bluuebunny/crossref_metadata_2025_split huggingface dataset:
Raw material economics in their environmental context: an example from the Middle Palaeolithic of southern France
Authors: Wilson Lucy 
Published: February 2011

Abstract

To understand the human behaviour reflected in stone tool assemblages, we must take into account the characteristics of the lithic resources, their distribution across the landscape, the characteristics of the landscape itself, the distribution of other resources such as water and food, and human strategies of mobility and resource exploitation. The assemblage from one layer of a Middle Palaeolithic rock shelter site, the Bau de l'Aubesier, shows that raw materials from different areas were used in different ways: they are more or less common in the assemblage, and they are more or less likely to have been brought in as raw material and knapped
in situ
. Various factors may have influenced this pattern. Measures of terrain difficulty and energy expenditure, the raw material quality, and characteristics of the sources are woven together to determine the attractiveness of each source. This is then placed in the context of the geology and geography of the area to distinguish a ‘main’ or core territory from a more extended territory visited during longer trips. The results show the value of taking a geoarchaeological perspective, which sees nature and culture as inextricably intertwined.
Reassessing Hypsithermal human-environment interaction on the Northern Plains
Authors: Robertson Elizabeth C. 
Published: February 2011

Abstract
Palaeoenvironmental records from the Northern Plains of North America attest to an extended period of Middle Holocene warming and drying, making this a useful region and period for research on long-term human response to marked climate change. However, archaeological perspectives on human–environment interaction during this episode have remained preoccupied with a refugial model that incorporates limited latitude for dynamic human adaptation. In part, this situation reflects the challenging geomorphological and typological obstacles faced by those studying this period. However, this paper argues that our failure to develop new perspectives also reflects a longstanding and continued conservatism that casts Northern Plains lifeways as inflexible and unchanging, rather than dynamic and adaptable.
Environmental limitations on agricultural development of the forest zone of the East European Plain (Russian Federation)
Authors: Trapeznikova Olga N. 
Published: February 2011

Abstract
Intensive agricultural development of the forest zone of the East European Plain started in the second part of the first millennium AD. Although the majority of the mediaeval population were peasants, archaeological study of ancient rural settlements is much less developed than that of ancient towns. The analysis of interrelationships between environmental conditions and the agricultural pattern across space, including the corresponding pattern of rural settlements, helps us to delimit the spatial frame in which it is possible to find rural settlements of different historical epochs, even if they have since disappeared. Five areas with different historical types of agricultural landscapes were revealed, based on their geological and climatic characteristics. Another analysis essential for archaeology deals with the age of contemporary agricultural landscapes and rural settlements along with the factors and laws that control their changes through time and space.
Quaternary landscape evolution and human occupation in northwestern Argentina
Authors: Vattuone M. M. Sampietro , Neder L. 
Published: February 2011

Abstract
Our study area is located in northwestern Argentina. It is a semiarid valley in which developed agricultural pre-Columbian settlements were located. The objectives of our research were to establish the geomorphological characteristics of the area, its relative chronological development, and the relationships between geomorphological development and pre-Columbian settlements.
Pre-Quaternary lithologies are represented by a metamorphic basement that is commonly exposed on slopes and belongs to the Precambrian and Cambrian periods. Tertiary sediments from several formations are exposed over an extensive surface forming cuesta relief landforms. Quaternary landscape units were classified according to their genesis into structural–denudational landforms (denudational slopes and structural scarps), denudational landforms (covered glacis), fluvio-alluvial landforms (alluvial fans, fluvial fans, and fluvial terraces) and aeolian forms (stabilized dunes).
Archaeological sites belonging to the Formative (500 BC–AD 1000) and Regional Development (AD 1000–1500) periods were identified. The main archaeological sites are located on the surfaces of debris-flow deposits and some covered glacis. They are characterized by the presence of residential units together with agricultural structures (terraces and irrigation channels). The earlier settlements (Formative period) are restricted to alluvial fan landforms (debris-flow deposits), where present hydrological supply is lower than in the rest of the study area. Later settlements (Regional Development period) are juxtaposed with earlier settlements in the south of the area, where present hydrological supply is higher owing to larger river catchments and moisture-laden winds from the SE.
δ
13
C, δ
18
O and deposition rate of tufa in Xiangshui River, SW China: implications for land-cover change caused by climate and human impact during the late Holocene
Authors: Liu Zaihua , Sun Hailong , Li Hongchun , Wan Naijung 
Published: February 2011

Abstract

Measurements of δ
13
C and δ
18
O values of the riverine tufa samples dated by the accelerating mass spectrometry-
14
C method have been used for discussion of land-cover change in the catchment area of the Xiangshui River, SW China during the late Holocene. The results show that tufa was deposited in this short river only between
c
. 4280 and
c
. 110 years BP. Based on the characteristics of δ
13
C values of the complete tufa profile in the river, three stages of land-cover conditions in the headwater area could be identified. The earliest, Stage I, contained the most extensive vegetation cover with mainly C3 plants, as shown by the lightest δ
13
C value, whereas the latest, Stage III, had the least land cover, reflected by the heaviest δ
13
C value. By comparison of speleothem and historical records, it was found that the land cover in Stage I was controlled mainly by climate change, whereas the land-cover changes in the later two stages were most probably related to major human disturbance (land use), especially since the Qin Dynasty and Ming Dynasty, in the headwater area of the river.
Identification of a Clinically Relevant Androgen-Dependent Gene Signature in Prostate Cancer
Authors: Heemers Hannelore V. , Schmidt Lucy J. , Sun Zhifu , Regan Kevin M. , Anderson S. Keith , Duncan Kelly , Wang Dan , Liu Song , Ballman Karla V. , Tindall Donald J. 
Published: February 2011

Abstract
The androgen receptor (AR) is the principal target for treatment of non–organ-confined prostate cancer (PCa). Androgen deprivation therapies (ADT) directed against the AR ligand–binding domain do not fully inhibit androgen-dependent signaling critical for PCa progression. Thus, information that could direct the development of more effective ADTs is desired. Systems and bioinformatics approaches suggest that considerable variation exists in the mechanisms by which AR regulates expression of effector genes, pointing to a role for secondary transcription factors. A combination of microarray and in silico analyses led us to identify a 158-gene signature that relies on AR along with the transcription factor SRF (serum response factor), representing less than 6% of androgen-dependent genes. This AR-SRF signature is sufficient to distinguish microdissected benign and malignant prostate samples, and it correlates with the presence of aggressive disease and poor outcome. The AR-SRF signature described here associates more strongly with biochemical failure than other AR target gene signatures of similar size. Furthermore, it is enriched in malignant versus benign prostate tissues, compared with other signatures. To our knowledge, this profile represents the first demonstration of a distinct mechanism of androgen action with clinical relevance in PCa, offering a possible rationale to develop novel and more effective forms of ADT. Cancer Res; 71(5); 1978–88. ©2011 AACR.
Protein Kinase C Inhibitor Sotrastaurin Selectively Inhibits the Growth of CD79 Mutant Diffuse Large B-Cell Lymphomas
Authors: Naylor Tara L. , Tang Huaping , Ratsch Boris A. , Enns Andreas , Loo Alice , Chen Liqing , Lenz Peter , Waters Nigel J. , Schuler Walter , Dörken Bernd , Yao Yung-mae , Warmuth Markus , Lenz Georg , Stegmeier Frank 
Published: February 2011

Abstract
The activated B-cell–like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) correlates with poor prognosis. The ABC subtype of DLBCL is associated with constitutive activation of the NF-κB pathway, and oncogenic lesions have been identified in its regulators, including CARD11/CARMA1 (caspase recruitment domain-containing protein 11), A20/TNFAIP3, and CD79A/B. In this study, we offer evidence of therapeutic potential for the selective PKC (protein kinase C) inhibitor sotrastaurin (STN) in preclinical models of DLBCL. A significant fraction of ABC DLBCL cell lines exhibited strong sensitivity to STN, and we found that the molecular nature of NF-κB pathway lesions predicted responsiveness. CD79A/B mutations correlated with STN sensitivity, whereas CARD11 mutations rendered ABC DLBCL cell lines insensitive. Growth inhibitory effects of PKC inhibition correlated with NF-κB pathway inhibition and were mediated by induction of G1-phase cell-cycle arrest and/or cell death. We found that STN produced significant antitumor effects in a mouse xenograft model of CD79A/B-mutated DLBCL. Collectively, our findings offer a strong rationale for the clinical evaluation of STN in ABC DLBCL patients who harbor CD79 mutations also illustrating the necessity to stratify DLBCL patients according to their genetic abnormalities. Cancer Res; 71(7); 2643–53. ©2011 AACR.
Coactivation of AKT and β-Catenin in Mice Rapidly Induces Formation of Lipogenic Liver Tumors
Authors: Stauffer Jimmy K. , Scarzello Anthony J. , Andersen Jesper B. , De Kluyver Rachel L. , Back Timothy C. , Weiss Jonathan M. , Thorgeirsson Snorri S. , Wiltrout Robert H. 
Published: February 2011

Abstract
Obesity is a risk factor for development of certain cancers but the basis for this risk is unclear. In this study, we developed a novel mouse model that demonstrates directly how lipogenic phenotypes commonly associated with diet-induced metabolic syndromes can influence hepatic cancer development. Activated AKT and β-catenin (AKT/CAT) genes were hydrodynamically codelivered using the Sleeping Beauty transposon to initiate liver tumorigenesis. AKT/CAT and MET/CAT combination induced microscopic tumor foci by 4 weeks, whereas no tumorigenesis resulted from delivery of AKT, MET, or CAT alone. Primary AKT/CAT tumor cells were steatotic (fatty) hepatocellular adenomas which progressed to hepatocellular carcinomas (HCC) upon in vivo passage, whereas primary MET/CAT tumors emerged directly as frank HCC. Conversion of AKT/CAT tumor cells to frank HCC during passage was associated with induction of the human HCC marker α-fetoprotein and the stem cell marker CD133. Using hierarchical clustering and gene set enrichment analysis, we compared the primary murine AKT/CAT and MET/CAT tumors to a panel of 53 human HCCs and determined that these two mouse models could be stratified as distinct subtypes associated in humans with poor clinical prognosis. The chief molecular networks identified in primary and passaged AKT/CAT tumors were steatosis and lipid metabolic pathways, respectively. Our findings show how coactivation of the AKT and CAT pathways in hepatocytes can efficiently model development of a lipogenic tumor phenotype. Furthermore, we believe that our approach could speed the dissection of microenvironmental factors responsible for driving steatotic-neoplastic transformation to frank carcinoma, through genetic modification of existing immunodefined transgenic models. Cancer Res; 71(7); 2718–27. ©2011 AACR.
Sphingosine Kinase-1 Enhances Resistance to Apoptosis through Activation of PI3K/Akt/NF-κB Pathway in Human Non–Small Cell Lung Cancer
Authors: Song Libing , Xiong Huaping , Li Jun , Liao Wenting , Wang Lan , Wu Jueheng , Li Mengfeng 
Published: February 2011

Abstract
Purpose: The present study was to examine the effect of sphingosine kinase-1 (SPHK1) on chemotherapeutics-induced apoptosis in non–small cell lung cancer (NSCLC) cells, which is relatively insensitive to chemotherapy, and its clinical significance in NSCLC progression.
Experimental Design: The correlation of SPHK1 expression and clinical features of NSCLC was analyzed in 218 paraffin-embedded archived NSCLC specimens by immunohistochemical analysis. The effect of SPHK1 on apoptosis induced by chemotherapeutics was examined both in vitro and in vivo, using Annexin V staining and TUNEL (terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling) assays. Western blotting and luciferase analysis were performed to examine the impact of SPHK1 on the PI3K/Akt/NF-κB signaling.
Results: The expression of SPHK1 was markedly increased in NSCLC and correlated with tumor progression and poor survival of patients with NSCLC. Upregulation of SPHK1 significantly inhibited doxorubicin- or docetaxel-induced apoptosis, associated with induction of antiapoptotic proteins Bcl-xl, c-IAP1, c-IAP2, and TRAF1. In contrast, silencing SPHK1 expression or inhibiting SPHK1 activity with specific inhibitor, SK1-I, significantly enhanced the sensitivity of NSCLC cells to apoptosis induced by chemotherapeutics both in vitro and in vivo. Moreover, we demonstrated that upregulation of SPHK1 activated the PI3K/Akt/NF-κB pathway, and that inhibition of the PI3K/Akt/NF-κB pathway abrogated the antiapoptotic effect of SPHK1 on NSCLC cells.
Conclusions: Our results suggest that SPHK1 is a potential pharmacologic target for the treatment of NSCLC and inhibition of SPHK1 expression or its kinase activity might represent a novel strategy to sensitize NSCLC to chemotherapy. Clin Cancer Res; 17(7); 1839–49. ©2011 AACR.
A Multilocus Technique for Risk Evaluation of Patients with Neuroblastoma
Authors: Ambros Inge M. , Brunner Bettina , Aigner Gerhard , Bedwell Clare , Beiske Klaus , Bénard Jean , Bown Nick , Combaret Valerie , Couturier Jerome , Defferrari Raffaella , Gross Nicole , Jeison Marta , Lunec John , Marques Barbara , Martinsson Tommy , Mazzocco Katia , Noguera Rosa , Schleiermacher Gudrun , Speleman Frank , Stallings Ray , Tonini Gian Paolo , Tweddle Deborah A. , Valent Alexander , Vicha Ales , Roy Nadine Van , Villamon Eva , Ziegler Andrea , Preuner Sandra , Drobics Mario , Ladenstein Ruth , Amann Gabriele , Schuit Robert J.L. , Pötschger Ulrike , Ambros Peter F. 
Published: February 2011

Abstract
Purpose: Precise and comprehensive analysis of neuroblastoma genetics is essential for accurate risk evaluation and only pangenomic/multilocus approaches fulfill the present-day requirements. We present the establishment and validation of the PCR-based multiplex ligation-dependent probe amplification (MLPA) technique for neuroblastoma.
Experimental Design: A neuroblastoma-specific MLPA kit was designed by the SIOP Europe Neuroblastoma Biology Committee in cooperation with MRC-Holland. The contained target sequences cover 19 chromosomal arms and reference loci. Validation was performed by single locus and pangenomic techniques (n = 174). Dilution experiments for determination of minimal tumor cell percentage were performed and testing of reproducibility was checked by interlaboratory testing (n = 15). Further 156 neuroblastomas were used for establishing the amplification cutoff level.
Results: The MLPA technique was tested in 310 neuroblastomas and 8 neuroblastoma cell lines (including validation and amplification cutoff level testing). Intertechnique validation showed a high concordance rate (99.5%). Interlaboratory MLPA testing (κ = 0.95, P &lt; 0.01) revealed 7 discrepant of 1,490 results (0.5%). Validation by pangenomic techniques showed a single discordance of 190 consensus results (0.5%). The test results led to formulation of interpretation standards and to a kit revision. The minimal tumor cell percentage was fixed at 60%.
Conclusions: The recently designed neuroblastoma-specific MLPA kit covers all chromosomal regions demanded by the International Neuroblastoma Risk Group for therapy stratification and includes all hitherto described genetic loci of prognostic interest for future studies and can be modified or extended at any time. Moreover, the technique is cost effective, reliable, and robust with a high interlaboratory and intertechnique concordance. Clin Cancer Res; 17(4); 792–804. ©2011 AACR.
Antitumor Efficacy of PKI-587, a Highly Potent Dual PI3K/mTOR Kinase Inhibitor
Authors: Mallon Robert , Feldberg Larry R. , Lucas Judy , Chaudhary Inder , Dehnhardt Christoph , Santos Efren Delos , Chen Zecheng , dos Santos Osvaldo , Ayral-Kaloustian Semiramis , Venkatesan Aranapakam , Hollander Irwin 
Published: February 2011

Abstract
Purpose: The aim of this study was to show preclinical efficacy and clinical development potential of PKI-587, a dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor.
Experimental Design: In vitro class 1 PI3K enzyme and human tumor cell growth inhibition assays and in vivo five tumor xenograft models were used to show efficacy.
Results: In vitro, PKI-587 potently inhibited class I PI3Ks (IC50 vs. PI3K-α = 0.4 nmol/L), PI3K-α mutants, and mTOR. PKI-587 inhibited growth of 50 diverse human tumor cell lines at IC50 values of less than 100 nmol/L. PKI-587 suppressed phosphorylation of PI3K/mTOR effectors (e.g., Akt), and induced apoptosis in human tumor cell lines with elevated PI3K/mTOR signaling. MDA-MB-361 [breast; HER2+, PIK3CA mutant (E545K)] was particularly sensitive to this effect, with cleaved PARP, an apoptosis marker, induced by 30 nmol/L PKI-587 at 4 hours.
In vivo, PKI-587 inhibited tumor growth in breast (MDA-MB-361, BT474), colon (HCT116), lung (H1975), and glioma (U87MG) xenograft models. In MDA-MB-361 tumors, PKI-587 (25 mg/kg, single dose i.v.) suppressed Akt phosphorylation [at threonine(T)308 and serine(S)473] for up to 36 hours, with cleaved PARP (cPARP) evident up to 18 hours. PKI-587 at 25 mg/kg (once weekly) shrank large (∼1,000 mm3) MDA-MB-361 tumors and suppressed tumor regrowth. Tumor regression correlated with suppression of phosphorylated Akt in the MDA-MB-361 model. PKI-587 also caused regression in other tumor models, and efficacy was enhanced when given in combination with PD0325901 (MEK 1/2 inhibitor), irinotecan (topoisomerase I inhibitor), or HKI-272 (neratinib, HER2 inhibitor).
Conclusion: Significant antitumor efficacy and a favorable pharmacokinetic/safety profile justified phase 1 clinical evaluation of PKI-587. Clin Cancer Res; 17(10); 3193–203. ©2011 AACR.
Identification of Soluble Candidate Biomarkers of Therapeutic Response to Sunitinib in Medullary Thyroid Carcinoma in Preclinical Models
Authors: Broutin Sophie , Ameur Nabahet , Lacroix Ludovic , Robert Thomas , Petit Benoit , Oumata Nassima , Talbot Monique , Caillou Bernard , Schlumberger Martin , Dupuy Corinne , Bidart Jean-Michel 
Published: February 2011

Abstract
Purpose: Medullary thyroid carcinoma (MTC), an aggressive rare tumor due to activating mutations in the proto-oncogene RET, requires new therapeutic strategies. Sunitinib, a potent inhibitor of RET, VEGF receptor (VEGFR)-1, VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor (PDGFR)α/β, has been reported as clinically effective in some patients with advanced MTC. In this study, we examine molecular mechanisms of action of sunitinib and identify candidate soluble biomarkers of response.
Experimental Design: Both in vitro and in vivo assays, using the human TT RETC634W MTC cell line, were done to assess the activity of sunitinib. Kinetic microarray studies were used to analyze molecular pathways modified by sunitinib and to identify candidate biomarkers that were subsequently investigated in the serum of patients.
Results: Sunitinib displayed antiproliferative and antiangiogenic activities and inhibited RET autophosphorylation and activation of downstream signaling pathways. We showed that sunitinib treatment induced major changes in the expression of genes involved in tissue invasion and metastasis including vimentin (VIM), urokinase plasminogen (PLAU), tenascin-C (TN-C), SPARC, and CD44. Analyzing downregulated genes, we identified those encoding secreted proteins and, among them, interleukin (IL)-8 was found to be modulated in the serum of xenografted mice under sunitinib treatment. Furthermore, we demonstrated that metastatic MTC patients presented increased serum levels of IL-8 and TGF-β2.
Conclusions: Experimental models confirm the clinical efficacy of sunitinib observed in a few studies. Molecular pathways revealed by genomic signatures underline the impact of sunitinib on tissue invasion. Selected soluble candidate biomarkers could be of value for monitoring sunitinib response in metastatic MTC patients. Clin Cancer Res; 17(7); 2044–54. ©2011 AACR.
Large-Scale Analysis of KIT Aberrations in Chinese Patients with Melanoma
Authors: Kong Yan , Si Lu , Zhu Yanyan , Xu Xiaowei , Corless Christopher L. , Flaherty Keith T. , Li Li , Li Haifu , Sheng Xinan , Cui Chuanliang , Chi Zhihong , Li Siming , Han Mei , Mao Lili , Lu Aiping , Guo Jun 
Published: February 2011

Abstract
Purpose: KIT aberrations were described in acral and mucosal melanomas in largely Caucasian populations. Asian populations are more prone to develop acral and mucosal than cutaneous melanomas, and may harbor a high frequency of KIT aberrations.
Experimental Design: Melanoma subtypes (n = 502) were analyzed histologically to determine melanoma subtype. Tissue samples were analyzed for mutations in exons 9, 11, 13, 17, and 18 of KIT gene in genomic DNA by PCR amplification and Sanger sequencing. The copy numbers of the KIT gene were analyzed by quantitative PCR, and protein expression levels of KIT (CD117) were determined by immunohistochemistry.
Results: The most common melanoma subtypes were acral (38.4%) and mucosal (33.3%) melanomas in this population. The overall incidence of somatic mutations within the KIT gene was 10.8% (54/502), and all subtypes of melanoma contained KIT mutations. Increases in KIT gene copy numbers were correlated to CD117 overexpression. The genetic mutations of KIT were unrelated to the age, gender, stage, thickness, and ulceration of primary melanomas. Importantly, the overall survival of melanoma patients with KIT mutations (P = 0.001) or with KIT aberrations (mutation plus amplification, P = 0.0002) was significantly shorter than that of patients without such alterations.
Conclusion: In China, the prevalent melanomas are acral and mucosal melanomas. KIT mutations are detected in all melanoma subtypes. Our study suggests that increases in KIT gene copy numbers, but not KIT mutations, may be correlated to CD117 overexpression. For the first time, our study suggests that genetic KIT aberration is an adverse prognostic factor for melanoma. Clin Cancer Res; 17(7); 1684–91. ©2011 AACR.