bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fluvial response to Holocene glacier fluctuations in the Nostetuko River valley, southern Coast Mountains, British Columbia
Authors: Wilkie Kenna , Clague John J. 
Published: July 2009

Abstract

Mountain rivers, like alpine glaciers, are sensitive indicators of climate change. Some rivers may provide a more complete record of Holocene climate change than the glaciers in their headwaters. We illustrate these points by examining the record preserved in the upper part of the alluvial fill in the Nostetuko River valley in the southern Coast Mountains, British Columbia (Canada). Glacier advances in the upper part of the watershed triggered valley-wide aggradation and complex changes in river planform. Periods when glaciers were restricted in extent coincide with periods of incision of the valley fill and floodplain stability. As many as 10 overbank aggradation units are separated by peat layers containing tree roots and stems in growth position. Twenty-five radiocarbon ages on roots, tree stems and woody plant detritus in several of the peat layers closely delimit periods of aggradation. The oldest phase of aggradation occurred about 6500 years
bp
and coincides with the Garibaldi Advance documented elsewhere in the southern Coast Mountains. A second phase of aggradation, recorded by several units of clastic sediment, dates to about 2500 years
bp
, near the peak of the middle Neoglacial Tiedemann Advance. The third phase occurred shortly after 1400 years
bp
during or shortly after the First Millennium Advance, which has been recently documented in coastal British Columbia and Alaska. The most recent phase of aggradation began about 800 years
bp
and continued until recently. It coincides with the Little Ice Age, when glaciers in the Nostetuko River basin and elsewhere in the southern Coast Mountains attained their greatest Holocene size. Several periods of peat deposition during the Little Ice Age indicate periods of floodplain stability separated by brief intervals of floodplain aggradation that coincide with Little Ice Age glacier advances in western Canada. The results imply that the west fork of Nostetuko River is sensitive to upvalley glacier fluctuations and, indirectly, to relatively minor changes in climate.
Glacially conditioned rock-slope failures and disturbance-regime landscapes, Upper Indus Basin, northern Pakistan
Authors: Hewitt Kenneth 
Published: July 2009

Abstract

The possible role of paraglacial adjustments in catastrophic rock-slope failures is investigated. Most of some 250 rockslide–rock-avalanche events identified in the Upper Indus Basin descended from slopes affected by Quaternary glaciations. Examples from the lower Gilgit Basin in the Karakoram Himalaya illustrate relations of rock-wall failure to former glacier activity and post-glacial responses, including
sackung
features. In many cases there is strong morphological evidence for paraglacial adjustments. However, other conditions must be considered as partial or alternative controls. They include a complex bedrock geology and seismo-tectonic conditions, and vertical shifts in periglacial and moisture climates. Given the enormous relief, the landslides themselves may involve a range of temporal and spatial distributions influenced by different topo-climates, geological terranes and stages of deglaciation. Meanwhile, post-glacial rock avalanche barriers have blocked and fragmented the river system. They exercise a major control over intermontane sedimentation and valley morphology. These impacts are treated as part of a broader ‘disturbance-regime’ geomorphology, where late Quaternary landscape evolution is driven by transient, but recurring, interactions among geomorphic process systems. Post-glacial conditions have also tended to partition the landscape into subunits with different mixes of geomorphic activity or rates of adjustment. The findings presented here depart from existing interpretations of Quaternary events in the region, and pose challenges for process geomorphology and the role of large landslides.
From climatic to global change geomorphology: contemporary shifts in periglacial geomorphology
Authors: André Marie-Françoise 
Published: July 2009

Abstract
Periglacial geomorphology developed in the 1940s–1960s as a branch of climatic geomorphology, focusing first on Quaternary studies and palaeoenvironmental reconstructions, then on current geomorphic activity in cold regions. The ‘periglacial fever’ of the 1960s–1970s was dominated by the ‘freeze–thaw dogma’: periglacial areas were regarded as necessarily submitted to efficient frost-driven processes ruling over the geomorphic activity. Such a view was severely criticized in the 1980s–1990s based both on monitoring studies and on time–space multiscale approaches that pointed to the need to cross the ‘smokescreen of the periglacial scenery’ to search for the real past and present processes responsible for the landform geometry. The role of non-cold-related processes in the making of ‘periglacial’ landcapes was re-evaluated, and the necessity to better take into account the rock properties and the pre-Quaternary history of slope systems was emphasized. Whereas the part of the cold-related processes was being minimized, the interest of genuine periglacial landforms as geoindicators of climate change was growing, providing a new legitimacy to periglacial geomorphology. Polar and Alpine regions are nowadays considered as key observatories of ongoing climate change, and periglacial geomorphologists are involved in the detection, monitoring and prediction of environmental changes. Finally, the evolution of ‘periglacial geomorphology’ over the past six decades is in accordance with the development of the whole geomorphology. Based on the quantitative and technological revolution, it tends to find a balance between the functional and historical approaches.
Paraglacial rock slope failure as an agent of glacial trough widening
Authors: Jarman David 
Published: July 2009

Abstract

Rock slope failure (RSF) generates the largest single erosional events in the glacial–paraglacial land system, leaving numerous obvious cavities and less obviously weakened valley walls. Its contribution to trough widening in a mountain range has not previously been systematically quantified. Map-based measures of RSF ‘depth of bite’ are applied to five sample areas in the Scottish Highlands, and a comparator area in north Norway, all in metasediments structurally conducive to mass deformation and block sliding. Problems in applying map-based measures include bedrock cavities remaining partially occupied by failed debris or subsequent infill, and multiple planes of reference. The most practical measure is of maximum recess depth on any single contour (
D
MAX
). This is a standardizable single-point indicator of visible impact, not a measure of actual cavity depth, nor an average applying to the whole RSF. In four of the five areas, average
D
MAX
is consistent at 40–45 m. RSF breadth averages 270–600 m over the five areas. RSF affects 9% and 14% of total valley wall length in the two densest RSF areas, rising to 47% and 52% on two specific valley sides. The depth:breadth ratio in areas dominated by slope deformation can be twice that in areas of translational sliding. An evolutionary model of glacial–paraglacial cycling proposes a ‘zone of paraglacial relaxation’ in which RSF is intense in early cycles as fluvial profiles adjust to ice discharge, diminishing with maturity as trough walls become stress-hardened, and reviving in response to neotectonic and glaciological perturbations, notably ice piracy via transfluent breaching. However, a major unknown is the efficacy of glacial exploitation of RSFs: if it takes several cycles to evacuate debris and pare back cavity angles, cumulative RSF impact is lessened. Glacial–paraglacial cycling is a classic positive feedback loop, promoting valley widening beyond the parabolic norm. Preferential exploitation of structure by RSF promotes asymmetrical trough profiles. RSF acts both as a scarp retreat process, and as a slope reduction counterpoint to glacial slope steepening. In landscape evolution, it is a powerful agent in destruction of paleic relief, notably around watersheds that are undergoing breaching by transfluent ice, where trough development and widening is still vigorous.
Rockfall talus slopes and associated talus-foot features in the glaciated uplands of Great Britain and Ireland: periglacial, paraglacial or composite landforms?
Authors: Wilson Peter 
Published: July 2009

Abstract
The traditional interpretation of talus slopes and talus-foot landforms in the glaciated uplands of Great Britain and Ireland has been that they are periglacial landforms associated with freeze–thaw activity and permafrost. Since about 1990 some reassessment of this widely held view has occurred, and paraglacial rockfall and rock-slope failure are now considered to have played a significant role in the development of some talus landforms; in certain cases a wholly paraglacial origin is advocated. In order to determine formative processes, critical site-specific evidence (morphological and sedimentological) needs to be obtained. This will enable models of the deglacial–post-glacial evolution of these landscapes to be proposed and allow the palaeoenvironmental significance of the landforms to be established. Distinguishing between a periglacial and paraglacial origin might be assisted by application of cosmogenic isotope surface-exposure dating, which may demonstrate a Holocene age for a particular landform and thus rule out a permafrost-related origin. However, there will be instances where the application of dating will not differentiate, as in the case of Late Glacial landforms that could be either periglacial or paraglacial. It is likely that equifinality applies with respect to these landforms and a composite origin for them should also be considered. This latter issue is one that has not previously been given much consideration, probably because of the inherent difficulties in recognizing the products of different processes in landforms for which exposures of their constituent materials are rare.
Loss of Histone Deacetylase 4 Causes Segregation Defects during Mitosis of p53-Deficient Human Tumor Cells
Authors: Cadot Bruno , Brunetti Mirko , Coppari Sabina , Fedeli Silvia , de Rinaldis Emanuele , Russo Claudio Dello , Gallinari Paola , De Francesco Raffaele , Steinkühler Christian , Filocamo Gessica 
Published: July 2009

Abstract
We investigated the role of histone deacetylase 4 (HDAC4) using RNA interference (RNAi) and knockout cells to specifically address its role in cell cycle progression in tumor and normal cells. Ablation of HDAC4 led to growth inhibition in human tumor cells but not to detectable effects in normal human dermal fibroblasts (NHDF) or myelopoietic progenitors. HDAC4−/+ or HDAC4−/− murine embryonic fibroblasts showed no detectable growth defects. On the other hand, HDAC4 RNAi in HeLa cells produced mitotic arrest followed by caspase-dependent apoptosis. Mitotically arrested cells showed chromosome segregation defects. Even though the growth of both p53–wild-type and p53-null tumor cells were affected by HDAC4 ablation, segregation defects were observed only in p53-null cells. HDAC4 associates with the PP2A-B56 regulatory subunit, which is known to be involved in chromosome segregation, and RNAi of either the structural subunit A or the regulatory subunit B56 of PP2A also caused chromosome segregation defects. We conclude that HDAC4 is required for cell cycle progression of tumor cells by multiple mechanisms, one of which seems to be specific to p53-deficient cells through chromosome segregation defects. On the contrary, HDAC4 is not required for the progression of NHDF. We therefore suggest that systemic selective interference with the expression or function of HDAC4 is expected to have a significant therapeutic window, in particular, for p53-deficient tumors. [Cancer Res 2009;69(15):6074–82]
Differentiation-Related Gene-1 Decreases Bim Stability by Proteasome-Mediated Degradation
Authors: Ambrosini Grazia , Seelman Sharon L. , Schwartz Gary K. 
Published: July 2009

Abstract
Drg1 was identified as a differentiation-related, putative metastatic suppressor gene in human colon and prostate cancer. Its expression is associated with resistance to irinotecan (CPT-11) therapy in preclinical colorectal cancer models both in vitro and in vivo. However, the functional significance of Drg1 in these processes is unknown. We have shown for the first time that Drg1 directly binds to the BH3-only proapoptotic protein Bim. Depletion of Drg1 by small interfering RNA induced up-regulation of Bim and its accumulation in the mitochondria, which correlated with loss of mitochondrial membrane potential and induction of apoptosis in cells exposed to SN-38. Further analyses revealed that Drg1 promotes degradation of Bim through the Cullin2/ElonginB-CIS ubiquitin-protein ligase complex. Conversely, in the absence of Drg1, Bim was stabilized and bound more abundantly to Hsp70. These results show that Drg1 renders cancer cells more resistant to chemotherapy through enhanced proteasome-mediated Bim degradation. [Cancer Res 2009;69(15):6115–21]
Immunity to Murine Prostatic Tumors: Continuous Provision of T-Cell Help Prevents CD8 T-Cell Tolerance and Activates Tumor-Infiltrating Dendritic Cells
Authors: Shafer-Weaver Kimberly A. , Watkins Stephanie K. , Anderson Michael J. , Draper Lauren J. , Malyguine Anatoli , Alvord W. Gregory , Greenberg Norman M. , Hurwitz Arthur A. 
Published: July 2009

AbstractWe reported previously that tumor-specific CD8+ T cells (TcR-I) become tolerant in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. In this study, we show that CD4+ TcR transgenic (TcR-II) T cells transferred into TRAMP mice became activated in lymph nodes, trafficked to the prostate, and initially functioned as TH1 cells. Although a single cotransfer of TcR-II cells delayed TcR-I cell tolerization, repeated transfer of TcR-II cells was required to prevent TcR-I cell tolerization and significantly slowed progression of TRAMP prostate tumors. After transfer of TcR-II cells, dendritic cells within the tumor expressed higher levels of costimulatory molecules and displayed an enhanced ability to stimulate proliferation of naive T cells. Blockade of CD40-CD40L interactions during TcR-II transfer resulted in a profound reduction in dendritic cell stimulatory capacity and a partial loss of TcR-I effector functions and tumor immunity. These data show that sustained provision of activated tumor-specific CD4+ T cells alters the immunosuppressive tumor microenvironment, ultimately leading to the control of tumor growth. These findings will assist in the design of more effective immunotherapeutic approaches for cancer. [Cancer Res 2009;69(15):6256–64]
Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis
Authors: Yang Eric , Boire Adrienne , Agarwal Anika , Nguyen Nga , O'Callaghan Katie , Tu Powen , Kuliopulos Athan , Covic Lidija 
Published: July 2009

Abstract
Protease-activated receptor 1 (PAR1) is a G protein–coupled receptor that is not expressed in normal breast epithelia but is up-regulated in invasive breast carcinomas. In the present study, we found that matrix metalloprotease-1 (MMP-1) robustly activates the PAR1-Akt survival pathway in breast carcinoma cells. This process is blocked by a cell-penetrating lipopeptide “pepducin,” P1pal-7, which is a potent inhibitor of cell viability in breast carcinoma cells expressing PAR1. Both a MMP-1 inhibitor and P1pal-7 significantly promote apoptosis in breast tumor xenografts and inhibit metastasis to the lungs by up to 88%. Dual therapy with P1pal-7 and Taxotere inhibits the growth of MDA-MB-231 xenografts by 95%. Consistently, biochemical analysis of xenograft tumors treated with P1pal-7 or MMP-1 inhibitor showed attenuated Akt activity. Ectopic expression of constitutively active Akt rescues breast cancer cells from the synergistic cytotoxicity of P1pal-7 and Taxotere, suggesting that Akt is a critical component of PAR1-dependent cancer cell viability. Together, these findings indicate that blockade of MMP1-PAR1 signaling may provide a benefit beyond treatment with Taxotere alone in advanced, metastatic breast cancer. [Cancer Res 2009;69(15):6223–31]
Tumor Vascular Changes Mediated by Inhibition of Oncogenic Signaling
Authors: Qayum Naseer , Muschel Ruth J. , Im Jae Hong , Balathasan Lukxmi , Koch Cameron J. , Patel Sonal , McKenna W. Gillies , Bernhard Eric J. 
Published: July 2009

Abstract
Many inhibitors of the epidermal growth factor receptor (EGFR)-RAS-phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway are in clinical use or under development for cancer therapy. Here, we show that treatment of mice bearing human tumor xenografts with inhibitors that block EGFR, RAS, PI3K, or AKT resulted in prolonged and durable enhancement of tumor vascular flow, perfusion, and decreased tumor hypoxia. The vessels in the treated tumors had decreased tortuosity and increased internodal length accounting for the functional alterations. Inhibition of tumor growth cannot account for these results, as the drugs were given at doses that did not alter tumor growth. The tumor cell itself was an essential target, as HT1080 tumors that lack EGFR did not respond to an EGFR inhibitor but did respond with vascular alterations to RAS or PI3K inhibition. We extended these observations to spontaneously arising tumors in MMTV-neu mice. These tumors also responded to PI3K inhibition with decreased tumor hypoxia, increased vascular flow, and morphologic alterations of their vessels, including increased vascular maturity and acquisition of pericyte markers. These changes are similar to the vascular normalization that has been described after the antiangiogenic treatment of xenografts. One difficulty in the use of vascular normalization as a therapeutic strategy has been its limited duration. In contrast, blocking tumor cell RAS-PI3K-AKT signaling led to persistent vascular changes that might be incorporated into clinical strategies based on improvement of vascular flow or decreased hypoxia. These results indicate that vascular alterations must be considered as a consequence of signaling inhibition in cancer therapy. [Cancer Res 2009;69(15):6347–54]
Host-Derived Tumor Endothelial Marker 8 Promotes the Growth of Melanoma
Authors: Cullen Mike , Seaman Steven , Chaudhary Amit , Yang Mi Young , Hilton Mary Beth , Logsdon Daniel , Haines Diana C. , Tessarollo Lino , St. Croix Brad 
Published: July 2009

Abstract
Tumor endothelial marker 8 (TEM8) was initially identified as a gene overexpressed in the vasculature of human tumors and was subsequently identified as an anthrax toxin receptor. To assess the functional role of TEM8, we disrupted the TEM8 gene in mice by targeted homologous recombination. TEM8−/− mice were viable and reached adulthood without defects in physiologic angiogenesis. However, histopathologic analysis revealed an excess of extracellular matrix in several tissues, including the ovaries, uterus, skin, and periodontal ligament of the incisors, the latter resulting in dental dysplasia. When challenged with B16 melanoma, tumor growth was delayed in TEM8−/− mice, whereas the growth of other tumors, such as Lewis lung carcinoma, was unaltered. These studies show that host-derived TEM8 promotes the growth of certain tumors and suggest that TEM8 antagonists may have utility in the development of new anticancer therapies. [Cancer Res 2009;69(15):6021–6]
Genome-Wide Identification of Direct Target Genes Implicates Estrogen-Related Receptor α as a Determinant of Breast Cancer Heterogeneity
Authors: Deblois Geneviève , Hall Jacqueline A. , Perry Marie-Claude , Laganière Josée , Ghahremani Majid , Park Morag , Hallett Michael , Giguère Vincent 
Published: July 2009

Abstract
Estrogen-related receptor α (ERRα) is an orphan nuclear receptor, the expression of which correlates with negative prognosis in breast cancer. ERRα shares functional features with the estrogen receptor α (ERα) and its activity is modulated by the ERBB2 signaling pathway. Using genome-wide binding sites location analyses in ERα-positive and ERα-negative breast cancer cell lines, we show that ERRα and ERα display strict binding site specificity and maintain independent mechanisms of transcriptional activation. Nonetheless, ERRα and ERα coregulate a small subset of common target genes via binding either to a dual-specificity binding site or to distinct cognate binding sites located within the extended promoter region of the gene. Although ERRα signaling in breast cancer cells is mostly independent of ERα, the small fraction of common ERRα/ERα targets comprises genes with high relevance to breast tumor biology, including genes located within the ERBB2 amplicon and GATA3. Finally, unsupervised hierarchical clustering based on the expression profiling of ERRα direct target genes in human breast tumors revealed four main clusters that recapitulate established tumor subtypes. Taken together, the identification and functional characterization of the ERRα transcriptional network implicate ERRα signaling as a determinant of breast cancer heterogeneity. [Cancer Res 2009;69(15):6149–57]
Effective Treatment of Advanced Human Melanoma Metastasis in Immunodeficient Mice Using Combination Metronomic Chemotherapy Regimens
Authors: Cruz-Munoz William , Man Shan , Kerbel Robert S. 
Published: July 2009

Abstract
Purpose: The development of effective therapeutic approaches for treatment of metastatic melanoma remains an immense challenge. Present therapies offer minimal benefit. Although dacarbazine chemotherapy remains the standard therapy, it mediates only low response rates, usually of short duration, even when combined with other chemotherapeutic agents. Thus, new therapeutic strategies are urgently needed.
Experimental Design: Using a newly developed preclinical model, we evaluated the efficacy of various doublet metronomic combination chemotherapy against established advanced melanoma metastasis and compared these with the standard maximum tolerated dose dacarbazine (alone or in combination with chemotherapeutic agents or vascular endothelial growth factor receptor–blocking antibody).
Results: Whereas maximum tolerated dose dacarbazine therapy did not cause significant improvement in median survival, a doublet combination of low-dose metronomic vinblastine and low-dose metronomic cyclophosphamide induced a significant increase in survival with only minimal toxicity. Furthermore, we show that the incorporation of the low-dose metronomic vinblastine/low-dose metronomic cyclophosphamide combination with a low-dose metronomic dacarbazine regimen also results in a significant increase in survival, but not when combined with maximum tolerated dose dacarbazine therapy. We also show that a combination of metronomic vinblastine therapy and a vascular endothelial growth factor receptor 2–blocking antibody (DC101) results in significant control of metastatic disease and that the combination of low-dose metronomic vinblastine/DC101 and low-dose metronomic dacarbazine induced a significant improvement in median survival.
Conclusions: The effective control of advanced metastatic melanoma achieved by these metronomic-based chemotherapeutic approaches warrants clinical consideration of this treatment concept, given the recent results of a number of metronomic-based chemotherapy clinical trials.