bluuebunny/crossref_metadata_2025_split huggingface dataset:
Internal geometry of fault damage zones in interbedded siliciclastic sediments
Authors: Johansen Tord Erlend Skeie , Fossen Haakon 
Published: July 2008

Abstract
The geometry, orientation and distribution of deformation bands and fractures in eolian sandstones, siltstones and shales of the San Rafael Desert and Moab Fault area have been investigated. The results show that deformation bands, which are cataclastic in eolian sandstones and disaggregation structures in siltstones, are unevenly distributed throughout the damage zone in the form of individual bands, deformation band zones and deformation band clusters. The density of bands increases with increasing grain size. In thin (<3 m) eolian sandstones deformation band frequency is significantly lower than in thicker eolian sandstones, whereas above this thickness the frequency seems not to be related to layer thickness. Furthermore, large faults do not develop higher concentrations of deformation bands. Somewhat simplified, this suggests that damage zone growth occurs by expansion into its hanging wall and footwall. Still, the highest concentrations of deformation bands occur close to the main fault, which is of importance when considering their effect on fluid flow. Their general fault-parallel conjugate arrangements favour intra-damage zone flow parallel to rather than perpendicular to the fault.
Fault damage zones dominated by high-angle fractures within layer-parallel brittle shear zones: examples from the eastern Alps
Authors: Brosch Franz-Josef , Kurz Walter 
Published: July 2008

Abstract
In this study, we focus on the transition from the host rock to the damage zone within brittle shear zones in order to document the structures forming during the initial phases of deformation, i.e., the fractures that formed prior to the formation of fault breccias and cataclasites. Structural analyses of rock samples from sites of the Talhof– and Palten–Liesing faults in the eastern Alps show that in these cases well-known R- and P-fracture patterns do not play a dominant role in the early stages of the generation of brittle fracture zones. In the studied layered marble and foliated impure quartzite samples, the boundary between the host rock and the damage zone is characterized by the formation of closely spaced fractures at high angles (70–90°) to the shear zone boundaries, being parallel to pre-existing layering/foliation planes. These fractures bound and define slender slab-like or columnar rock elements, here being termed lamellae. It is assumed that subsequent rotation of these lamellae in the bookshelf and domino modes associated with impeded dilation across the actual shear zone boundaries leads to kinking, splitting and final granulation of the lamellae to generate breccias of later fault core zones parallel to the shear zone boundary. In some cases, the observed bending and buckling of lamellae indicate additional ductile deformation subsequent to the development of the dominant lamellar structures formed by brittle fracturing.
C-Myc Is a Critical Mediator of the Phenotypes of Apc Loss in the Intestine
Authors: Wilkins Julie A. , Sansom Owen J. 
Published: July 2008

Abstract
The Adenomatous polyposis coli (Apc) gene is mutated in up to 80% of sporadic colorectal cancers. After Apc loss, there is deregulation of the Wnt signaling pathway and transactivation of T-cell factor/leukemia enhancing factor target genes such as C-Myc. This review focuses on recent data highlighting the importance of the C-Myc oncogene and its transcriptional targets in establishing all of the phenotypes caused by the deletion of the Apc tumor suppressor gene within the intestinal epithelium. The importance of investigating Apc and C-Myc gene function in the correct tissue context is also discussed. [Cancer Res 2008;68(13):4963–6]
Loss of the ssecks/gravin/akap12 Gene Results in Prostatic Hyperplasia
Authors: Akakura Shin , Huang Changhui , Nelson Peter J. , Foster Barbara , Gelman Irwin H. 
Published: July 2008

Abstract
SSeCKS/Gravin/AKAP12 (SSeCKS) is a kinase scaffolding protein that encodes metastasis-suppressor activity through the suppression of Src-mediated oncogenic signaling and vascular endothelial growth factor expression. SSeCKS expression is down-regulated in Src- and Ras-transformed fibroblasts, in human cancer cell lines and in several types of human cancer, including prostate. Normal human and mouse prostates express abundant SSeCKS in secretory epithelial cells and, to a lesser extent, in the surrounding mesenchyme. Here, we show that the loss of SSeCKS results in prostatic hyperplasia in the anterior and ventral lobes as well as increased levels of apoptosis throughout the prostate. Dysplastic foci were observed less frequently but were associated with the loss of E-cadherin staining and the loss of high molecular weight cytokeratin-positive basal epithelial cells. SSeCKS-null prostate tissues expressed significantly higher relative levels of AKTpoS473 compared with wild-type controls, suggesting that SSeCKS attenuates phosphatidylinositol-3-OH kinase signaling. The data suggest that SSeCKS-null mice have increased susceptibility for oncogenic transformation in the prostate. [Cancer Res 2008;68(13):5096–103]
Cross-talk between Notch and the Estrogen Receptor in Breast Cancer Suggests Novel Therapeutic Approaches
Authors: Rizzo Paola , Miao Haixi , D'Souza Gwendolyn , Osipo Clodia , Yun Jieun , Zhao Huiping , Mascarenhas Joaquina , Wyatt Debra , Antico Giovanni , Hao Lu , Yao Katharine , Rajan Prabha , Hicks Chindo , Siziopikou Kalliopi , Selvaggi Suzanne , Bashir Amina , Bhandari Deepali , Marchese Adriano , Lendahl Urban , Qin Jian-Zhong , Tonetti Debra A. , Albain Kathy , Nickoloff Brian J. , Miele Lucio 
Published: July 2008

Abstract
High expression of Notch-1 and Jagged-1 mRNA correlates with poor prognosis in breast cancer. Elucidating the cross-talk between Notch and other major breast cancer pathways is necessary to determine which patients may benefit from Notch inhibitors, which agents should be combined with them, and which biomarkers indicate Notch activity in vivo. We explored expression of Notch receptors and ligands in clinical specimens, as well as activity, regulation, and effectors of Notch signaling using cell lines and xenografts. Ductal and lobular carcinomas commonly expressed Notch-1, Notch-4, and Jagged-1 at variable levels. However, in breast cancer cell lines, Notch-induced transcriptional activity did not correlate with Notch receptor levels and was highest in estrogen receptor α–negative (ERα−), Her2/Neu nonoverexpressing cells. In ERα+ cells, estradiol inhibited Notch activity and Notch-1IC nuclear levels and affected Notch-1 cellular distribution. Tamoxifen and raloxifene blocked this effect, reactivating Notch. Notch-1 induced Notch-4. Notch-4 expression in clinical specimens correlated with proliferation (Ki67). In MDA-MB231 (ERα−) cells, Notch-1 knockdown or γ-secretase inhibition decreased cyclins A and B1, causing G2 arrest, p53-independent induction of NOXA, and death. In T47D:A18 (ERα+) cells, the same targets were affected, and Notch inhibition potentiated the effects of tamoxifen. In vivo, γ-secretase inhibitor treatment arrested the growth of MDA-MB231 tumors and, in combination with tamoxifen, caused regression of T47D:A18 tumors. Our data indicate that combinations of antiestrogens and Notch inhibitors may be effective in ERα+ breast cancers and that Notch signaling is a potential therapeutic target in ERα− breast cancers. [Cancer Res 2008;68(13):5226–35]
Dissecting and Targeting the Growth Factor–Dependent and Growth Factor–Independent Extracellular Signal-Regulated Kinase Pathway in Human Schwannoma
Authors: Ammoun Sylwia , Flaiz Christine , Ristic Natalia , Schuldt Jennifer , Hanemann C. Oliver 
Published: July 2008

Abstract
Schwannomas are tumors of the nervous system that occur sporadically and in patients with the cancer predisposition syndrome neurofibromatosis type 2 (NF2). Schwannomas and all NF2-related tumors are caused by loss of the tumor suppressor merlin. Using our human in vitro model for schwannoma, we analyzed extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT signaling pathways, their upstream growth factor receptors, and their role in schwannoma cell proliferation and adhesion to find new systemic therapies for these tumors that, to date, are very difficult to treat. We show here that human primary schwannoma cells show an enhanced basal Raf/mitogen-activated protein/ERK kinase/ERK1/2 pathway activity compared with healthy Schwann cells. Due to a strong and prolonged activation of platelet-derived growth factor receptor β (PDGFRβ), which is highly overexpressed, ERK1/2 and AKT activation was further increased in schwannoma, leading to increased proliferation. Using specific inhibitors, we discovered that ERK1/2 activation involves the integrin/focal adhesion kinase/Src/Ras signaling cascades and PDGFRβ-mediated ERK1/2 activation is triggered through the phosphatidylinositol 3-kinase/protein kinase C/Src/c-Raf pathway. Due to the complexity of signals leading to schwannoma cell proliferation, potential new therapeutic agents should target several signaling pathways. The PDGFR and c-Raf inhibitor sorafenib (BAY 43-9006; Bayer Pharmaceuticals), currently approved for treatment of advanced renal cell cancer, inhibits both basal and PDGFRβ-mediated ERK1/2 and AKT activity and decreases cell proliferation in human schwannoma cells, suggesting that this drug constitutes a promising tool to treat schwannomas. We conclude that our schwannoma in vitro model can be used to screen for new therapeutic targets in general and that sorafenib is possible candidate for future clinical trials. [Cancer Res 2008;68(13):5236–45]
Noninvasive Imaging and Quantification of Epidermal Growth Factor Receptor Kinase Activation In vivo
Authors: Li Wenrong , Li Fang , Huang Qian , Frederick Barbara , Bao Shideng , Li Chuan-Yuan 
Published: July 2008

Abstract
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) critical in tumor growth and a major target for anticancer drug development. However, thus far, there is no effective system to monitor its activities in vivo. Here, we report a novel approach to monitor EGFR activation based on the bifragment luciferase reconstitution system. The EGFR receptor and its interacting partner proteins (EGFR, growth factor receptor binding protein 2, and Src homology 2 domain-containing) were fused to NH2 terminal and COOH terminal fragments of the firefly luciferase. After establishing tumor xenograft from cells transduced with the reporter genes, we show that the activation of EGFR and its downstream factors could be quantified through optical imaging of reconstituted luciferase. Changes in EGFR activation could be visualized after radiotherapy or EGFR inhibitor treatment. Rapid and sustained radiation-induced EGFR activation and inhibitor-mediated signal suppression were observed in the same xenograft tumors over a period of weeks. Our data therefore suggest a new methodology where activities of RTKs can be imaged and quantified optically in mice. This approach should be generally applicable to study biological regulation of RTK, as well as to develop and evaluate novel RTK-targeted therapeutics. [Cancer Res 2008;68(13):4990–7]
Mitochondrial Cholesterol Contributes to Chemotherapy Resistance in Hepatocellular Carcinoma
Authors: Montero Joan , Morales Albert , Llacuna Laura , Lluis Josep M. , Terrones Oihana , Basañez Gorka , Antonsson Bruno , Prieto Jesús , García-Ruiz Carmen , Colell Anna , Fernández-Checa José C. 
Published: July 2008

Abstract
Cholesterol metabolism is deregulated in carcinogenesis, and cancer cells exhibit enhanced mitochondrial cholesterol content whose role in cell death susceptibility and cancer therapy has not been investigated. Here, we describe that mitochondria from rat or human hepatocellular carcinoma (HC) cells (HCC) or primary tumors from patients with HC exhibit increased mitochondrial cholesterol levels. HCC sensitivity to chemotherapy acting via mitochondria is enhanced upon cholesterol depletion by inhibition of hydroxymethylglutaryl-CoA reductase or squalene synthase (SS), which catalyzes the first committed step in cholesterol biosynthesis. HCC transfection with siRNA targeting the steroidogenic acute regulatory protein StAR, a mitochondrial cholesterol–transporting polypeptide which is overexpressed in HCC compared with rat and human liver, sensitized HCC to chemotherapy. Isolated mitochondria from HCC with increased cholesterol levels were resistant to mitochondrial membrane permeabilization and release of cytochrome c or Smac/DIABLO in response to various stimuli including active Bax. Similar behavior was observed in cholesterol-enriched mitochondria or liposomes and reversed by restoring mitochondrial membrane order or cholesterol extraction. Moreover, atorvastatin or the SS inhibitor YM-53601 potentiated doxorubicin-mediated HCC growth arrest and cell death in vivo. Thus, mitochondrial cholesterol contributes to chemotherapy resistance by increasing membrane order, emerging as a novel therapeutic niche in cancer therapy. [Cancer Res 2008;68(13):5246–56]
A Syngeneic Variance Library for Functional Annotation of Human Variation: Application toBRCA2
Authors: Hucl Tomas , Rago Carlo , Gallmeier Eike , Brody Jonathan R. , Gorospe Myriam , Kern Scott E. 
Published: July 2008

AbstractThe enormous scope of natural human genetic variation is now becoming defined. To accurately annotate these variants, and to identify those with clinical importance, is often difficult to assess through functional assays. We explored systematic annotation by using homologous recombination to modify a native gene in hemizygous (wt/Δexon) human cancer cells, generating a novel syngeneic variance library (SyVaL). We created a SyVaL of BRCA2 variants: nondeleterious, proposed deleterious, deleterious, and of uncertain significance. We found that the null states BRCA2Δex11/Δex11 and BRCA2Δex11/Y3308X were deleterious as assessed by a loss of RAD51 focus formation on genotoxic damage and by acquisition of toxic hypersensitivity to mitomycin C and etoposide, whereas BRCA2Δex11/Y3308Y, BRCA2Δex11/P3292L, and BRCA2Δex11/P3280H had wild-type function. A proposed phosphorylation site at codon 3291 affecting function was confirmed by substitution of an acidic residue (glutamate, BRCA2Δex11/S3291E) for the native serine, but in contrast to a prior report, phosphorylation was dispensable (alanine, BRCA2Δex11/S3291A) for BRCA2-governed cellular phenotypes. These results show that SyVaLs offer a means to comprehensively annotate gene function, facilitating numerical and unambiguous readouts. SyVaLs may be especially useful for genes in which functional assays using exogenous expression are toxic or otherwise unreliable. They also offer a stable, distributable cellular resource for further research. [Cancer Res 2008;68(13):5023–30]
OX40 Agonist Therapy Enhances CD8 Infiltration and Decreases Immune Suppression in the Tumor
Authors: Gough Michael J. , Ruby Carl E. , Redmond William L. , Dhungel Birat , Brown Alexis , Weinberg Andrew D. 
Published: July 2008

AbstractAcquisition of full T-cell effector function and memory differentiation requires appropriate costimulatory signals, including ligation of the costimulatory molecule OX40 (TNFRSF4, CD134). Tumors often grow despite the presence of tumor-specific T cells and establish an environment with weak costimulation and immune suppression. Administration of OX40 agonists has been shown to significantly increase the survival of tumor-bearing mice and was dependent on the presence of both CD4 and CD8 T cells during tumor-specific priming. To understand how OX40 agonists work in mice with established tumors, we developed a model to study changes in immune cell populations within the tumor environment. We show here that systemic administration of OX40 agonist antibodies increased the proportion of CD8 T cells at the tumor site in three different tumor models. The function of the CD8 T cells at the tumor site was also increased by administration of OX40 agonist antibody, and we observed an increase in the proportion of antigen-specific CD8 T cells within the tumor. Despite decreases in the proportion of T regulatory cells at the tumor site, T regulatory cell function in the spleen was unaffected by OX40 agonist antibody therapy. Interestingly, administration of OX40 agonist antibody caused significant changes in the tumor stroma, including decreased macrophages, myeloid-derived suppressor cells, and decreased expression of transforming growth factor-β. Thus, therapies targeting OX40 dramatically changed the tumor environment by enhancing the infiltration and function of CD8 T cells combined with diminished suppressive influences within the tumor. [Cancer Res 2008;68(13):5206–15]
A Gene Signature Predicting for Survival in Suboptimally Debulked Patients with Ovarian Cancer
Authors: Bonome Tomas , Levine Douglas A. , Shih Joanna , Randonovich Mike , Pise-Masison Cindy A. , Bogomolniy Faina , Ozbun Laurent , Brady John , Barrett J. Carl , Boyd Jeff , Birrer Michael J. 
Published: July 2008

Abstract
Despite the existence of morphologically indistinguishable disease, patients with advanced ovarian tumors display a broad range of survival end points. We hypothesize that gene expression profiling can identify a prognostic signature accounting for these distinct clinical outcomes. To resolve survival-associated loci, gene expression profiling was completed for an extensive set of 185 (90 optimal/95 suboptimal) primary ovarian tumors using the Affymetrix human U133A microarray. Cox regression analysis identified probe sets associated with survival in optimally and suboptimally debulked tumor sets at a P value of &lt;0.01. Leave-one-out cross-validation was applied to each tumor cohort and confirmed by a permutation test. External validation was conducted by applying the gene signature to a publicly available array database of expression profiles of advanced stage suboptimally debulked tumors. The prognostic signature successfully classified the tumors according to survival for suboptimally (P = 0.0179) but not optimally debulked (P = 0.144) patients. The suboptimal gene signature was validated using the independent set of tumors (odds ratio, 8.75; P = 0.0146). To elucidate signaling events amenable to therapeutic intervention in suboptimally debulked patients, pathway analysis was completed for the top 57 survival-associated probe sets. For suboptimally debulked patients, confirmation of the predictive gene signature supports the existence of a clinically relevant predictor, as well as the possibility of novel therapeutic opportunities. Ultimately, the prognostic classifier defined for suboptimally debulked tumors may aid in the classification and enhancement of patient outcome for this high-risk population. [Cancer Res 2008;68(13):5478–86]
Molecular Dependence of Estrogen Receptor–Negative Breast Cancer on a Notch-Survivin Signaling Axis
Authors: Lee Connie W. , Raskett Christopher M. , Prudovsky Igor , Altieri Dario C. 
Published: July 2008

Abstract
Despite progress in the management of breast cancer, the molecular underpinnings of clinically aggressive subtypes of the disease are not well-understood. Here, we show that activation of Notch developmental signaling in estrogen receptor (ER)–negative breast cancer cells results in direct transcriptional up-regulation of the apoptosis inhibitor and cell cycle regulator survivin. This response is associated with increased expression of survivin at mitosis, enhanced cell proliferation, and heightened viability at cell division. Conversely, targeting Notch signaling with a peptidyl γ-secretase inhibitor suppressed survivin levels, induced apoptosis, abolished colony formation in soft agar, and inhibited localized and metastatic tumor growth in mice, without organ or systemic toxicity. In contrast, ER+ breast cancer cells, or various normal cell types, were insensitive to Notch stimulation. Therefore, ER− breast cancer cells become dependent on Notch-survivin signaling for their maintenance, in vivo. Therapeutic targeting of this pathway may be explored for individualized treatment of patients with clinically aggressive, ER− breast cancer. [Cancer Res 2008;68(13):5273–81]
Activation of Protein Kinase G Increases the Expression of p21CIP1, p27KIP1, and Histidine Triad Protein 1 through Sp1
Authors: Cen Bo , Deguchi Atsuko , Weinstein I. Bernard 
Published: July 2008

Abstract
The anticancer role of cyclic guanosine 3′,5′-monophosphate (cGMP)–dependent protein kinase G (PKG) has become of considerable interest, but the underlying mechanisms are not fully established. In this study, we examined the effects of activation of PKG on the expression of three tumor suppressor proteins in human SW480 colon cancer cells. Our results revealed that treatment with cell permeable cGMP derivatives, or the cGMP phosphodiesterase inhibitor sulindac sulfone (exisulind, aptosyn, hereafter called exisulind) led to increased expression of the tumor suppressor proteins p21CIP1, p27KIP1, and Histidine triad protein 1 (HINT1), and their corresponding mRNAs. Overexpression of PKG Iβ also caused increased expression of the p21CIP1, p27KIP1, and HINT1 proteins. Both the p21CIP1 and p27KIP1 promoters contain Sp1 binding sites and they were activated by PKG in luciferase reporter assays. Specific Sp1 sites in the p21 and p27 promoters were sufficient to mediate PKG-induced luciferase reporter activity, suggesting an interaction between Sp1 and PKG. Indeed, we found that PKG can phosphorylate Sp1 on serine residue(s) and this resulted in transcriptional activation of Sp1. Knockdown of Sp1 expression with siRNA inhibited the increased expression of p21CIP1, p27KIP1, and HINT1 induced by the cGMP derivative 8-pCPT-cGMP in SW480 cells. These novel effects of PKG activation on the expression of three tumor suppressor genes may explain, at least in part, the anticancer effects of activation of PKG. They also provide a rationale for further developing activators of PKG for the prevention and treatment of cancer. [Cancer Res 2008;68(13):5355–62]
Zebrafish with Mutations in Mismatch Repair Genes Develop Neurofibromas and Other Tumors
Authors: Feitsma Harma , Kuiper Raoul V. , Korving Jeroen , Nijman Isaac J. , Cuppen Edwin 
Published: July 2008

Abstract
Defective mismatch repair (MMR) in humans causes hereditary nonpolyposis colorectal cancer. This genetic predisposition to colon cancer is linked to heterozygous familial mutations, and loss-of-heterozygosity is necessary for tumor development. In contrast, the rare cases with biallelic MMR mutations are juvenile patients with brain tumors, skin neurofibromas, and café-au-lait spots, resembling the neurofibromatosis syndrome. Many of them also display lymphomas and leukemias, which phenotypically resembles the frequent lymphoma development in mouse MMR knockouts. Here, we describe the identification and characterization of novel knockout mutants of the three major MMR genes, mlh1, msh2, and msh6, in zebrafish and show that they develop tumors at low frequencies. Predominantly, neurofibromas/malignant peripheral nerve sheath tumors were observed; however, a range of other tumor types was also observed. Our findings indicate that zebrafish mimic distinct features of the human disease and are complementary to mouse models. [Cancer Res 2008;68(13):5059–66]