bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Growth-Promoting and Stress Response Activities of the
Bacillus subtilis
GTP Binding Protein Obg Are Separable by Mutation
Authors: Kuo Shrin , Demeler Borries , Haldenwang W. G. 
Published: August 2008

ABSTRACT

Bacillus subtilis
Obg is a ribosome-associating GTP binding protein that is needed for growth, sporulation, and induction of the bacterium's general stress regulon (GSR). It is unclear whether the roles of Obg in sporulation and stress responsiveness are direct or a secondary effect of its growth-promoting functions. The present work addresses this question by an analysis of two
obg
alleles whose phenotypes argue for direct roles for Obg in each process. The first allele [
obg
(
G92D
)] encodes a missense change in the protein's highly conserved “obg fold” region. This mutation impairs cell growth and the ability of Obg to associate with ribosomes but fails to block sporulation or the induction of the GSR. The second
obg
mutation [
obg
(Δ
22
)] replaces the 22-amino-acid carboxy-terminal sequence of Obg with an alternative 26-amino-acid sequence. This Obg variant cofractionates with ribosomes and allows normal growth but blocks sporulation and impairs the induction of the GSR. Additional experiments revealed that the block on sporulation occurs early, preventing the activation of the essential sporulation transcription factor Spo0A, while inhibition of the GSR appears to involve a failure of the protein cascade that normally activates the GSR to effectively catalyze the reactions needed to activate the GSR transcription factor (σ
B
).
COOH-Terminal Truncated HBV X Protein Plays Key Role in Hepatocarcinogenesis
Authors: Ma Ning-Fang , Lau Sze Hang , Hu Liang , Xie Dan , Wu Jun , Yang Jun , Wang Yi , Wu Meng-Chao , Fung Jackie , Bai Xueyan , Tzang Chi-Hung , Fu Li , Yang Mengsu , Su Yan An , Guan Xin-Yuan 
Published: August 2008

Abstract
Purpose: X protein (HBx), a product of hepatitis B virus, has been closely associated with the development of hepatocellular carcinoma (HCC). Based on observations that the COOH-terminal truncated HBx was frequently detected in HCC, the aim of this study is to evaluate the function of COOH-terminal truncated HBx in hepatocarcinogenesis.
Experimental Design: Expression pattern of HBx was analyzed by immunohistochemistry on tissue microarray containing 194 pairs of HCCs and their matched nontumor liver tissues. MIHA and HepG2 cells transfected with full-length (X2) and COOH-terminal truncated HBx (X1) were tested for their ability to grow in soft agar and form tumors in vivo. Proliferation and apoptosis were assessed using 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt and terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling assays, respectively. To gain additional insight, the expression profile of HepG2-X2 and HepG2-X1 were compared using cDNA microarray.
Results: COOH-terminal truncated HBx was frequently detected in HCCs (79.3%, n = 111), and our in vitro and in vivo studies showed that the truncated rather than the full-length HBx could effectively transform immortalized liver cell line MIHA. Interestingly, expression profiling revealed differential expression of key genes implicated in the control of cell cycle and apoptosis.
Conclusions: These findings strongly suggest that the COOH-terminal truncated HBx plays a critical role in the HCC carcinogenesis via the activation of cell proliferation.
Clinical-Translational Approaches to the Nm23-H1 Metastasis Suppressor
Authors: Steeg Patricia S. , Horak Christine E. , Miller Kathy D. 
Published: August 2008

AbstractNm23-H1 significantly reduces metastasis without effects on primary tumor size and was the first discovered metastasis suppressor gene. At least three mechanisms are thought to contribute to the metastasis-suppressive effect of Nm23-H1: (a) its histidine kinase activity toward ATP-citrate lyase, aldolase C, and the kinase suppressor of ras, with the last inactivating mitogen-activated protein kinase signaling; (b) binding proteins that titer out “free” Nm23-H1 and inhibit its ability to suppress metastasis; and (c) altered gene expression downstream of Nm23-H1, particularly an inverse association with the lysophosphatidic acid receptor endothelial differentiation gene-28 (EDG2). Most metastasis suppressor genes, including Nm23-H1, affect metastatic colonization, which is the outgrowth of tumor cells in distant locations; therefore, they are of high translational interest. A phase II trial is ongoing to test the hypothesis that a compound, high-dose medroxyprogesterone acetate (MPA), used as an unconventional gluocorticoid, will stimulate breast cancer cells to reexpress Nm23-H1 and limit subsequent metastatic colonization.
Enhanced Antitumor Therapy by Inhibition of p21waf1 in Human Malignant Mesothelioma
Authors: Lazzarini Raffaella , Moretti Simona , Orecchia Sara , Betta Pier-Giacomo , Procopio Antonio , Catalano Alfonso 
Published: August 2008

Abstract
Purpose: The p21 cyclin-dependent kinase inhibitor was frequently expressed in human malignant pleural mesothelioma (MPM) tissues as well as cell lines. Recent data indicate that p21 keeps tumor cells alive after DNA damage, favoring a survival advantage. In this study, we assessed the possibility of p21 suppression as a therapeutic target for MPM.
Experimental Design: We established two different MPM-derived (from H28 and H2052 cells) subclones using vector-based short hairpin RNA (shRNA). Then, chemosensitivity against low doses of antineoplastic DNA-damaging agents was investigated by colony formation assays, and furthermore, the type of cell response induced by these drugs was analyzed. To examine the effect of p21 shRNA on chemosensitivity in vivo, tumor formation assays in nude mice were done.
Results: In colony formation assay, the IC50 of doxorubicin was 33 ± 3.0 nmol/L in p21 shRNA-transfected cells with respect to 125 ± 10 nmol/L of control vector–transfected cells. This enhancement of growth inhibition was achieved by converting a senescence-like growth arrest to apoptosis in response to doxorubicin, etoposide, and CPT11. In the in vivo assays, CPT11 and loss-of-expression of p21 in combination led to considerable suppression of tumor growth associated with a substantially enhanced apoptotic response, whereas CPT11 alone was ineffective at inducing these responses.
Conclusions: These results indicated that p21 might play an important role in chemosensitivity to anticancer agents, and the suppression of its expression might be a potential therapeutic target for MPM.
Incidence and Prognostic Impact of FoxP3+ Regulatory T Cells in Human Gliomas
Authors: Heimberger Amy B. , Abou-Ghazal Mohamed , Reina-Ortiz Chantal , Yang David S. , Sun Wei , Qiao Wei , Hiraoka Nobuyoshi , Fuller Gregory N. 
Published: August 2008

AbstractPurpose: The incidence of regulatory T cells (Treg) in intrinsic central nervous system malignancies is unknown. Immunotherapeutic approaches that inhibit the Treg population may be limited to a subset of patients with gliomas. Our hypothesis is that only the most malignant gliomas have a prominent glioma-infiltrating Treg population that contributes to the immunosuppressive biology and that the presence of Tregs is a negative prognostic variable.Experimental Design: We measured the incidence of Tregs in 135 glial tumors (including all pathologic types) in a glioma microarray using immunohistochemical analysis. Results were categorized according to the total number of Tregs within the tumors. Correlation of the presence of Tregs with prognosis was evaluated using univariate and multivariate analyses.Results: Tregs were not present in normal brain tissue and were very rarely found in low-grade gliomas and oligodendrogliomas. We observed significant differences in the prevalence of Tregs between astrocytic and oligodendroglial tumors, between tumors of different grades, and between different pathologic types of tumors. We identified Tregs most frequently in glioblastoma multiforme (GBM) but very rarely in low-grade astrocytomas. The presence of Tregs within GBMs did not alter the median survival in patients from whom the tumors were obtained.Conclusions: Treg infiltration differed significantly in the tumors according to lineage, pathology, and grade. Tregs seemed to have the highest predilection for tumors of the astrocytic lineage and specifically in the high-grade gliomas, such as GBM. In both univariate and multivariate analysis, the presence of Tregs in GBMs seemed to be prognostically neutral.
Survivin: Key Regulator of Mitosis and Apoptosis and Novel Target for Cancer Therapeutics
Authors: Mita Alain C. , Mita Monica M. , Nawrocki Steffan T. , Giles Francis J. 
Published: August 2008

Abstract
Survivin, a member of the family of inhibitor of apoptosis proteins, functions as a key regulator of mitosis and programmed cell death. Initially, survivin was described as an inhibitor of caspase-9. However, over the last years, research studies have shown that the role of survivin in cancer pathogenesis is not limited to apoptosis inhibition but also involves the regulation of the mitotic spindle checkpoint and the promotion of angiogenesis and chemoresistance. Survivin gene expression is transcriptionally repressed by wild-type p53 and can be deregulated in cancer by several mechanisms, including gene amplification, hypomethylation, increased promoter activity, and loss of p53 function. This article reviews the multiple functions of survivin in the regulation of apoptosis, the promotion of tumorigenesis, and the development of survivin inhibitors as a novel anticancer therapeutic strategy.
Effect of Speaking Rate on the Identification of Word Boundaries
Authors: Schwab Sandra , Miller Joanne L. , Grosjean François , Mondini Michèle 
Published: August 2008

Abstract
Two experiments were conducted to determine whether listeners’ ability to use allophonic variation to identify word boundaries is influenced by speaking rate. Listeners in both experiments were presented two-word sequences (such as great eyes) spoken by naturally fast and naturally slow talkers; in one experiment the sequences were presented in quiet and in the other they were presented in noise. The listeners’ task was to identify the intended sequence from among four choices with alternative segmentations (e.g. great eyes, gray ties, great ties, gray eyes). In both experiments performance was worse for the sequences produced by the naturally fast talkers than for those produced by the naturally slow talkers. This finding suggests that the extent to which allophonic variation contributes to the identification of word boundaries may depend on the rate at which the speech was produced.
Le Logos et l'empereur, nouveaux Orphée « Postérité d'une image entrée dans la littérature avec Clément d'Alexandrie »
Authors: Jourdan Fabienne 
Published: August 2008

AbstractIn the Protrepticus, Clement of Alexandria suggests Orpheus' song is a prefiguration of the power of the Word. In the fourth century A. D., Eusebius and Themistius will apply this interpretation of Orpheus' song respectively to the Logos and to the Emperor. In the image proposed by Eusebius the Alexandrian's influence is obvious, whereas its transformation in Themistius illustrates its political evolution. An examination of these two different applications shows not only Clement's role in the transfer of a symbolic figure, but also the originality of its first Christian transposition in the Protrepticus.
Maintenance of a normal thymic microenvironment and T-cell homeostasis require Smad4-mediated signaling in thymic epithelial cells
Authors: Jeker Lukas T. , Barthlott Thomas , Keller Marcel P. , Zuklys Saulius , Hauri-Hohl Mathias , Deng Chu-Xia , Holländer Georg A. 
Published: August 2008

AbstractSignals mediated by the transforming growth factor-β superfamily of growth factors have been implicated in thymic epithelial cell (TEC) differentiation, homeostasis, and function, but a direct reliance on these signals has not been established. Here we demonstrate that a block in canonical transforming growth factor-β signaling by the loss of Smad4 expression in TECs leads to qualitative changes in TEC function and a progressively disorganized thymic microenvironment. Moreover, the number of thymus resident early T-lineage progenitors is severely reduced in the absence of Smad4 expression in TECs and directly correlates with extensive thymic and peripheral lymphopenia. Our observations hence place Smad4 within the signaling events in TECs that determine total thymus cellularity by controlling the number of early T-lineage progenitors.
Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations
Authors: Tunstall-Pedoe Oliver , Roy Anindita , Karadimitris Anastasios , de la Fuente Josu , Fisk Nicholas M. , Bennett Phillip , Norton Alice , Vyas Paresh , Roberts Irene 
Published: August 2008

Abstract
Down syndrome (DS) children have a high frequency of acute megakaryoblastic leukemia (AMKL) in early childhood. At least 2 in utero genetic events are required, although not sufficient, for DS-AMKL: trisomy 21 (T21) and N-terminal–truncating GATA1 mutations. To investigate the role of T21 in DS-AMKL, we compared second trimester hemopoiesis in DS without GATA1 mutations to gestation-matched normal controls. In all DS fetal livers (FLs), but not marrows, megakaryocyte-erythroid progenitor frequency was increased (55.9% ± 4% vs 17.1% ± 3%, CD34+CD38+ cells; P < .001) with common myeloid progenitors (19.6% ± 2% vs 44.0% ± 7%) and granulocyte-monocyte (GM) progenitors (15.8% ± 4% vs 34.5% ± 9%) commensurately reduced. Clonogenicity of DS-FL versus normal FL CD34+ cells was markedly increased (78% ± 7% vs 15% ± 3%) affecting megakaryocyte-erythroid (∼ 7-fold higher) and GM and colony-forming unit–granulocyte, erythrocyte macrophage, megakaryocyte (CFU-GEMM) progenitors. Replating efficiency of CFU-GEMM was also markedly increased. These data indicate that T21 itself profoundly disturbs FL hemopoiesis and they provide a testable hypothesis to explain the increased susceptibility to GATA1 mutations in DS-AMKL and DS-associated transient myeloproliferative disorder.
Evolutionary conservation of zinc finger transcription factor binding sites in promoters of genes co-expressed with WT1 in prostate cancer
Authors: Eisermann Kurtis , Tandon Sunpreet , Bazarov Anton , Brett Adina , Fraizer Gail , Piontkivska Helen 
Published: August 2008

AbstractBackgroundGene expression analyses have led to a better understanding of growth control of prostate cancer cells. We and others have identified the presence of several zinc finger transcription factors in the neoplastic prostate, suggesting a potential role for these genes in the regulation of the prostate cancer transcriptome. One of the transcription factors (TFs) identified in the prostate cancer epithelial cells was the Wilms tumor gene (WT1). To rapidly identify coordinately expressed prostate cancer growth control genes that may be regulated by WT1, we used anin silicoapproach.ResultsEvolutionary conserved transcription factor binding sites (TFBS) recognized by WT1, EGR1, SP1, SP2, AP2 and GATA1 were identified in the promoters of 24 differentially expressed prostate cancer genes from eight mammalian species. To test the relationship between sequence conservation and function, chromatin of LNCaP prostate cancer and kidney 293 cells were tested for TF binding using chromatin immunoprecipitation (ChIP). Multiple putative TFBS in gene promoters of placental mammals were found to be shared with those in human gene promoters and some were conserved between genomes that diverged about 170 million years ago (i.e., primates and marsupials), therefore implicating these sites as candidate binding sites. Among those genes coordinately expressed withWT1was the kallikrein-related peptidase 3 (KLK3) gene commonly known as the prostate specific antigen (PSA) gene. This analysis located several potential WT1 TFBS in thePSAgene promoter and led to the rapid identification of a novel putative binding site confirmedin vivoby ChIP. Conversely for two prostate growth control genes, androgen receptor (AR) and vascular endothelial growth factor (VEGF), known to be transcriptionally regulated by WT1, regulatory sequence conservation was observed and TF bindingin vivowas confirmed by ChIP.ConclusionOverall, this targeted approach rapidly identified important candidate WT1-binding elements in genes coordinately expressed with WT1 in prostate cancer cells, thus enabling a more focused functional analysis of the most likely target genes in prostate cancer progression. Identifying these genes will help to better understand how gene regulation is altered in these tumor cells.
Cigarette smoke induces endoplasmic reticulum stress and the unfolded protein response in normal and malignant human lung cells
Authors: Jorgensen Ellen , Stinson Andy , Shan Lin , Yang Jin , Gietl Diana , Albino Anthony P 
Published: August 2008

Abstract

Background
Although lung cancer is among the few malignancies for which we know the primary etiological agent (i.e., cigarette smoke), a precise understanding of the temporal sequence of events that drive tumor progression remains elusive. In addition to finding that cigarette smoke (CS) impacts the functioning of key pathways with significant roles in redox homeostasis, xenobiotic detoxification, cell cycle control, and endoplasmic reticulum (ER) functioning, our data highlighted a defensive role for the unfolded protein response (UPR) program. The UPR promotes cell survival by reducing the accumulation of aberrantly folded proteins through translation arrest, production of chaperone proteins, and increased degradation. Importance of the UPR in maintaining tissue health is evidenced by the fact that a chronic increase in defective protein structures plays a pathogenic role in diabetes, cardiovascular disease, Alzheimer's and Parkinson's syndromes, and cancer.

Methods
Gene and protein expression changes in CS exposed human cell cultures were monitored by high-density microarrays and Western blot analysis. Tissue arrays containing samples from 110 lung cancers were probed with antibodies to proteins of interest using immunohistochemistry.

Results
We show that: 1) CS induces ER stress and activates components of the UPR; 2) reactive species in CS that promote oxidative stress are primarily responsible for UPR activation; 3) CS exposure results in increased expression of several genes with significant roles in attenuating oxidative stress; and 4) several major UPR regulators are increased either in expression (i.e., BiP and eIF2α) or phosphorylation (i.e., phospho-eIF2α) in a majority of human lung cancers.

Conclusion
These data indicate that chronic ER stress and recruitment of one or more UPR effector arms upon exposure to CS may play a pivotal role in the etiology or progression of lung cancers, and that phospho-eIF2α and BiP may have diagnostic and/or therapeutic potential. Furthermore, we speculate that upregulation of UPR regulators (in particular BiP) may provide a pro-survival advantage by increasing resistance to cytotoxic stresses such as hypoxia and chemotherapeutic drugs, and that UPR induction is a potential mechanism that could be attenuated or reversed resulting in a more efficacious treatment strategy for lung cancer.
Tetratricopeptide repeat domain 9A is an interacting protein for tropomyosin Tm5NM-1
Authors: Cao Shenglan , Ho Gay Hui , Lin Valerie CL 
Published: August 2008

Abstract

Background
Tetratricopeptide repeat domain 9A (TTC9A) protein is a recently identified protein which contains three tetratricopeptide repeats (TPRs) on its C-terminus. In our previous studies, we have shown that TTC9A was a hormonally-regulated gene in breast cancer cells. In this study, we found that TTC9A was over-expressed in breast cancer tissues compared with the adjacent controls (P < 0.00001), suggesting it might be involved in the breast cancer development process. The aim of the current study was to further elucidate the function of TTC9A.

Methods
Breast samples from 25 patients including the malignant breast tissues and the adjacent normal tissues were processed for Southern blot analysis. Yeast-two-hybrid assay, GST pull-down assay and co-immunoprecipitation were used to identify and verify the interaction between TTC9A and other proteins.

Results
Tropomyosin Tm5NM-1 was identified as one of the TTC9A partner proteins. The interaction between TTC9A and Tm5NM-1 was further confirmed by GST pull-down assay and co-immunoprecipitation in mammalian cells. TTC9A domains required for the interaction were also characterized in this study. The results suggested that the first TPR domain and the linker fragment between the first two TPR domains of TTC9A were important for the interaction with Tm5NM-1 and the second and the third TPR might play an inhibitory role.

Conclusion
Since the primary function of tropomyosin is to stabilize actin filament, its interaction with TTC9A may play a role in cell shape and motility. In our previous results, we have found that progesterone-induced TTC9A expression was associated with increased cell motility and cell spreading. We speculate that TTC9A acts as a chaperone protein to facilitate the function of tropomyosins in stabilizing microfilament and it may play a role in cancer cell invasion and metastasis.
Comparison of the mismatch-specific endonuclease method and denaturing high-performance liquid chromatography for the identification of HBB gene mutations
Authors: Hung Chia-Cheng , Su Yi-Ning , Lin Chia-Yun , Chang Yin-Fei , Chang Chien-Hui , Cheng Wen-Fang , Chen Chi-An , Lee Chien-Nan , Lin Win-Li 
Published: August 2008

Abstract

Background
Beta-thalassemia is a common autosomal recessive hereditary disease in the Meditertanean, Asia and African areas. Over 600 mutations have been described in the beta-globin (HBB), of which more than 200 are associated with a beta-thalassemia phenotype.

Results
We used two highly-specific mutation screening methods, mismatch-specific endonuclease and denaturing high-performance liquid chromatography, to identify mutations in the HBB gene. The sensitivity and specificity of these two methods were compared. We successfully distinguished mutations in the HBB gene by the mismatch-specific endonuclease method without need for further assay. This technique had 100% sensitivity and specificity for the study sample.

Conclusion
Compared to the DHPLC approach, the mismatch-specific endonuclease method allows mutational screening of a large number of samples because of its speed, sensitivity and adaptability to semi-automated systems. These findings demonstrate the feasibility of using the mismatch-specific endonuclease method as a tool for mutation screening.