for detection of the β-catenin protein and direct sequencing of exon 3 of theβ-cateningene.Results:Nuclear expression of β-catenin was found in the lining component of 23 tumours (62%) and in the polygonal component of 11 tumours (30%). The expression of β-catenin was stronger in the lining component, but weaker in the polygonal component. Interestingly, all the tumours with expression of β-catenin in the polygonal component also expressed β-catenin in the lining component. However, mutation of exon 3 of theβ-cateningene was detected in only one tumour that expressed nuclear β-catenin in lining and polygonal components.Conclusions:The Wnt/β-catenin pathway is involved in the genesis of PSH, but mutation of exon 3 of theβ-cateningene rarely contributes to the activation of the Wnt/β-catenin pathway in PSH.
Value of multicolour fluorescence in situ hybridisation (UroVysion) in the differential diagnosis of flat urothelial lesions
Authors: Schwarz S , Rechenmacher M , Filbeck T , Knuechel R , Blaszyk H , Hartmann A , Brockhoff G 
Published: August 2007

Aims:During the past 10 years, multitarget fluorescence in situ hybridisation has been established as a valuable adjunct in the cytological diagnosis of precancerous and malignant lesions of the urinary tract. The aim of the present study was to define its value in detecting chromosomal imbalances in patients with various flat urothelial lesions in routine paraffin-embedded bladder biopsy samples. In addition, the HER2 gene amplification and HER2 expression pattern were examined, since alterations of the HER2 expression patterns have been demonstrated in invasive bladder cancer.Methods:29 samples of normal urothelium and 86 flat urothelial lesions (hyperplasia, reactive atypia, dysplasia and carcinoma in situ (CIS)) from 73 patients were analysed patients using tissue microarrays and centromeric probes for chromosomes 3, 7 and 17, and gene-specific probes for 9p21/P16 and HER2 (UroVysion, PathVysion). The expression of HER2 was studied by immunohistochemistry.Results:Polysomy of at least one of the chromosomes was found in about half of the dysplastic cells, and in more than 90% of cells in CIS or cells in invasive bladder tumours. Polysomic cells were found in only 17% of urothelial hyperplasia, reactive atypia and normal urothelium of healthy patients, whereas about 30% of non-neoplastic lesions in patients with concomitant urothelial carcinoma showed polysomy of at least one chromosome. These alterations indicate a field effect and are associated with synchronous development of dysplastic lesions of a higher grade. Deletion of the P16 locus was most frequently observed in aneuploid lesions, whereas overexpression of HER2 was found in 10–20% of invasive urothelial carcinomas, and only occasionally in CIS (5%). An altered HER2 expression pattern was present in non-neoplastic lesions (25%).Conclusions:UroVysion fluorescence in situ hybridisation is a valuable tool for the detection of genetically unstable flat urothelial lesions, and can help to resolve difficult cases, particularly the differential diagnosis of reactive atypia and dysplasia.
Small bowel gastric metaplasia: a report of three cases in children
Authors: Drut R , Altamirano E 
Published: August 2007

Aims:To report three children displaying gastric metaplasia antral pyloric type of the small bowel mucosa.Methods:Analysis of clinical, histopathological and immunohistochemical data.Results:The first patient was a 14-year-old girl with history of chronic intestinal pseudo-obstruction and chronic jejunitis; the second patient was a 6-year-old girl with a long-lasting jejunostomy; and the third patient was a 5-year-old girl with ileal–rectal anastomosis. The foci of gastric metaplasia were obvious with H&E-stained sections. The cells at the gastric metaplasia mucosa proved to be MUC-1 and sialyl-Tn positive by immunohistochemistry and they were in a pattern that was different from that of the adjacent mucosa; the cells were autofluorescent in H&E-stained sections.Conclusions:Gastric metaplasia of the small bowel mucosa in these cases seems to have resulted from chronic inflammation and persistent regenerative activity. This has rarely been reported outside Crohn disease, and if ever in children.
Sequential Down-regulation of E-Cadherin with Squamous Cell Carcinoma Progression: Loss of E-Cadherin via a Prostaglandin E2-EP2–Dependent Posttranslational Mechanism
Authors: Brouxhon Sabine , Kyrkanides Stephanos , O'Banion M. Kerry , Johnson Renee , Pearce David A. , Centola Gina M. , Miller Jen-nie H. , McGrath Kieran H. , Erdle Brandon , Scott Glynis , Schneider Sandra , VanBuskirk JoAnne , Pentland Alice P. 
Published: August 2007

Abstract
The incidence of skin cancer is on the rise, with over 1 million new cases yearly. Although it is known that squamous cell cancers (SCC) are caused by UV light, the mechanism(s) involved remains poorly understood. In vitro studies with epithelial cells or reports examining malignant skin lesions suggest that loss of E-cadherin–mediated cell-cell contacts may contribute to SCCs. Other studies show a pivotal role for cyclooxygenase-dependent prostaglandin E2 (PGE2) synthesis in this process. Using chronically UV-irradiated SKH-1 mice, we show a sequential loss of E-cadherin–mediated cell-cell contacts as lesions progress from dysplasia to SCCs. This E-cadherin down-regulation was also evident after acute UV exposure in vivo. In both chronic and acute UV injury, E-cadherin levels declined at a time when epidermal PGE2 synthesis was enhanced. Inhibition of PGE2 synthesis by indomethacin in vitro, targeted deletion of EP2 in primary mouse keratinocyte (PMK) cultures or deletion of the EP2 receptor in vivo abrogated this UV-induced E-cadherin down-regulation. In contrast, addition of PGE2 or the EP2 receptor agonist butaprost to PMK produced a dose- and time-dependent decrease in E-cadherin. We also show that UV irradiation, via the PGE2-EP2 signaling pathway, may initiate tumorigenesis in keratinocytes by down-regulating E-cadherin–mediated cell-cell contacts through its mobilization away from the cell membrane, internalization into the cytoplasm, and shuttling through the lysosome and proteasome degradation pathways. Further understanding of how UV-PGE2-EP2 down-regulates E-cadherin may lead to novel chemopreventative strategies for the treatment of skin and other epithelial cancers. [Cancer Res 2007;67(16):7654–64]
Up-regulation of 14-3-3ζ in Lung Cancer and Its Implication as Prognostic and Therapeutic Target
Authors: Fan Tao , Li Ruiyun , Todd Nevins W. , Qiu Qi , Fang Hong-Bin , Wang Huijun , Shen Jianjun , Zhao Richard Y. , Caraway Nancy P. , Katz Ruth L. , Stass Sanford A. , Jiang Feng 
Published: August 2007

Abstract
A functional genomic approach integrating microarray and proteomic analyses done in our laboratory has identified 14-3-3ζ as a putative oncogene whose activation was common and driven by its genomic amplification in lung adenocarcinomas. 14-3-3ζ is believed to function in cell signaling, cycle control, and apoptotic death. Following our initial finding, here, we analyzed its expression in lung tumor tissues obtained from 205 patients with various histologic and stage non–small cell lung cancers (NSCLC) using immunohistochemistry and then explored the effects of specific suppression of the gene in vitro and in a xenograft model using small interfering RNA. The increased 14-3-3ζ expression was positively correlated with a more advanced pathologic stage and grade of NSCLCs (P = 0.001 and P = 0.006, respectively) and was associated with overall and cancer-specific survival rates of the patients (P = 0.022 and P = 0.018, respectively). Down-regulation of 14-3-3ζ in lung cancer cells led to a dose-dependent increased sensitivity to cisplatin-induced cell death, which was associated with the inhibition of cell proliferation and increased G2-M arrest and apoptosis. The result was further confirmed in the animal model, which showed that the A549 lung cancer cells with reduced 14-3-3ζ grew significantly slower than the wild-type A549 cells after cisplatin treatment (P = 0.008). Our results suggest that 14-3-3ζ is a potential target for developing a prognostic biomarker and therapeutics that can enhance the antitumor activity of cisplatin for NSCLC. [Cancer Res 2007;67(16):7901–6]
The let-7 MicroRNA Represses Cell Proliferation Pathways in Human Cells
Authors: Johnson Charles D. , Esquela-Kerscher Aurora , Stefani Giovanni , Byrom Mike , Kelnar Kevin , Ovcharenko Dmitriy , Wilson Mike , Wang Xiaowei , Shelton Jeffrey , Shingara Jaclyn , Chin Lena , Brown David , Slack Frank J. 
Published: August 2007

Abstract
MicroRNAs play important roles in animal development, cell differentiation, and metabolism and have been implicated in human cancer. The let-7 microRNA controls the timing of cell cycle exit and terminal differentiation in Caenorhabditis elegans and is poorly expressed or deleted in human lung tumors. Here, we show that let-7 is highly expressed in normal lung tissue, and that inhibiting let-7 function leads to increased cell division in A549 lung cancer cells. Overexpression of let-7 in cancer cell lines alters cell cycle progression and reduces cell division, providing evidence that let-7 functions as a tumor suppressor in lung cells. let-7 was previously shown to regulate the expression of the RAS lung cancer oncogenes, and our work now shows that multiple genes involved in cell cycle and cell division functions are also directly or indirectly repressed by let-7. This work reveals the let-7 microRNA to be a master regulator of cell proliferation pathways. [Cancer Res 2007;67(16):7713–22]
The Development and Characterization of a Human Midgut Carcinoid Cell Line
Authors: Van Buren George , Rashid Asif , Yang Anthony D. , Abdalla Eddie K. , Gray Michael J. , Liu Wenbiao , Somcio Ray , Fan Fan , Camp E. Ramsay , Yao James C. , Ellis Lee M. 
Published: August 2007

Abstract
Purpose: Gastrointestinal neuroendocrine tumors (NET) are rare heterogeneous tumors that hypersecrete neuropeptides. The scarcity of good gastrointestinal NET models has limited the ability to study potential therapeutic agents. We describe and characterize the establishment of a human midgut carcinoid tumor cell line carcinoid tumor 2 (CNDT2).
Experimental Design: Tumor cells (CNDT2) were isolated from a liver metastasis from a patient with a primary ileal carcinoid. After 9 weeks in culture, the cells were plated in soft agar, and cells from a single colony were put back in culture (CNDT2.1). Those CNDT2.1 cells were injected s.c. into nude mice. Cells were isolated from a single resultant tumor (CNDT2.5), cultured, and characterized by electron microscopy, reverse transcription-PCR, serotonin enzyme immunoassay, Western blotting, and immunohistochemical analysis for NET markers and potential therapeutic targets.
Results: CNDT2 cells grew in monolayers in vitro, formed colonies in soft agar, and formed tumors in mice. Electron microscopy revealed round, pleomorphic, electron-dense neurosecretory granules characteristic of NETs. Tumor xenografts exhibited the appearance of NETs with small “salt-and-pepper” nuclei on H&E staining and chromogranin A, synaptophysin, and CD56 on immunohistochemical staining. CNDT2.5 cells produced serotonin and expressed insulin-like growth factor receptor-I, platelet-derived growth factor receptor-β, vascular endothelial growth factor receptor-1, cMET, epidermal growth factor receptor, neuropilin-1, and somatostatin receptors 1 to 5. Cytogenetic analysis revealed the presence of deletions at 2p and 6q and numerous translocations.
Conclusion: The establishment of this human midgut carcinoid tumor cell line may serve as a useful model system for studying cell biology and novel targeted agents in preclinical models.
Hydroxamic Acid Analogue Histone Deacetylase Inhibitors Attenuate Estrogen Receptor-α Levels and Transcriptional Activity: A Result of Hyperacetylation and Inhibition of Chaperone Function of Heat Shock Protein 90
Authors: Fiskus Warren , Ren Yuan , Mohapatra Alex , Bali Purva , Mandawat Aditya , Rao Rekha , Herger Bryan , Yang Yonghua , Atadja Peter , Wu Jie , Bhalla Kapil 
Published: August 2007

Abstract
Purpose: The molecular chaperone heat shock protein (hsp)-90 maintains estrogen receptor (ER)-α in an active conformation, allowing it to bind 17β-estradiol (E2) and transactivate genes, including progesterone receptor (PR)-β and the class IIB histone deacetylase HDAC6. By inhibiting HDAC6, the hydroxamic acid analogue pan-HDAC inhibitors (HA-HDI; e.g., LAQ824, LBH589, and vorinostat) induce hyperacetylation of the HDAC6 substrates α-tubulin and hsp90. Hyperacetylation of hsp90 inhibits its chaperone function, thereby depleting hsp90 client proteins. Here, we determined the effect of HA-HDIs on the levels and activity of ERα, as well as on the survival of ERα-expressing, estrogen-responsive human breast cancer MCF-7 and BT-474 cells.
Experimental Design: Following exposure to HA-HDIs, hsp90 binding, polyubiquitylation levels, and transcriptional activity of ERα, as well as apoptosis and loss of survival, were determined in MCF-7 and BT-474 cells.
Results: Treatment with HA-HDI induced hsp90 hyperacetylation, decreased its binding to ERα, and increased polyubiquitylation and depletion of ERα levels. HA-HDI treatment abrogated E2-induced estrogen response element-luciferase expression and attenuated PRβ and HDAC6 levels. Exposure to HA-HDI also depleted p-Akt, Akt, c-Raf, and phospho-extracellular signal–regulated kinase-1/2 levels, inhibited growth, and sensitized ERα-positive breast cancer cells to tamoxifen.
Conclusions: These findings show that treatment with HA-HDI abrogates ERα levels and activity and could sensitize ERα-positive breast cancers to E2 depletion or ERα antagonists.
Secreted Frizzled-Related Protein 1 Loss Contributes to Tumor Phenotype of Clear Cell Renal Cell Carcinoma
Authors: Gumz Michelle L. , Zou Hongzhi , Kreinest Pamela A. , Childs April C. , Belmonte Leandra S. , LeGrand Shauna N. , Wu Kevin J. , Luxon Bruce A. , Sinha Mala , Parker Alexander S. , Sun L-Z. , Ahlquist David A. , Wood Christopher G. , Copland John A. 
Published: August 2007

Abstract
Purpose: Incidence and mortality rates for renal cell carcinoma (RCC) have been rising for decades. Unfortunately, the molecular events that support RCC carcinogenesis remain poorly understood. In an effort to gain a better understanding of signaling events in clear cell RCC (cRCC), we investigated the antitumor activity of secreted frizzled-related protein 1 (sFRP1), a negative regulator of Wnt signaling.
Experimental Design: Genomic profiling of cRCC tumors and patient-matched normal tissues was done and confirmed using quantitative PCR and immunohistochemistry. Methylation-specific PCR was done on patient samples to evaluate the mechanism responsible for sFRP1 loss. sFRP1 expression was restored in cRCC cells and the effects on tumor phenotype were characterized.
Results: Genomic profiling, quantitative PCR, and immunohistochemistry indicated that loss of sFRP1 occurred in cRCC and papillary RCC patient tissues. Twelve Wnt-regulated genes were up-regulated in cRCC tissues, including c-myc and cyclin D1, potentiators of cell proliferation and survival. Methylation of the sFRP1 gene was one mechanism identified for attenuation of sFRP1 mRNA. Stable reexpression of sFRP1 in cRCC cells resulted in decreased expression of Wnt target genes, decreased growth in cell culture, inhibition of anchorage-independent growth, and decreased tumor growth in athymic nude mice.
Conclusions: To our knowledge, this is the first report to show that stable restoration of sFRP1 expression in cRCC cells attenuates the cRCC tumor phenotype. Our data support a role for sFRP1 as a tumor suppressor in cRCC and that perhaps loss of sFRP1 is an early, aberrant molecular event in renal cell carcinogenesis.
Vascular Endothelial Growth Factor-Trap Overcomes Defects in Dendritic Cell Differentiation but Does Not Improve Antigen-Specific Immune Responses
Authors: Fricke Ingo , Mirza Noweeda , Dupont Jakob , Lockhart Craig , Jackson Autumn , Lee Ji-Hyun , Sosman Jeffrey A. , Gabrilovich Dmitry I. 
Published: August 2007

AbstractPurpose: Induction of antitumor immune responses requires adequate function of dendritic cells. Dendritic cell defects in cancer patients have been implicated in tumor escape and the limited efficacy of cancer vaccines. Previous studies have shown that vascular endothelial growth factor (VEGF) plays a major role in abnormal dendritic cell differentiation and function in cancer. It has been proposed that inhibition of VEGF may result in improved immune responses. The goal of this study was to test this hypothesis.Experimental Design: Fifteen patients with refractory solid tumors were enrolled into a phase I clinical trial of VEGF-Trap. Phenotype and function of different subsets of mononuclear cells were measured before and at different time points after the start of treatment.Results: VEGF-Trap treatment did not affect the total population of dendritic cells, their myeloid or plasmacytoid subsets, myeloid-derived suppressor cells (MDSC), or regulatory T cells. It significantly increased the proportion of mature dendritic cells. However, that improvement was not associated with an overall increase in immune responses to various antigens and mitogens. A subset analysis revealed significant improvement in immune responses in patients who had no increase in the proportion of MDSC. An improvement in immune responses was absent in patients with an increase in the proportion of MDSC.Conclusions: Inhibition of VEGF signaling may improve differentiation of dendritic cells in cancer patients. However, it was not sufficient to improve immune responses. This shows multifaceted nature of immune deficiency and points out to the need for complex approach to modulation of immune reactivity in cancer.