bluuebunny/crossref_metadata_2025_split huggingface dataset:
Infracambrian hydrocarbon source rock potential and petroleum prospectivity of NW Africa
Authors: Lüning S. , Kolonic S. , Geiger M. , Thusu B. , Bell J. S. , Craig J. 
Published: October 2009

Abstract

Proven Infracambrian hydrocarbon plays occur in various parts of the world, including Oman, the former Soviet Union, India, Pakistan and Australia. Organic-rich strata also occur in NW Africa, and gas shows originating from Infracambrian hydrocarbon source rocks are known from well Abolag-1 in the Mauritanian part of the Taoudenni Basin. The distribution of Infracambrian source rocks in North Africa is patchy and deposition commonly occurred in half-graben and pull-apart basins. In these intra-shelf basins, marine, organic-rich shales and limestones were deposited beneath the turbulent wave zone, away from the coarse siliciclastic Pan-African molasse detritus. On the West African Craton (including the Taoudenni Basin) organic-rich horizons were also deposited earlier, in pre- and syn-Pan-African times between 0.5 and 2 Ga (Ga is 10
9
years). The long-lasting sedimentation history in this area contrasts with that of the Pan-African regions, such as Oman, which lies in the Pan-African province of the East African Orogen, where preserved sediments are rarely older than 640 Ma. Infracambrian black phyllites in the Anti-Atlas region of Morocco were deposited on a continental slope of a short-lived ocean lying to the north of the West African Craton. Hydrocarbons generated during Infracambrian times from these deposits, however, have a low preservation potential.

Infracambrian organic-rich and/or black-pyritic deposits in North Africa are proven in the Taoudenni Basin, the Anti-Atlas and the Ahnet Basin. Thick carbonate successions exist in the Taoudenni Basin, indicating deposition in areas some distance from contaminating coarse siliciclastic hinterland influx. Infracambrian strata may also occur in the Tindouf Basin. However, their deep burial and consequent early maturation history may be unfavourable for the preservation of Infracambrian-sourced hydrocarbons in this area. Local development of Infracambrian source facies may also occur in the Reggane, Ahnet, Mouydir and Iullemeden basins, as indicated by black shales in wells MKRN-1 and MKRS-1 in the Ahnet Basin. Generally, however, these basins appear to be close to the active Pan-African orogenic belt and, consequently, probably received large quantities of coarse siliciclastic sediment, largely of continental facies, which may have diluted any significant hydrocarbon source potential.
p73 and p63 Sustain Cellular Growth by Transcriptional Activation of Cell Cycle Progression Genes
Authors: Lefkimmiatis Konstantinos , Caratozzolo Mariano Francesco , Merlo Paola , D'Erchia Anna Maria , Navarro Beatriz , Levrero Massimo , Sbisa' Elisabetta , Tullo Apollonia 
Published: October 2009

Abstract
Despite extensive studies on the role of tumor suppressor p53 protein and its homologues, p73 and p63, following their overexpression or cellular stress, very little is known about the regulation of the three proteins in cells during physiologic cell cycle progression. We report a role for p73 and p63 in supporting cellular proliferation through the transcriptional activation of the genes involved in G1-S and G2-M progression. We found that in MCF-7 cells, p73 and p63, but not p53, are modulated during the cell cycle with a peak in S phase, and their silencing determines a significant suppression of proliferation compared with the control. Chromatin immunoprecipitation analysis shows that in cycling cells, p73 and p63 are bound to the p53-responsive elements (RE) present in the regulatory region of cell cycle progression genes. On the contrary, when the cells are arrested in G0-G1, p73 detaches from the REs and it is replaced by p53, which represses the expression of these genes. When the cells move in S phase, p73 is recruited again and p53 is displaced or is weakly bound to the REs. These data open new possibilities for understanding the involvement of p73 and p63 in cancer. The elevated concentrations of p73 and p63 found in many cancers could cause the aberrant activation of cell growth progression genes and therefore contribute to cancer initiation or progression under certain conditions. [Cancer Res 2009;69(22):8563–71]
Tumor Growth Instability and Its Implications for Chemotherapy
Authors: Castorina Paolo , Carcò Daniela , Guiot Caterina , Deisboeck Thomas S. 
Published: October 2009

Abstract
Optimal delivery of chemotherapy intensity is dependent on host- and tumor-specific characteristics. In this article, the chemotherapy late intensity schedule is revised to account for tumor growth instability, where a small tumor cell fraction emerges that exhibits a higher proliferation rate than the parent strain. Modeling this instability as simplified two-population dynamics, we find that: (a) if this instability precedes the onset of treatment, the slope of the linear increase of the drug concentration for the standard “Norton-Simon late intensity schedule” changes and the initial value of the dose strongly depends on the ratio of the two tumor cell populations and on their distinct growth rates; and (b) if the instability trails the initial treatment, the effective chemotherapeutic drug concentration changes as well. Both cases point toward testable potential refinements of the Norton-Simon late intensity schedule. [Cancer Res 2009;69(21):8507–15]
Noninvasive Multiparametric Imaging of Metastasis-Permissive Microenvironments in a Human Prostate Cancer Xenograft
Authors: Penet Marie-France , Pathak Arvind P. , Raman Venu , Ballesteros Paloma , Artemov Dmitri , Bhujwalla Zaver M. 
Published: October 2009

Abstract
Metastasis continues to be one of the major causes of mortality from prostate cancer. Because human malignant cell lines metastasize more readily from orthotopic sites than from heterotopic sites, to identify metastasis-permissive tumor microenvironments, we used noninvasive imaging to compare the in vivo vascular, metabolic, and physiologic characteristics of a human prostate cancer xenograft implanted orthotopically in the prostate or s.c. in the flank. Hypoxia was detected in these xenografts by placing an enhanced green fluorescence protein optical reporter under the control of a hypoxia response element. A multiparametric analysis of hypoxia, extracellular pH, vascularization, and metabolism provided a characterization of environments that are permissive for metastasis to occur. We found that orthotopic tumors, which metastasized more easily, were characterized by higher vascular volume, permeability, and total choline and a more acidic extracellular pH. Interestingly, metastatic deposits in the lymph nodes as well as cancer cells in ascites fluid were found to be hypoxic, explaining, in part, the refractory nature of metastatic disease. These results also provide the basis for clinically translatable noninvasive imaging markers for predicting metastatic risk in prostate cancer. [Cancer Res 2009;69(22):8822–9]
Fanconi Anemia Complementation Group FANCD2 Protein Serine 331 Phosphorylation Is Important for Fanconi Anemia Pathway Function and BRCA2 Interaction
Authors: Zhi Gang , Wilson James B. , Chen Xiaoyong , Krause Diane S. , Xiao Yuxuan , Jones Nigel J. , Kupfer Gary M. 
Published: October 2009

Abstract
Fanconi anemia is a cancer-prone inherited bone marrow failure and cancer susceptibility syndrome with at least 13 complementation groups (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, and FANCN). Our laboratory has previously described several regulatory phosphorylation events for core complex member proteins FANCG and FANCA by phosphorylation. In this study, we report a novel phosphorylation site serine 331 (S331) of FANCD2, the pivotal downstream player of the Fanconi anemia pathway. Phosphorylation of S331 is important for its DNA damage–inducible monoubiquitylation, resistance to DNA cross-linkers, and in vivo interaction with FANCD1/BRCA2. A phosphomimetic mutation at S331 restores all of these phenotypes to wild-type. In vitro and in vivo experiments show that phosphorylation of S331 is mediated by CHK1, the S-phase checkpoint kinase implicated in the Fanconi anemia DNA repair pathway. [Cancer Res 2009;69(22):8775–83]
Prognostic Significance of Molecular Markers and Extent of Resection in Primary Glioblastoma Patients
Authors: Felsberg Jörg , Rapp Marion , Loeser Simon , Fimmers Rolf , Stummer Walter , Goeppert Matthias , Steiger Hans-Jacob , Friedensdorf Britta , Reifenberger Guido , Sabel Michael C. 
Published: October 2009

AbstractPurpose: Despite multimodal aggressive treatment glioblastoma patients still face a rather poor prognosis. Recent data indicate that certain molecular markers, in particular MGMT promoter hypermethylation, are associated with response to alkylating chemotherapy and longer survival. The clinical significance of other glioblastoma-associated molecular aberrations and their relationship to MGMT promoter hypermethylation is still poorly understood.Experimental Design: We conducted a translational study involving 67 newly diagnosed glioblastoma patients treated at our institution from 1998 to 2004. All patients were treated by open resection, followed by radiotherapy and adjuvant temozolomide chemotherapy. The tumors were investigated for MGMT promoter methylation, mRNA and protein expression, as well as presence of MGMT sequence polymorphisms. In addition, we screened for genetic aberrations of the EGFR, TP53, CDK4, MDM2, and PDGFRA genes as well as allelic losses on chromosomal arms 1p, 10q, and 19q.Results: Correlation of molecular findings with clinical data revealed significantly longer time to progression after onset of chemotherapy and longer overall survival of patients with MGMT-hypermethylated tumors. In contrast, MGMT protein expression, MGMT polymorphisms, and aberrations in any of the other genes and chromosomes were not significantly linked to patient outcome. Multivariate analysis identified MGMT promoter hypermethylation and near-complete tumor resection as the most important parameters associated with better prognosis.Conclusion: Our study provides novel insights into the significance of molecular and clinical markers in predicting the prognosis of glioblastoma patients, which may improve stratification of patients into distinct prognostic subgroups. (Clin Cancer Res 2009;15(20):6683–93)
Validation of TPX2 as a Potential Therapeutic Target in Pancreatic Cancer Cells
Authors: Warner Steven L. , Stephens Bret J. , Nwokenkwo Stanley , Hostetter Galen , Sugeng Anastasia , Hidalgo Manuel , Trent Jeffery M. , Han Haiyong , Von Hoff Daniel D. 
Published: October 2009

Abstract
Purpose: The targeting protein for Xklp2 (TPX2) has recently gained attention as a putative oncogene possibly amplified in several human malignancies, including pancreatic adenocarcinoma. In this work, we sought to evaluate the copy number and expression of TPX2 in pancreatic cancer cell lines and tumor tissues and to further explore the potential of TPX2 as a therapeutic target.
Experimental Design: The DNA copy number and expression of the TPX2 gene were surveyed in pancreatic cancer cell lines and tumor tissues and compared with those of immortalized normal pancreatic ductal cells and normal pancreatic tissues. The cellular effects of TPX2 knockdown using small interfering RNA oligonucleotides in pancreatic cancer cells, such as growth in tissue culture, in soft agar, and in nude mice; apoptosis; and sensitivity to paclitaxel, were also investigated using various assays.
Results: Low-copy-number TPX2 amplification was found in pancreatic cancer cell lines and low-passage pancreatic cancer tumor xenografts. TPX2 expression was upregulated in pancreatic cancer cell lines at both the mRNA and protein levels relative to the immortalized pancreatic ductal epithelial cell line HPDE6. Immunohistochemical staining of a tissue microarray showed that TPX2 expression was higher in pancreatic tumors compared with their normal counterparts. Treatment with TPX2 targeting small interfering RNAs effectively reduced pancreatic cancer cell growth in tissue culture, induced apoptosis, and inhibited growth in soft agar and in nude mice. Knockdown of TPX2 also sensitized pancreatic cancer cells to paclitaxel treatment.
Conclusions: Our results suggest that TPX2 might be an attractive target for pancreatic cancer therapy. (Clin Cancer Res 2009;15(21):6519–28)
Intratumoral Expression of Mature Human Neutrophil Peptide-1 Mediates Antitumor Immunity in Mice
Authors: Wang Yong-sheng , Li Dan , Shi Hua-shan , Wen Yan-jun , Yang Li , Xu Ning , Chen Xian-cheng , Chen Xiang , Chen Ping , Li Jiong , Deng Hong-xin , Wang Chun-ting , Xie Gang , Huang Shan , Mao Yong-qiu , Chen Li-juan , Zhao Xia , Wei Yu-quan 
Published: October 2009

AbstractPurpose: Human neutrophil peptides (HNP1-3), small molecular antimicrobial peptides, are expressed within tumors and associated with tumor necrosis and inhibition of angiogenesis. Recent investigations have suggested that HNP1-3 are likely to be involved in the host immune responses to tumors.Experimental Design: We used recombinant pSec-HNP1, which expresses a secretable form of HNP1, to obtain expression of HNP1 in the tumor milieu in immunocompetent mice to explore the possible roles of HNP1 in tumor immunity. The antitumor effects were investigated in established CT26 colon cancer and 4T1 breast cancer models.Results: HNP1-mediated chemotactic and activating effects on immature dendritic cells were detected both in vitro and in vivo. Intratumoral expression of HNP1 resulted in not only significant tumor growth inhibition but also increased CTL infiltration within tumors. Adoptive transfer of splenocytes and a 51Cr release assay revealed specific cellular immune responses. Furthermore, increased antibodies were also found in sera from pSec-HNP1treated mice supporting specific humoral immune responses. Increased apoptosis and decreased angiogenesis were also shown in treated tumors.Conclusions: These findings indicate that HNP1 can exert multiple antitumor effects through different mechanisms; more importantly, HNP1 mediates host immune responses to tumors in situ through the recruitment and subsequent activation of immature dendritic cells and thus shows promising potential in cancer therapy. (Clin Cancer Res 2009;15(22):690111)
Comprehensive Genomic Analysis Reveals Clinically Relevant Molecular Distinctions between Thymic Carcinomas and Thymomas
Authors: Girard Nicolas , Shen Ronglai , Guo Tianhua , Zakowski Maureen F. , Heguy Adriana , Riely Gregory J. , Huang James , Lau Christopher , Lash Alex E. , Ladanyi Marc , Viale Agnes , Antonescu Cristina R. , Travis William D. , Rusch Valerie W. , Kris Mark G. , Pao William 
Published: October 2009

Abstract
Purpose: Thymomas and thymic carcinomas are rare intrathoracic malignancies that can be invasive and refractory to conventional treatment. Because these tumors both originate from the thymus, they are often grouped together clinically. However, whether the underlying biology of these tumors warrants such clustering is unclear, and the optimum treatment of either entity is unknown.
Experimental Design: All thymic tumors were profiled for mutations in genes encoding components of the EGFR and KIT signaling pathways, assessed for EGFR and KIT expression by immunohistochemistry, and analyzed by array-based comparative genomic hybridization. Previously untreated tumors were subjected to global gene expression arrays.
Results: We analyzed 45 thymic tumors [thymoma, n = 38 (type A, n = 8; type B2, n = 22; type B3, n = 8); thymic carcinoma, n = 7]. One thymoma and one thymic carcinoma harbored KRAS mutations (G12A and G12V, respectively), and one thymoma had a G13V HRAS mutation. Three tumors displayed strong KIT staining. Two thymic carcinomas harbored somatic KIT mutations (V560del and H697Y). In cell viability assays, the V560del mutant was associated with similar sensitivities to imatinib and sunitinib, whereas the H697Y mutant displayed greater sensitivity to sunitinib. Genomic profiling revealed distinct differences between type A to B2 thymomas versus type B3 and thymic carcinomas. Moreover, array-based comparative genomic hybridization could readily distinguish squamous cell carcinomas of the thymus versus the lung, which can often present a diagnostic challenge.
Conclusions: Comprehensive genomic analysis suggests that thymic carcinomas are molecularly distinct from thymomas. These data have clinical, pathologic, and therapeutic implications for the treatment of thymic malignancies. (Clin Cancer Res 2009;15(22):67909)
Genomic and Expression Profiling of Glioblastoma Stem Cell–Like Spheroid Cultures Identifies Novel Tumor-Relevant Genes Associated with Survival
Authors: Ernst Aurélie , Hofmann Stefanie , Ahmadi Rezvan , Becker Natalia , Korshunov Andrey , Engel Felix , Hartmann Christian , Felsberg Jörg , Sabel Michael , Peterziel Heike , Durchdewald Moritz , Hess Jochen , Barbus Sebastian , Campos Benito , Starzinski-Powitz Anna , Unterberg Andreas , Reifenberger Guido , Lichter Peter , Herold-Mende Christel , Radlwimmer Bernhard 
Published: October 2009

Abstract
Purpose: Glioblastoma spheroid cultures are enriched in tumor stem-like cells and therefore may be more representative of the respective primary tumors than conventional monolayer cultures. We exploited the glioma spheroid culture model to find novel tumor-relevant genes.
Experimental Design: We carried out array-based comparative genomic hybridization of spheroid cultures derived from 20 glioblastomas. Microarray-based gene expression analysis was applied to determine genes with differential expression compared with normal brain tissue and to nonneoplastic brain spheroids in glioma spheroid cultures. The protein expression levels of three candidates were determined by immunohistochemistry on tissue microarrays and correlated with clinical outcome. Functional analysis of PDPN was done.
Results: Genomic changes in spheroid cultures closely resembled those detected in primary tumors of the corresponding patients. In contrast, genomic changes in serum-grown monolayer cultures established from the same patients did not match well with the respective primary tumors. Microarray-based gene expression analysis of glioblastoma spheroid cultures identified a set of novel candidate genes being upregulated or downregulated relative to normal brain. Quantitative real-time PCR analyses of 8 selected candidate genes in 20 clinical glioblastoma samples validated the microarray findings. Immunohistochemistry on tissue microarrays revealed that expression of AJAP1, EMP3, and PDPN was significantly associated with overall survival of astrocytic glioma patients. Invasive capacity and RhoA activity were decreased in PDPN-silenced spheroids.
Conclusion: We identified a set of novel candidate genes that likely play a role in glioblastoma pathogenesis and implicate AJAP1, EMP3, and PDPN as molecular markers associated with the clinical outcome of glioma patients. (Clin Cancer Res 2009;15(21):6541–50)
Quantifying Antivascular Effects of Monoclonal Antibodies to Vascular Endothelial Growth Factor: Insights from Imaging
Authors: O'Connor James P.B. , Carano Richard A.D. , Clamp Andrew R. , Ross Jed , Ho Calvin C.K. , Jackson Alan , Parker Geoff J.M. , Rose Chris J. , Peale Franklin V. , Friesenhahn Michel , Mitchell Claire L. , Watson Yvonne , Roberts Caleb , Hope Lynn , Cheung Sue , Reslan Hani Bou , Go Mary Ann T. , Pacheco Glenn J. , Wu Xiumin , Cao Tim C. , Ross Sarajane , Buonaccorsi Giovanni A. , Davies Karen , Hasan Jurjees , Thornton Paula , del Puerto Olivia , Ferrara Napoleone , van Bruggen Nicholas , Jayson Gordon C. 
Published: October 2009

Abstract
Purpose: Little is known concerning the onset, duration, and magnitude of direct therapeutic effects of anti–vascular endothelial growth factor (VEGF) therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early-phase clinical trials.
Experimental Design: Preclinical studies were done using ex vivo microcomputed tomography and in vivo ultrasound imaging to characterize tumor vasculature in a human HM-7 colorectal xenograft model treated with the anti-VEGF antibody G6-31. Clinical evaluation was by quantitative magnetic resonance imaging in 10 patients with metastatic colorectal cancer treated with bevacizumab.
Results: Microcomputed tomography experiments showed reduction in perfused vessels within 24 to 48 h of G6-31 drug administration (P ≤ 0.005). Ultrasound imaging confirmed reduced tumor blood volume within the same time frame (P = 0.048). Consistent with the preclinical results, reductions in enhancing fraction and fractional plasma volume were detected in patient colorectal cancer metastases within 48 h after a single dose of bevacizumab that persisted throughout one cycle of therapy. These effects were followed by resolution of edema (P = 0.0023) and tumor shrinkage in 9 of 26 tumors at day 12.
Conclusion: These data suggest that VEGF-specific inhibition induces rapid structural and functional effects with downstream significant antitumor activity within one cycle of therapy. This finding has important implications for the design of early-phase clinical trials that incorporate physiologic imaging. The study shows how animal data help interpret clinical imaging data, an important step toward the validation of image biomarkers of tumor structure and function. (Clin Cancer Res 2009;15(21):6674–82)
Reciprocal Regulation of c-Src and STAT3 in Non-Small Cell Lung Cancer
Authors: Byers Lauren Averett , Sen Banibrata , Saigal Babita , Diao Lixia , Wang Jing , Nanjundan Meera , Cascone Tina , Mills Gordon B. , Heymach John V. , Johnson Faye M. 
Published: October 2009

AbstractPurpose: Signal transducer and activator of transcription-3 (STAT3) is downstream of growth factor and cytokine receptors, and regulates key oncogenic pathways in nonsmall cell lung cancer (NSCLC). Activation of STAT3 by cellular Src (c-Src) promotes tumor progression. We hypothesized that c-Src inhibition could activate STAT3 by inducing a homeostatic feedback loop, contributing to c-Src inhibitor resistance.Experimental Design: The effects of c-Src inhibition on total and phosphorylated STAT3 were measured in NSCLC cell lines and in murine xenograft models by Western blotting. c-Src and STAT3 activity as indicated by phosphorylation was determined in 46 human tumors and paired normal lung by reverse phase protein array. Modulation of dasatinib (c-Src inhibitor) cytotoxicity by STAT3 knockdown was measured by MTT, cell cycle, and apoptosis assays.Results: Depletion of c-Src by small interfering RNA or sustained inhibition by dasatinib increased pSTAT3, which could be blocked by inhibition of JAK. Similarly, in vivo pSTAT3 levels initially decreased but were strongly induced after sustained dasatinib treatment. In human tumors, phosphorylation of the autoinhibitory site of c-Src (Y527) correlated with STAT3 phosphorylation (r = 0.64; P = 2.5 106). STAT3 knockdown enhanced the cytotoxicity of dasatinib.Conclusions: c-Src inhibition leads to JAK-dependent STAT3 activation in vitro and in vivo. STAT3 knockdown enhances the cytotoxicity of dasatinib, suggesting a compensatory pathway that allows NSCLC survival. Data from human tumors showed a reciprocal regulation of c-Src and STAT3 activation, suggesting that this compensatory pathway functions in human NSCLC. These results provide a rationale for combining c-Src and STAT3 inhibition to improve clinical responses. (Clin Cancer Res 2009;15(22):685261)