bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Nongenomic Activation of Phosphatidylinositol 3-Kinase/Akt and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase/Extracellular Signal-Regulated Kinase 1/2 Pathways in 1,25D3-Mediated Apoptosis in Squamous Cell Carcinoma Cells
Authors: Ma Yingyu , Yu Wei-Dong , Kong Rui-Xian , Trump Donald L. , Johnson Candace S. 
Published: August 2006

Abstract
Vitamin D is a steroid hormone that regulates calcium homeostasis and bone metabolism. The active form of vitamin D [1α,25-dihydroxyvitamin D3 (1,25D3)] acts through both genomic and nongenomic pathways. 1,25D3 has antitumor effects in a variety of cancers, including colorectal, prostate, breast, ovarian, and skin cancers. 1,25D3 exerts growth-inhibitory effects in cancer cells through the induction of apoptosis, cell cycle arrest, and differentiation. The mechanisms regulating 1,25D3-induced apoptosis remain unclear. We investigated the role of nongenomic signaling in 1,25D3-mediated apoptosis in squamous cell carcinoma (SCC) cells. 1,25D3 induced rapid and sustained activation of phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) 1/2 pathways in SCC cells. These effects were nongenomic: they occurred rapidly and were not inhibited by cycloheximide or actinomycin D. To examine whether the nongenomic activation of Akt and ERK1/2 plays a role in 1,25D3-mediated apoptosis, the expression of Akt or ERK1/2 was reduced by small interfering RNA (siRNA). siRNA-Akt significantly enhanced 1,25D3-induced apoptosis as indicated by increased levels of Annexin V–positive cells and increased sub-G1 population and DNA fragmentation. In contrast, siRNA-ERK1/2 had no effects on 1,25D3-induced apoptosis. In addition, siRNA-Akt transfection followed by 1,25D3 treatment induced apoptosis much sooner than 1,25D3 alone. siRNA-Akt and 1,25D3 induced caspase-10 activation, suppressed the expression of c-IAP1 and XIAP, and promoted 1,25D3-induced caspase-3 activation. These results support a link between 1,25D3-induced nongenomic signaling and apoptosis. 1,25D3 induces the activation of phosphatidylinositol 3-kinase/Akt, which suppresses 1,25D3-mediated apoptosis and prolongs the survival of SCC cells. (Cancer Res 2006; 66(16): 8131-8)
Spontaneous Fusion with, and Transformation of Mouse Stroma by, Malignant Human Breast Cancer Epithelium
Authors: Jacobsen Britta M. , Harrell J. Chuck , Jedlicka Paul , Borges Virginia F. , Varella-Garcia Marileila , Horwitz Kathryn B. 
Published: August 2006

Abstract
Adenocarcinoma cells from the pleural effusion of a patient with breast cancer were injected into the mammary glands of nude mice and grown into solid tumors. A cell line derived from these tumors expressed α-smooth muscle actin but not human cytokeratin 7, indicating “activated” stroma of mouse origin. Cells in mitosis exhibited mainly polyploid mouse karyotypes, but 30% had mixed mouse and human chromosomes, among which 8% carried mouse/human translocations. Nuclei of interphase cells were 64% hybrid. Hybrid mouse/human nuclei were also detected in the primary xenograft. Thus, synkaryons formed in the solid tumor by spontaneous fusion between the malignant human epithelium and the surrounding normal host mouse stroma. The transformed stroma-derived cells are tumorigenic with histopathologic features of malignancy, suggesting a new mechanism for tumor progression. (Cancer Res 2006; 66(16): 8274-9)
Emergence of Androgen Independence at Early Stages of Prostate Cancer Progression in Nkx3.1; Pten Mice
Authors: Gao Hui , Ouyang Xuesong , Banach-Petrosky Whitney A. , Shen Michael M. , Abate-Shen Cory 
Published: August 2006

Abstract
Although androgen deprivation therapy is a widely used treatment for patients with advanced prostate cancer, it ultimately results in the emergence of a hormone-refractory disease that is invariably fatal. To provide insights into the genesis of this disease, we have employed an in vivo model to investigate how and when prostate epithelial cells can acquire the ability to survive and proliferate in the absence of androgens. In particular, we have been studying the evolution of androgen independence in Nkx3.1; Pten mutant mice, which develop prostatic intraepithelial neoplasia and adenocarcinoma as a consequence of aging, as well as androgen-independent phenotypes following castration. We now find that the prostate epithelial cells from these Nkx3.1; Pten mutant mice are capable of surviving and proliferating in the absence of androgens and that they develop androgen-independent phenotypes well before they display overt prostatic intraepithelial neoplasia or cancer phenotypes. Our findings in this mouse model show that acquisition of androgen independence can be uncoupled from overt cancer progression and raise the possibility that hormone-refractory disease can arise at early stages of prostate carcinogenesis. (Cancer Res 2006; 66(16): 7929-33)
GRP78 as a Novel Predictor of Responsiveness to Chemotherapy in Breast Cancer
Authors: Lee Eunjung , Nichols Peter , Spicer Darcy , Groshen Susan , Yu Mimi C. , Lee Amy S. 
Published: August 2006

Abstract
The discovery of predictive factors for chemoresistance is critical for improving adjuvant therapy for cancer patients. The 78-kDa glucose-regulated protein (GRP78), widely used as an indicator of the unfolded protein response (UPR), is induced in the tumor microenvironment. In vitro studies suggest that GRP78 confers chemoresistance to topoisomerase inhibitors, such as Adriamycin (doxorubicin). Here, we report on a retrospective cohort study of 127 stage II and III breast cancer patients who were treated with Adriamycin-based chemotherapy. Archival tumor specimens were available for analysis and the relationship of GRP78 expression level to “time to recurrence” (TTR), used as a surrogate marker for drug resistance, was examined. Our data show that 67% of the study subjects expressed high level of GRP78 in their tumors before the initiation of chemotherapy and suggest an association between GRP78 positivity and shorter TTR [hazard ratio (HR), 1.78; P = 0.16]. Interestingly, subgroup analysis reveals that the HR for the GRP78-positive group increased significantly among patients who did not receive further taxane treatment (HR, 3.00; P = 0.022) and among mastectomy patients (HR, 3.33; P = 0.027). The HR was even stronger among mastectomy patients who did not receive further taxane treatment (HR, 4.82; P = 0.010). The use of GRP78 as a predictor for chemoresponsiveness and the potential interaction of GRP78 and/or the UPR pathways with taxanes warrant larger studies. (Cancer Res 2006; 66(16): 7849-53)
Tsc1Haploinsufficiency without Mammalian Target of Rapamycin Activation Is Sufficient for Renal Cyst Formation inTsc1+/− Mice
Authors: Wilson Catherine , Bonnet Cleo , Guy Carol , Idziaszczyk Shelley , Colley James , Humphreys Vikki , Maynard Julie , Sampson Julian R. , Cheadle Jeremy P. 
Published: August 2006

AbstractTuberous sclerosis complex (TSC) is caused by mutations in either the TSC1 or TSC2 gene. Both genes are generally considered to act as tumor suppressors that fulfill Knudson's “two-hit hypothesis” and that function within the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin (mTOR) pathway. We previously generated Tsc1+/− mice that are predisposed to renal cysts, which develop into cystadenomas and renal cell carcinomas. Here, we identified somatic Tsc1 mutations (second hits) in ∼80% of cystadenomas and renal cell carcinomas, but only 31.6% of cysts from Tsc1+/− mice (P &lt; 0.0003), raising the possibility that haploinsufficiency for Tsc1 plays a role in cyst formation. Consistent with this proposal, many cysts showed little or no staining for phosphorylated mTOR (53%) and phosphorylated S6 ribosomal protein (37%), whereas &gt;90% of cystadenomas and renal cell carcinomas showed strong staining for both markers (P &lt; 0.0005). We also sought somatic mutations in renal lesions from Tsc1+/− Blm−/− mice that have a high frequency of somatic loss of heterozygosity, thereby facilitating the detection of second hits. We also found significantly less somatic mutations in cysts as compared with cystadenomas and renal cell carcinomas from these mice (P = 0.017). Our data indicate that although activation of the mTOR pathway is an important step in Tsc-associated renal tumorigenesis, it may not be the key initiating event in this process. (Cancer Res 2006; 66(16): 7934-8)
MIRA-Assisted Microarray Analysis, a New Technology for the Determination of DNA Methylation Patterns, Identifies Frequent Methylation of Homeodomain-Containing Genes in Lung Cancer Cells
Authors: Rauch Tibor , Li Hongwei , Wu Xiwei , Pfeifer Gerd P. 
Published: August 2006

AbstractWe present a straightforward and comprehensive approach for DNA methylation analysis in mammalian genomes. The methylated-CpG island recovery assay (MIRA), which is based on the high affinity of the MBD2/MBD3L1 complex for methylated DNA, has been used to detect cell type–dependent differences in DNA methylation on a microarray platform. The procedure has been verified and applied to identify a series of novel candidate lung tumor suppressor genes and potential DNA methylation markers that contain methylated CpG islands. One gene of particular interest was DLEC1, located at a commonly deleted area on chromosome 3p22-p21.3, which was frequently methylated in primary lung cancers and melanomas. Among the identified methylated genes, homeodomain-containing genes were unusually frequent (11 of the top 50 hits) and were targeted on different chromosomes. These genes included LHX2, LHX4, PAX7, HOXB13, LBX1, SIX2, HOXD3, DLX1, HOXD1, ONECUT2, and PAX9. The data show that MIRA-assisted microarray analysis has a low false-positive rate and has the capacity to catalogue methylated CpG islands on a genome-wide basis. The results support the hypothesis that cancer-associated DNA methylation events do not occur randomly throughout the genome but at least some are targeted by specific mechanisms. (Cancer Res 2006; 66(16): 7939-47)
Detecting the limits of regulatory element conservation and divergence estimation using pairwise and multiple alignments
Authors: Pollard Daniel A , Moses Alan M , Iyer Venky N , Eisen Michael B 
Published: August 2006

Abstract

Background
Molecular evolutionary studies of noncoding sequences rely on multiple alignments. Yet how multiple alignment accuracy varies across sequence types, tree topologies, divergences and tools, and further how this variation impacts specific inferences, remains unclear.

Results
Here we develop a molecular evolution simulation platform, CisEvolver, with models of background noncoding and transcription factor binding site evolution, and use simulated alignments to systematically examine multiple alignment accuracy and its impact on two key molecular evolutionary inferences: transcription factor binding site conservation and divergence estimation. We find that the accuracy of multiple alignments is determined almost exclusively by the pairwise divergence distance of the two most diverged species and that additional species have a negligible influence on alignment accuracy. Conserved transcription factor binding sites align better than surrounding noncoding DNA yet are often found to be misaligned at relatively short divergence distances, such that studies of binding site gain and loss could easily be confounded by alignment error. Divergence estimates from multiple alignments tend to be overestimated at short divergence distances but reach a tool specific divergence at which they cease to increase, leading to underestimation at long divergences. Our most striking finding was that overall alignment accuracy, binding site alignment accuracy and divergence estimation accuracy vary greatly across branches in a tree and are most accurate for terminal branches connecting sister taxa and least accurate for internal branches connecting sub-alignments.

Conclusion
Our results suggest that variation in alignment accuracy can lead to errors in molecular evolutionary inferences that could be construed as biological variation. These findings have implications for which species to choose for analyses, what kind of errors would be expected for a given set of species and how multiple alignment tools and phylogenetic inference methods might be improved to minimize or control for alignment errors.
V-MitoSNP: visualization of human mitochondrial SNPs
Authors: Chuang Li-Yeh , Yang Cheng-Hong , Cheng Yu-Huei , Gu De-Leung , Chang Phei-Lang , Tsui Ke-Hung , Chang Hsueh-Wei 
Published: August 2006

Abstract

Background
Mitochondrial single nucleotide polymorphisms (mtSNPs) constitute important data when trying to shed some light on human diseases and cancers. Unfortunately, providing relevant mtSNP genotyping information in mtDNA databases in a neatly organized and transparent visual manner still remains a challenge. Amongst the many methods reported for SNP genotyping, determining the restriction fragment length polymorphisms (RFLPs) is still one of the most convenient and cost-saving methods. In this study, we prepared the visualization of the mtDNA genome in a way, which integrates the RFLP genotyping information with mitochondria related cancers and diseases in a user-friendly, intuitive and interactive manner. The inherent problem associated with mtDNA sequences in BLAST of the NCBI database was also solved.

Description
V-MitoSNP provides complete mtSNP information for four different kinds of inputs: (1) color-coded visual input by selecting genes of interest on the genome graph, (2) keyword search by locus, disease and mtSNP rs# ID, (3) visualized input of nucleotide range by clicking the selected region of the mtDNA sequence, and (4) sequences mtBLAST. The V-MitoSNP output provides 500 bp (base pairs) flanking sequences for each SNP coupled with the RFLP enzyme and the corresponding natural or mismatched primer sets. The output format enables users to see the SNP genotype pattern of the RFLP by virtual electrophoresis of each mtSNP. The rate of successful design of enzymes and primers for RFLPs in all mtSNPs was 99.1%. The RFLP information was validated by actual agarose electrophoresis and showed successful results for all mtSNPs tested. The mtBLAST function in V-MitoSNP provides the gene information within the input sequence rather than providing the complete mitochondrial chromosome as in the NCBI BLAST database. All mtSNPs with rs number entries in NCBI are integrated in the corresponding SNP in V-MitoSNP.

Conclusion
V-MitoSNP is a web-based software platform that provides a user-friendly and interactive interface for mtSNP information, especially with regard to RFLP genotyping. Visual input and output coupled with integrated mtSNP information from MITOMAP and NCBI make V-MitoSNP an ideal and complete visualization interface for human mtSNPs association studies.
A general pipeline for the development of anchor markers for comparative genomics in plants
Authors: Fredslund Jakob , Madsen Lene H , Hougaard Birgit K , Nielsen Anna Marie , Bertioli David , Sandal Niels , Stougaard Jens , Schauser Leif 
Published: August 2006

Abstract

Background
Complete or near-complete genomic sequence information is presently only available for a few plant species representing a large phylogenetic diversity among plants. In order to effectively transfer this information to species lacking sequence information, comparative genomic tools need to be developed. Molecular markers permitting cross-species mapping along co-linear genomic regions are central to comparative genomics. These "anchor" markers, defining unique loci in genetic linkage maps of multiple species, are gene-based and possess a number of features that make them relatively sparse. To identify potential anchor marker sequences more efficiently, we have established an automated bioinformatic pipeline that combines multi-species Expressed Sequence Tags (EST) and genome sequence data.

Results
Taking advantage of sequence data from related species, the pipeline identifies evolutionarily conserved sequences that are likely to define unique orthologous loci in most species of the same phylogenetic clade. The key features are the identification of evolutionarily conserved sequences followed by automated design of intron-flanking Polymerase Chain Reaction (PCR) primer pairs. Polymorphisms can subsequently be identified by size- or sequence variation of PCR products, amplified from mapping parents or populations. We illustrate our procedure in legumes and grasses and exemplify its application in legumes, where model plant studies and the genome- and EST-sequence data available have a potential impact on the breeding of crop species and on our understanding of the evolution of this large and diverse family.

Conclusion
We provide a database of 459 candidate anchor loci which have the potential to serve as map anchors in more than 18,000 legume species, a number of which are of agricultural importance. For grasses, the database contains 1335 candidate anchor loci. Based on this database, we have evaluated 76 candidate anchor loci with respect to marker development in legume species with no sequence information available, demonstrating the validity of this approach.
Wnt expression and canonical Wnt signaling in human bone marrow B lymphopoiesis
Authors: Døsen Guri , Tenstad Ellen , Nygren Marit Kveine , Stubberud Heidi , Funderud Steinar , Rian Edith 
Published: August 2006

AbstractBackgroundThe early B lymphopoiesis in mammals is regulated through close interactions with stromal cells and components of the intracellular matrix in the bone marrow (BM) microenvironment. Although B lymphopoiesis has been studied for decades, the factors that are implicated in this process, both autocrine and paracrine, are inadequately explored. Wnt signaling is known to be involved in embryonic development and growth regulation of tissues and cancer. Wnt molecules are produced in the BM, and we here ask whether canonical Wnt signaling has a role in regulating human BM B lymphopoiesis.ResultsExamination of the mRNA expression pattern of Wnt ligands, Fzd receptors and Wnt antagonists revealed that BM B progenitor cells and stromal cells express a set of ligands and receptors available for induction of Wnt signaling as well as antagonists for fine tuning of this signaling. Furthermore, different B progenitor maturation stages showed differential expression of Wnt receptors and co-receptors, β-catenin, plakoglobin, LEF-1 and TCF-4 mRNAs, suggesting canonical Wnt signaling as a regulator of early B lymphopoiesis. Exogenous Wnt3A induced stabilization and nuclear accumulation of β-catenin in primary lineage restricted B progenitor cells. Also, Wnt3A inhibited B lymphopoiesis of CD133+CD10-hematopoietic progenitor cells and CD10+B progenitor cells in coculture assays using a supportive layer of stromal cells. This effect was blocked by the Wnt antagonists sFRP1 or Dkk1. Examination of early events in the coculture showed that Wnt3A inhibits cell division of B progenitor cells.ConclusionThese results indicate that canonical Wnt signaling is involved in human BM B lymphopoiesis where it acts as a negative regulator of cell proliferation in a direct or stroma dependent manner.
Impact of DOTS expansion on tuberculosis related outcomes and costs in Haiti
Authors: Jacquet Vary , Morose Willy , Schwartzman Kevin , Oxlade Olivia , Barr Graham , Grimard Franque , Menzies Dick 
Published: August 2006

Abstract

Background
Implementation of the World Health Organization's DOTS strategy (Directly Observed Treatment Short-course therapy) can result in significant reduction in tuberculosis incidence. We estimated potential costs and benefits of DOTS expansion in Haiti from the government, and societal perspectives.

Methods
Using decision analysis incorporating multiple Markov processes (Markov modelling), we compared expected tuberculosis morbidity, mortality and costs in Haiti with DOTS expansion to reach all of the country, and achieve WHO benchmarks, or if the current situation did not change. Probabilities of tuberculosis related outcomes were derived from the published literature. Government health expenditures, patient and family costs were measured in direct surveys in Haiti and expressed in 2003 US$.

Results
Starting in 2003, DOTS expansion in Haiti is anticipated to cost $4.2 million and result in 63,080 fewer tuberculosis cases, 53,120 fewer tuberculosis deaths, and net societal savings of $131 million, over 20 years. Current government spending for tuberculosis is high, relative to the per capita income, and would be only slightly lower with DOTS. Societal savings would begin within 4 years, and would be substantial in all scenarios considered, including higher HIV seroprevalence or drug resistance, unchanged incidence following DOTS expansion, or doubling of initial and ongoing costs for DOTS expansion.

Conclusion
A modest investment for DOTS expansion in Haiti would provide considerable humanitarian benefit by reducing tuberculosis-related morbidity, mortality and costs for patients and their families. These benefits, together with projected minimal Haitian government savings, argue strongly for donor support for DOTS expansion.
Risk adjustment for inter-hospital comparison of primary cesarean section rates: need, validity and parsimony
Authors: Fantini Maria P , Stivanello Elisa , Frammartino Brunella , Barone Anna P , Fusco Danilo , Dallolio Laura , Cacciari Paolo , Perucci Carlo A 
Published: August 2006

Abstract
Background
Cesarean section rates is often used as an indicator of quality of care in maternity hospitals. The assumption is that lower rates reflect in developed countries more appropriate clinical practice and general better performances. Hospitals are thus often ranked on the basis of caesarean section rates.
The aim of this study is to assess whether the adjustment for clinical and sociodemographic variables of the mother and the fetus is necessary for inter-hospital comparisons of cesarean section (c-section) rates and to assess whether a risk adjustment model based on a limited number of variables could be identified and used.

Methods
Discharge abstracts of labouring women without prior cesarean were linked with abstracts of newborns discharged from 29 hospitals of the Emilia-Romagna Region (Italy) from 2003 to 2004. Adjusted ORs of cesarean by hospital were estimated by using two logistic regression models: 1) a full model including the potential confounders selected by a backward procedure; 2) a parsimonious model including only actual confounders identified by the "change-in-estimate" procedure. Hospital rankings, based on ORs were examined.

Results
24 risk factors for c-section were included in the full model and 7 (marital status, maternal age, infant weight, fetopelvic disproportion, eclampsia or pre-eclampsia, placenta previa/abruptio placentae, malposition/malpresentation) in the parsimonious model. Hospital ranking using the adjusted ORs from both models was different from that obtained using the crude ORs. The correlation between the rankings of the two models was 0.92. The crude ORs were smaller than ORs adjusted by both models, with the parsimonious ones producing more precise estimates.

Conclusion
Risk adjustment is necessary to compare hospital c-section rates, it shows differences in rankings and highlights inappropriateness of some hospitals. By adjusting for only actual confounders valid and more precise estimates could be obtained.