bluuebunny/crossref_metadata_2025_split huggingface dataset:
Case stories in general practice: a focus group study
Authors: Abildsnes Eirik , Flottorp Signe , Stensland Per 
Published: August 2012

ObjectivesTo explore the interactive process of sharing case stories in small-group activity in general practice.DesignQualitative focus group study.SettingPeer-group meetings of doctors attending specialist training or continuous medical education in general practice.ParticipantsTwenty female and 30 male doctors working in general practice in Norway.ResultsThe storyline of case presentations included detailed stories with emotional engagement, co-authored by other group members. The stories initiated discussions and reflections concerning patients’ and doctors’ perspectives, medical ethics as well as clinical problems. The safe atmosphere allowed testing out boundaries of socially shared knowledge.ConclusionsSharing case stories in small groups in general practice initiated interaction that facilitated meaning-making, reflection and peer support.
The dilatancy–diffusion hypothesis and earthquake predictability
Authors: Main Ian G. , Bell Andrew F. , Meredith Philip G. , Geiger Sebastian , Touati Sarah 
Published: August 2012

Abstract
The dilatancy–diffusion hypothesis was one of the first attempts to predict the form of potential geophysical signals that may precede earthquakes, and hence provide a possible physical basis for earthquake prediction. The basic hypothesis has stood up well in the laboratory, where catastrophic failure of intact rocks has been observed to be associated with geophysical signals associated both with dilatancy and pore pressure changes. In contrast, the precursors invoked to determine the predicted earthquake time and event magnitude have not stood up to independent scrutiny. There are several reasons for the lack of simple scaling between the laboratory and the field scales, but key differences are those of scale in time and space and in material boundary conditions, coupled with the sheer complexity and non-linearity of the processes involved. ‘Upscaling’ is recognized as a difficult task in multi-scale complex systems generally and in oil and gas reservoir engineering specifically. It may however provide a clue as to why simple local laws for dilatancy and diffusion do not scale simply to bulk properties at a greater scale, even when the fracture system that controls the mechanical and hydraulic properties of the reservoir rock is itself scale-invariant.
Andersonian and Coulomb stresses in Central Costa Rica and its fault slip tendency potential: new insights into their associated seismic hazard
Authors: López Allan 
Published: August 2012

Abstract

Plate boundary forces acting within the Cocos Plate that is being subducted at a rate of 8.5–9.0 cm a
−1
towards N32°E below the Caribbean Plate and the Panama microplate are found responsible for contemporaneous superimposed compressive, wrench and extensive fault patterns in Central Costa Rica. The stress inversion of fault-slip planes and focal mechanisms reveals a prevailing convergence-imposed N20°–45°E almost horizontal compression. Ellipsoid
R
values [
R
=(σ
1
–σ
2
)/(σ
2
–σ
3
)] in the range of 0.3–0.05 and 0.8–0.93 are responsible for the permutation of σ
2
to σ
3
and σ
2
to σ
1
, respectively, and show typical Andersonian configurations with one stress axis vertical or close to it. Coulomb failure stress (CFS) analysis reveals that up to 5 bars (0.5 MPa) of tectonic loading are being imposed on east–west thrusts and on critically oriented conjugate NW- and NE-trending strike-slip faults. Non-optimally oriented structures are potential targets for reactivation even with 2 bars (0.2 MPa) of load. Triggering and interaction with volcanic activity is highly suspected in one documented recent case. When the regional fault population was tested for its slip tendency (τ
/
σ
n
), a good correlation with CFS results was found.
Geomechanical modelling of fault reactivation in the Ceduna Sub-basin, Bight Basin, Australia
Authors: Macdonald J. , Backé G. , King R. , Holford S. , Hillis R. 
Published: August 2012

Abstract

The Ceduna Sub-basin is located within the Bight Basin on the Australian southern margin. Recent structural analysis using newly acquired two-dimensional (2D) and three-dimensional (3D) seismic data demonstrates two Late Cretaceous delta–deepwater fold–thrust belts (DDWFTBs), which are overlain by Cenozoic sediments. The present-day normal fault stress regime identified in the Bight Basin indicates that the maximum horizontal stress (
S
Hmax
) is margin parallel; Andersonain faulting theory therefore suggests the delta-top extensional faults are oriented favourably for reactivation. A breached hydrocarbon trap encountered in the Jerboa-1 well demonstrates this fault reactivation. Faults interpreted from 3D seismic data were modelled using the Poly3D
©
geomechanical code to determine the risk of reactivation. Results indicate delta-top extensional faults that dip 40–70° are at moderate–high risk of reactivation, while variations in the orientation of the fault planes results in an increased risk of reactivation. Two pulses of inversion are identified in the Ceduna Sub-basin and correlate with the onset of rifting and fault reactivation in the Santonian. We propose a ridge-push mechanism for this stress which selectively reactivates extensional faults on the delta-top, forming inversion anticlines that are prospective for hydrocarbon exploration.
Pressure conditions for shear and tensile failure around a circular magma chamber; insight from elasto-plastic modelling
Authors: Gerbault Muriel 
Published: August 2012

Abstract
Overpressure within a circular magmatic chamber embedded in an elastic half space is a widely used model in volcanology. However, this overpressure is generally assumed to be bounded by the bedrock tensile strength since gravity is neglected. Critical overpressure for wall failure is thus greater. It is shown analytically and numerically that wall failure occurs in shear rather than in tension, because the Mohr–Coulomb yield stress is less than the tensile yield stress. Numerical modelling of progressively increasing overpressure shows that bedrock failure develops in three stages: (1) tensile failure at the ground surface; (2) shear failure at the chamber wall; and (3) fault connection from the chamber wall to the ground surface. Predictions of surface deformation and stress with the theory of elasticity break down at stage 3. For wall tensile failure to occur at small overpressure, a state of lithostatic pore-fluid pressure is required in the bedrock which cancels the effect of gravity. Modelled eccentric shear band geometries are consistent with theoretical solutions from engineering plasticity and compare well with shear structures bordering exhumed intrusions. This study shows that the measured ground surface deformation may be misinterpreted when neither plasticity nor pore-fluid pressure is accounted for.

Supplementary material:

The numerical benchmark data are available at:
http://www.geolsoc.org.uk/SUP18517
.
Stress fluctuation during thrust-related folding: Boltaña anticline (Pyrenees, Spain)
Authors: Tavani S. , Fernandez O. , Muñoz J. A. 
Published: August 2012

Abstract
A common feature of thrust-related anticlines developing in thrust wedges is the presence of extensional structures paralleling the fold axial trend (i.e. longitudinal structures). These form in response to hinge-perpendicular stretching and indicate that the minimum stress component orients parallel to the regional shortening direction, that is, the maximum and minimum stress components locally invert. Under the assumption that the regional stress component paralleling the shortening direction is almost constant during folding, such an inversion requires a large local stress drop. In the thrust-related Boltaña anticline, folding was both predated and accompanied by the development of longitudinal extensional faults. Meso-scale contractional structures are only rarely found. Where contractional structures are present, cross-cutting relationships indicate that these structures episodically developed within a mainly extensional framework which was established during flexural bending of the foredeep and continued during thrust-related folding. We conclude that the coexistence of extensional and compressional structures relates to a stress fluctuation, with normal faulting and discontinuous fold growth occurring during ‘extensional’ and ‘compressional’ stages, respectively.
Hedgehog Signaling Is a Novel Therapeutic Target in Tamoxifen-Resistant Breast Cancer Aberrantly Activated by PI3K/AKT Pathway
Authors: Ramaswamy Bhuvaneswari , Lu Yuanzhi , Teng Kun-yu , Nuovo Gerard , Li Xiaobai , Shapiro Charles L. , Majumder Sarmila 
Published: August 2012

Abstract
Endocrine resistance is a major challenge in the management of estrogen receptor (ER)-positive breast cancers. Although multiple mechanisms leading to endocrine resistance have been proposed, the poor outcome of patients developing resistance to endocrine therapy warrants additional studies. Here we show that noncanonical Hedgehog (Hh) signaling is an alternative growth promoting mechanism that is activated in tamoxifen-resistant tumors. Importantly, phosphoinositide 3-kinase inhibitor/protein kinase B (PI3K/AKT) pathway plays a key role in regulating Hh signaling by protecting key components of this pathway from proteasomal degradation. The levels of Hh-signaling molecules SMO and GLI1 and the targets were significantly elevated in tamoxifen-resistant MCF-7 cells and T47D cells. Serial passage of the resistant cells in mice resulted in aggressive tumors that metastasized to distant organs with concurrent increases in Hh marker expression and epithelial mesenchymal transition. RNAi-mediated depletion of SMO or GLI1 in the resistant cells resulted in reduced proliferation, clonogenic survival and delayed G1–S transition. Notably, treatment of resistant cells with PI3K inhibitors decreased SMO and GLI1 protein levels and activity that was rescued upon blocking GSK3β and proteasomal degradation. Furthermore, treatment of tamoxifen-resistant xenografts with anti-Hh compound GDC-0449 blocked tumor growth in mice. Importantly, high GLI1 expression correlated inversely with disease-free and overall survival in a cohort of 315 patients with breast cancer. In summary, our results describe a signaling event linking PI3K/AKT pathway with Hh signaling that promotes tamoxifen resistance. Targeting Hh pathway alone or in combination with PI3K/AKT pathway could therefore be a novel therapeutic option in treating endocrine-resistant breast cancer. Cancer Res; 72(19); 5048–59. ©2012 AACR.
Abstract 1: Oncogenic extracellular domain mutations of ERBB2 in cancer
Authors: Greulich Heidi , Kaplan Bethany , Mertins Philipp , Chen Tzu-Hsiu , Tanaka Kumiko , Yun Cai-Hong , Imielinski Marcin , Banerji Shanatanu , Lawrence Michael S. , Walker Sarah , Winckler Wendy , Getz Gad , Frank David , Eck Michael , Jaffe Jacob D. , Carr Steven A. , Wong Kwok-Kin , Meyerson Matthew 
Published: August 2012

Abstract
The ERBB2 receptor tyrosine kinase gene is frequently amplified and mutated in human cancer. However, mutations characterized to date have been located in the kinase domain of the receptor. Using publically-available sequencing datasets, we have found that extracellular domain mutations of ERBB2 located beneath the dimerization arm recur in lung, breast, and ovarian cancers. We expressed cDNAs harboring these mutations in NIH-3T3 cells and found that the mutants support anchorage-independent proliferation. We furthermore found that substitution of any one of a number of amino acids in this region of the protein is oncogenic. We sought to biochemically characterize the extracellular domain mutations of ERBB2 and found that they cause oncogenic transformation by one of two mechanisms: elevation of C-terminal tail phosphorylation, or reduction-sensitive covalent dimerization unaccompanied by increases in C-terminal phosphorylation. Analysis of tyrosine phosphorylated proteins in the cell by stable isotope labeling followed by mass spectrometry (SILAC) revealed that both classes of mutant receptor phosphorylated the same set of proteins to effect transformation. The most prominent targets were proteins involved in cytoskeletal and membrane dynamics, controlling cell motility. STAT3 was also phosphorylated to a limited extent in ERBB2-transformed cells. Interestingly, STAT3 phosphorylation was mediated solely by a JAK-dependent autocrine loop in cells transformed by the ERBB2 mutants activated by reduction-sensitive dimerization; whereas both ERBB2 and JAK family kinases contributed to STAT3 phosphorylation in cells transformed by ERBB2 mutants exhibiting increased C-terminal phosphorylation. In order to characterize inhibitor sensitivity, we transformed Ba/F3 cells to IL-3 independence with the ERBB2 extracellular domain mutants. All extracellular domain mutants tested were sensitive to irreversible inhibitors of ERBB2, suggesting that treatment with such inhibitors may benefit patients harboring mutations of the extracellular domain of ERBB2.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1. doi:1538-7445.AM2012-1
Abstract 1010: Effect of dietary energy balance modulation on the ability of metformin to inhibit skin tumor promotion
Authors: Checkley Allyson , Moore Tricia , Rho Okkyung , DiGiovanni John 
Published: August 2012

Abstract
The prevalence of obesity has drastically increased over the last decade and is associated with increased risk for several cancers. In contrast, calorie restriction (CR) universally inhibits cancer. Plausible mechanisms for the energy balance-cancer link include differential signaling through Akt/mTOR via the IGF-1R as well as other growth factor receptors. Previous data from our lab, using topical administration of rapamycin, support the hypothesis that pharmacological disruption of mTORC1 signaling mimics some of the effects of CR on skin tumor promotion. To further explore the role of mTORC1 signaling in tumor promotion we have conducted studies using metformin. In the present study, metformin was administered in the drinking water at doses of 250 mg/kg and 50 mg/kg body weight per day to female FVB/N mice, to assess its ability to reverse the effects of overweight/obesity on skin tumor promotion during two-stage skin carcinogenesis. Metformin treatment during skin tumor promotion significantly inhibited tumor multiplicity in a dose dependent manner in mice on an overweight control diet (AIN76A). There was a 70% reduction in papillomas per mouse at the 250 mg/kg dose and a 35% reduction at the 50 mg/kg dose. Short term mechanistic experiments with these same doses revealed significant decreases in TPA-induced epidermal hyperproliferation (as measured by epidermal hyperplasia and labeling index) after oral administration of metformin. Metformin also activated AMP Kinase in the epidermis as measured by pAMPKαT172 at both doses used as well as attenuated signaling through mTORC1 at the highest dose as measured by downstream signaling proteins p70S6KT389 and prS6S235/236. Treatment with the higher dose of metformin also prevented TPA-induced mTORC1 mediated degradation of translational repressor PDCD4. Current experiments are assessing the ability of metformin to suppress skin tumor promotion in mice maintained on an obesity inducing diet (60kcal% fat) and these studies will also be presented. Overall, the current data support the hypothesis that selectively targeting mTORC1, either directly (rapamycin) or indirectly via AMPK activation, may be an effective strategy for reversing the effects of overweight and obesity on tumor development during epithelial carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1010. doi:1538-7445.AM2012-1010
Abstract 1014: Targeting cancer stem cells by a Notch2/Notch3 cross-reactive antibody inhibits tumor growth and delays tumor recurrence in pancreatic cancer
Authors: Fischer Marcus M. , Yen Wan-Ching , Wang Min , Kapoun Ann M. , Sato Aaron , Lewicki John , Gurney Austin , Hoey Timothy 
Published: August 2012

Abstract
Pancreatic cancer is a devastating disease with very poor prognosis and few treatment options. The Notch pathway has been implicated in the development of pancreatic cancer, and in particular both Notch2 and Notch3 are known to be important in this disease. In this report, we examined the in vivo efficacy of an antibody that was initially identified by binding to Notch2 and was subsequently shown to block signaling of both human and mouse Notch2 and Notch3. Utilizing a panel of minimally-passaged, patient-derived, pancreatic adenocarcinoma xenograft tumors, we performed in vivo growth inhibition and tumorigenicity studies with the Notch2/3 antibody alone or combined with the standard-of-care chemotherapeutic gemcitabine. We demonstrated that the Notch2/3 antibody was active as a single agent, and when combined with gemcitabine, the combination therapy resulted in improved efficacy over that of gemcitabine alone. Utilizing an in vivo limiting dilution tumorigenicity assay, we found that the cancer stem cell (CSC) frequency was increased by gemcitabine as a single agent, but significantly decreased by the combination of anti-Notch2/3 and gemcitabine. Analysis of cell surface markers associated with pancreatic cancer stem cells indicated that gemcitabine treatment results in an increase in the percentage of CSCs, while the Notch2/3 antibody significantly reduced the CSC population. Utilizing this pancreatic cancer xenograft model, we analyzed the ability of the Notch 2/3 antibody to delay tumor recurrence following gemcitabine induced tumor regression. While gemcitabine-treated tumors re-grew rapidly following treatment termination, the ability of tumors to recur was significantly delayed by the Notch2/3 antibody suggesting that the delay in tumor recurrence is in part due to the Notch2/3 antibody-mediated decrease in CSC frequency. Gene set enrichment analysis in tumors that responded to anti-Notch2/3 revealed that various stem cell gene sets were up-regulated in tumors treated by gemcitabine alone, but down-regulated by the combination of anti-Notch2/3 and gemcitabine. Findings from this study suggest that antagonists of Notch signaling may act as chemotherapeutic-sensitizing agents by interfering with CSC self renewal pathways and thereby enhancing the cytotoxic effects of chemotherapy on CSCs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1014. doi:1538-7445.AM2012-1014
Abstract 1017: Protooncogenic TLR4 generates NANOG-dependent tumor-initiating stem-like cells through LIN28-Let7 pathway in experimental and clinical carcinogenesis
Authors: Machida Keigo , Chen Chia-Lin , Liu Jian-Chang , Sher Linda , Mishra Lopa , Tsukamoto Hidekazu 
Published: August 2012

Abstract
[Background] TLR4 signaling activated by alcohol/obesity-associated endotoxemia, induces the stem cell marker Nanog to generate tumor-initiating stem-like cells (TISCs) and liver tumors in the HCV nonstructural protein Ns5a transgenic (Tg) mice but not in wild type or Ns5a Tg mice deficient in TLR4 (Machida and Tsukamoto, PNAS, 2009). However, it is unknown whether the TLR4-NANOG pathway serves as a universal oncogenic signaling in the genesis of TISCs and HCC in other etiological animal models and patients or how TLR4 is upregulated in TLR4-NANOG-dependent TISCs. [Aim] We aimed to determine whether TLR4 is a putative proto-oncogene for TIC in liver oncogenesis due to different etiologies and how TLR4 is regulated at the transcriptional and epigenetic levels. [Methods] CD133+/CD49f+ TISCs were isolated using FACS from HCC developed in HCV Core Tg mice fed alcohol, diethylnitrosamine (DEN)-treated mice, and alcoholic patients with or without HCV infection. We generated Tg mice with liver-selective overexpression of constitutively active (ca) TLR4 using LAP promoter-driven tTA and Tet-caTLR4. TLR4 promoter-reporter analysis was performed on TISCs from alcohol-fed Core Tg mice. [Results] CD133+/CD49f+ cells isolated from the animal models and patients are tumorigenic both in vitro and in a xenograft model, and TLR4 or NANOG silencing with shRNA attenuates their tumor initiating property. Hepatocyte specific expression of caTLR4 results in spontaneous development of HCC in 35% of the mice. LIN28 and TLR4 expression is 6-fold higher in TISCs compared to CD133-/CD49f+ cells, and the expression of LIN28 increases TLR4 expression with reduction of Let7 microRNA in CD133- cells but not TISCs, suggesting LIN28-mediated Let7 reduction drive TLR4 induction. TLR4 expression and promoter activity are further reduced by a silencing of LIN28 or expression of Let7. LIN28 and NANOG overexpression transform liver stem cells through activation of TLR4-NANOG pathway. [Conclusions] These results demonstrate that CD133+/CD49f+ cells are TLR4/NANOG-dependent TISCs in both experimental and clinical HCC. TLR4 is induced by LIN28 signaling and is a universal proto-oncogene responsible for the genesis of TLR4-NANOG dependent TISCs, and this pathway serves as a novel therapeutic target for HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1017. doi:1538-7445.AM2012-1017