bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of 23 364 patient-generated, physician-reviewed malpractice claims from a non-tort, blame-free, national patient insurance system: lessons learned from Sweden
Authors: Pukk-Härenstam K , Ask J , Brommels M , Thor J , Penaloza R V , Gaffney F A 
Published: August 2008

Abstract

Context
In Sweden, patient malpractice claims are handled administratively and compensated if an independent physician review confirms patient injury resulting from medical error. Full access to all malpractice claims and hospital discharge data for the country provided a unique opportunity to assess the validity of patient claims as indicators of medical error and patient injury.

Objective
To determine: (1) the percentage of patient malpractice claims validated by independent physician review, (2) actual malpractice claims rates (claims frequency ÷ clinical volume) and (3) differences between Swedish and other national malpractice claims rates.

Design, setting and material
Swedish national malpractice claims and hospital discharge data were combined, and malpractice claims rates were determined by county, hospital, hospital department, surgical procedure, patient age and sex and compared with published studies on medical error and malpractice.

Results
From 1997 to 2004, there were 23 364 inpatient malpractice claims filed by Swedish patients treated at hospitals reporting 11 514 798 discharges. The overall claims rate, 0.20%, was stable over the period of study and was similar to that found in other tort and administrative compensation systems. Over this 8-year period, 49.5% (range 47.0–52.6%) of filed claims were judged valid and eligible for compensation. Claims rates varied significantly across hospitals; surgical specialties accounted for 46% of discharges, but 88% of claims. There were also large differences in claims rates for procedures.

Conclusions
Patient-generated malpractice claims, as collected in the Swedish malpractice insurance system and adjusted for clinical volumes, have a high validity, as assessed by standardised physician review, and provide unique new information on malpractice risks, preventable medical errors and patient injuries. Systematic collection and analysis of patient-generated quality of care complaints should be encouraged, regardless of the malpractice compensation system in use.
Seasonal variation in size-dependent survival of juvenile Atlantic salmon (Salmo salar): performance of multistate capture–mark–recapture models
Authors: Letcher Benjamin H. , Horton Gregg E. 
Published: August 2008

We estimated the magnitude and shape of size-dependent survival (SDS) across multiple sampling intervals for two cohorts of stream-dwelling Atlantic salmon ( Salmo salar ) juveniles using multistate capture–mark–recapture (CMR) models. Simulations designed to test the effectiveness of multistate models for detecting SDS in our system indicated that error in SDS estimates was low and that both time-invariant and time-varying SDS could be detected with sample sizes of >250, average survival of >0.6, and average probability of capture of >0.6, except for cases of very strong SDS. In the field (N ∼750, survival 0.6–0.8 among sampling intervals, probability of capture 0.6–0.8 among sampling occasions), about one-third of the sampling intervals showed evidence of SDS, with poorer survival of larger fish during the age-2+ autumn and quadratic survival (opposite direction between cohorts) during age-1+ spring. The varying magnitude and shape of SDS among sampling intervals suggest a potential mechanism for the maintenance of the very wide observed size distributions. Estimating SDS using multistate CMR models appears complementary to established approaches, can provide estimates with low error, and can be used to detect intermittent SDS.
A preliminary national analysis of some key characteristics of Canadian lakes
Authors: Minns Charles K. , Moore James E. , Shuter Brian J. , Mandrak Nicholas E. 
Published: August 2008

Knowledge of Canada’s lakes is needed to manage environmental stresses. Lake inventory and lake feature databases were used to build a national impact assessment template and assess regional typology. There are ~910 400 lakes with area ≥ 0.1 km2(10 ha), 37% of the Earth’s total. Lake features (number of lakes by size class, maximum depth, mean–maximum depth ratio, Secchi depth, pH, and total dissolved solids) were modeled regionally by secondary watershed (SWS) using linear regression models. Lake trout ( Salvelinus namaycush ) occurrence was analyzed as a cofactor to highlight regional links between lake characteristics and aquatic biota. Significant (R2from 0.231 to 0.492) regional models were obtained using area or maximum depth, lake trout occurrence, and their cross products as covariates. Analyses of fitted SWS coefficients showed that ecozones were a better predictor of lake characteristics than primary watersheds. The national typology was consistent with previous regional assessments. The regional models were used to estimate the number, area, and volume of lake trout lakes by size class and ecozone. There are ~66 500 lake trout lakes covering ~3 510 000 km2primarily on Boreal and Taiga Shield areas. Regional lake resource models will enable national assessment of stresses such as climate change and invasive species.
Development of an NEHRP map for the Orleans suburb of Ottawa, Ontario
Authors: Motazedian Dariush , Hunter James 
Published: August 2008

The average shear-wave velocity to a depth of 30 m (Vs30) has been obtained for 73 sites in the Orleans area in the northeast part of the City of Ottawa. Measurements of Vs30 were made using both ground surface reflection and refraction methods. In addition, borehole data was used to estimate Vs versus depth profiles using average Vs values assigned to distinct geological units. High values of Vs (>1500 m/s) were obtained in areas of thin surficial sediments overlying Paleozoic bedrock, and low Vs values (<180 m/s) were calculated in areas of thick late–post-glacial clay. The Vs30 values have been used to prepare an NEHRP map for the study area. Much of the suburb of Orleans is classified as NEHRP zone E, whereas the perimeter areas and some isolated central areas are classified as zones ranging from zone D to zone A. The presence of thick unconsolidated late–post-glacial sediments deposited in the Champlain Sea is the main contributing factor to the wide range of average shear-wave velocities in the study area.
Impaired Dendritic Cell Function in Aging Leads to Defective Antitumor Immunity
Authors: Grolleau-Julius Annabelle , Harning Erin K. , Abernathy Lisa M. , Yung Raymond L. 
Published: August 2008

Abstract
We recently reported that bone marrow–derived dendritic cells (DC) from aged miced are less effective than their young counterparts in inducing the regression of B16-ovalbumin (OVA) melanomas. To examine the underlying mechanisms, we investigated the effect of aging on DC tumor antigen presentation and migration. Although aging does not affect the ability of DCs to present OVA peptide(257–264), DCs from aged mice are less efficient than those from young mice in stimulating OVA-specific T cells in vitro. Phenotypic analysis revealed a selective decrease in DC-specific/intracellular adhesion molecule type-3–grabbing nonintegrin (DC-SIGN) level in aged DCs. Adoptive transfer experiments showed defective in vivo DC trafficking in aging. This correlates with impaired in vitro migration and defective CCR7 signaling in response to CCL21 in aged DCs. Interestingly, vaccination of young mice using old OVA peptide(257–264)–pulsed DCs (OVA PP-DC) resulted in impaired activation of OVA-specific CD8+ T cells in vivo. Effector functions of these T cells, as determined by IFN-γ production and cytotoxic activity, were similar to those obtained from mice vaccinated with young OVA PP-DCs. A decreased influx of intratumor CD8+ T cells was also observed. Importantly, although defective in vivo migration could be restored by increasing the number of old DCs injected, the aging defect in DC tumor surveillance and OVA-specific CD8+ T-cell induction remained. Taken together, our findings suggest that defective T-cell stimulation contributes to the observed impaired DC tumor immunotherapeutic response in aging. [Cancer Res 2008;68(15):6341–9]
Phosphatidylinositol 3-Kinase Inhibition Broadly Sensitizes Glioblastoma Cells to Death Receptor– and Drug-Induced Apoptosis
Authors: Opel Daniela , Westhoff Mike-Andrew , Bender Ariane , Braun Veit , Debatin Klaus-Michael , Fulda Simone 
Published: August 2008

Abstract
The aberrant activity of the phosphatidylinositol 3-kinase (PI3K) pathway has been reported to correlate with adverse clinical outcome in human glioblastoma in vivo. However, the question of how this survival network can be successfully targeted to restore the sensitivity of glioblastoma to apoptosis induction has not yet been answered. Here, we report that inhibition of PI3K by LY294002 broadly sensitizes wild-type and mutant PTEN glioblastoma cells to both death receptor– and chemotherapy-induced apoptosis, whereas mammalian target of rapamycin (mTOR) inhibition is not sufficient to restore apoptosis sensitivity. LY294002 significantly enhances apoptosis triggered by tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), agonistic anti-CD95 antibodies, or several anticancer drugs (i.e., doxorubicin, etoposide, and vincristine) in a highly synergistic manner. In addition, LY294002 cooperates with TRAIL or doxorubicin to suppress colony formation, thus also showing a strong effect on long-term survival. Similarly, genetic knockdown of PI3K subunits p110α and/or p110β by RNA interference (RNAi) primes glioblastoma cells for TRAIL- or doxorubicin-mediated apoptosis. In contrast to PI3K inhibition, pharmacologic or genetic blockade of mTOR by RAD001 (everolimus), rapamycin, or RNAi fails to enhance TRAIL- or doxorubicin-induced apoptosis. Analysis of apoptosis pathways reveals that PI3K inhibition acts in concert with TRAIL or doxorubicin to trigger mitochondrial membrane permeabilization, caspase activation, and caspase-dependent apoptosis, which are abolished by the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. Most importantly, PI3K inhibition by LY294002 sensitizes primary cultured glioblastoma cells obtained from surgical specimens to TRAIL- or chemotherapy-induced cell death. By showing that PI3K inhibition broadly primes glioblastoma cells for apoptosis, our findings provide the rationale for using PI3K inhibitors in combination regimens to enhance TRAIL- or chemotherapy-induced apoptosis in glioblastoma. [Cancer Res 2008;68(15):6271–80]
Inhibition of Metastatic Outgrowth from Single Dormant Tumor Cells by Targeting the Cytoskeleton
Authors: Barkan Dalit , Kleinman Hynda , Simmons Justin L. , Asmussen Holly , Kamaraju Anil K. , Hoenorhoff Mark J. , Liu Zi-yao , Costes Sylvain V. , Cho Edward H. , Lockett Stephen , Khanna Chand , Chambers Ann F. , Green Jeffrey E. 
Published: August 2008

Abstract
Metastatic breast cancer may emerge from latent tumor cells that remain dormant at disseminated sites for many years. Identifying mechanisms regulating the switch from dormancy to proliferative metastatic growth has been elusive due to the lack of experimental models of tumor cell dormancy. We characterized the in vitro growth characteristics of cells that exhibit either dormant (D2.0R, MCF-7, and K7M2AS1.46) or proliferative (D2A1, MDA-MB-231, and K7M2) metastatic behavior in vivo. Although these cells proliferate readily in two-dimensional culture, we show that when grown in three-dimensional matrix, distinct growth properties of the cells were revealed that correlate to their dormant or proliferative behavior at metastatic sites in vivo. In three-dimensional culture, cells with dormant behavior in vivo remained cell cycle arrested with elevated nuclear expression of p16 and p27. The transition from quiescence to proliferation of D2A1 cells was dependent on fibronectin production and signaling through integrin β1, leading to cytoskeletal reorganization with filamentous actin (F-actin) stress fiber formation. We show that phosphorylation of myosin light chain (MLC) by MLC kinase (MLCK) through integrin β1 is required for actin stress fiber formation and proliferative growth. Inhibition of integrin β1 or MLCK prevents transition from a quiescent to proliferative state in vitro. Inhibition of MLCK significantly reduces metastatic outgrowth in vivo. These studies show that the switch from dormancy to metastatic growth may be regulated, in part, through epigenetic signaling from the microenvironment, leading to changes in the cytoskeletal architecture of dormant cells. Targeting this process may provide therapeutic strategies for inhibition of the dormant-to-proliferative metastatic switch. [Cancer Res 2008;68(15):6241–50]
The Arf/p53 Pathway in Cancer and Aging
Authors: Matheu Ander , Maraver Antonio , Serrano Manuel 
Published: August 2008

Abstract
Arf and p53 are regarded among the most relevant tumor suppressors based on their ubiquitous and frequent inactivation in human cancer. The Arf/p53 pathway protects cells against several types of damage and this is the basis of its tumor suppressor activity. Interestingly, aging is a process associated with the accumulation of damage derived from chronic stresses of small magnitude. In agreement with its damage protection role, it has been recently described that the Arf/p53 pathway not only protects mammalian organisms from cancer but also from aging. However, there is also evidence that p53, under certain circumstances, such as when constitutively active, can induce aging. We discuss here the current evidence linking the Arf/p53 pathway to the process of aging and present a unified model. [Cancer Res 2008;68(15):6031–4]
Oct-3/4 Expression Reflects Tumor Progression and Regulates Motility of Bladder Cancer Cells
Authors: Chang Chao-Ching , Shieh Gia-Shing , Wu Pensee , Lin Chia-Cheng , Shiau Ai-Li , Wu Chao-Liang 
Published: August 2008

AbstractCancer and embryonic stem cells exhibit similar behavior, including immortal, undifferentiated, and invasive activities. Here, we show that in clinical samples bladder tumors with intense expression of stem cell marker Oct-3/4 (also known as POU5F1) are associated with further disease progression, greater metastasis, and shorter cancer-related survival compared with those with moderate and low expressions. Expression of Oct-3/4 is detected in human bladder transitional cell carcinoma samples and cell lines. Overexpression of Oct-3/4 enhances, whereas knockdown of Oct-3/4 expression by RNA interference reduces, migration and invasion of bladder cancer cells. Oct-3/4 can up-regulate fibroblast growth factor-4 and matrix metalloproteinase-2 (MMP-2), MMP-9, and MMP-13 production, which may contribute to tumor metastasis. Finally, we show that Ad5WS4, an E1B-55 kD–deleted adenovirus driven by the Oct-3/4 promoter, exerts potent antitumor activity against bladder cancer in a syngeneic murine tumor model. Therefore, our results implicate that Oct-3/4 may be useful as a novel tumor biological and prognostic marker and probably as a potential therapeutic target for bladder cancer. [Cancer Res 2008;68(15):6281–91]
Genomic Profiling of MicroRNA and Messenger RNA Reveals Deregulated MicroRNA Expression in Prostate Cancer
Authors: Ambs Stefan , Prueitt Robyn L. , Yi Ming , Hudson Robert S. , Howe Tiffany M. , Petrocca Fabio , Wallace Tiffany A. , Liu Chang-Gong , Volinia Stefano , Calin George A. , Yfantis Harris G. , Stephens Robert M. , Croce Carlo M. 
Published: August 2008

Abstract
MicroRNAs are small noncoding RNAs that regulate the expression of protein-coding genes. To evaluate the involvement of microRNAs in prostate cancer, we determined genome-wide expression of microRNAs and mRNAs in 60 primary prostate tumors and 16 nontumor prostate tissues. The mRNA analysis revealed that key components of microRNA processing and several microRNA host genes, e.g., MCM7 and C9orf5, were significantly up-regulated in prostate tumors. Consistent with these findings, tumors expressed the miR-106b-25 cluster, which maps to intron 13 of MCM7, and miR-32, which maps to intron 14 of C9orf5, at significantly higher levels than nontumor prostate. The expression levels of other microRNAs, including a number of miR-106b-25 cluster homologues, were also altered in prostate tumors. Additional differences in microRNA abundance were found between organ-confined tumors and those with extraprostatic disease extension. Lastly, we found evidence that some microRNAs are androgen-regulated and that tumor microRNAs influence transcript abundance of protein-coding target genes in the cancerous prostate. In cell culture, E2F1 and p21/WAF1 were identified as targets of miR-106b, Bim of miR-32, and exportin-6 and protein tyrosine kinase 9 of miR-1. In summary, microRNA expression becomes altered with the development and progression of prostate cancer. Some of these microRNAs regulate the expression of cancer-related genes in prostate cancer cells. [Cancer Res 2008;68(15):6162–70]
Reciprocal Relationship betweenO6-Methylguanine-DNA Methyltransferase P140K Expression Level and Chemoprotection of Hematopoietic Stem Cells
Authors: Milsom Michael D. , Jerabek-Willemsen Moran , Harris Chad E. , Schambach Axel , Broun Emily , Bailey Jeff , Jansen Michael , Schleimer David , Nattamai Kalpana , Wilhelm Jamie , Watson Amanda , Geiger Hartmut , Margison Geoffrey P. , Moritz Thomas , Baum Christopher , Thomale Jürgen , Williams David A. 
Published: August 2008

AbstractRetroviral-mediated delivery of the P140K mutant O6-methylguanine-DNA methyltransferase (MGMTP140K) into hematopoietic stem cells (HSC) has been proposed as a means to protect against dose-limiting myelosuppressive toxicity ensuing from chemotherapy combining O6-alkylating agents (e.g., temozolomide) with pseudosubstrate inhibitors (such as O6-benzylguanine) of endogenous MGMT. Because detoxification of O6-alkylguanine adducts by MGMT is stoichiometric, it has been suggested that higher levels of MGMT will afford better protection to gene-modified HSC. However, accomplishing this goal would potentially be in conflict with current efforts in the gene therapy field, which aim to incorporate weaker enhancer elements to avoid insertional mutagenesis. Using a panel of self-inactivating gamma-retroviral vectors that express a range of MGMTP140K activity, we show that MGMTP140K expression by weaker cellular promoter/enhancers is sufficient for in vivo protection/selection following treatment with O6-benzylguanine/temozolomide. Conversely, the highest level of MGMTP140K activity did not promote efficient in vivo protection despite mediating detoxification of O6-alkylguanine adducts. Moreover, very high expression of MGMTP140K was associated with a competitive repopulation defect in HSC. Mechanistically, we show a defect in cellular proliferation associated with elevated expression of MGMTP140K, but not wild-type MGMT. This proliferation defect correlated with increased localization of MGMTP140K to the nucleus/chromatin. These data show that very high expression of MGMTP140K has a deleterious effect on cellular proliferation, engraftment, and chemoprotection. These studies have direct translational relevance to ongoing clinical gene therapy studies using MGMTP140K, whereas the novel mechanistic findings are relevant to the basic understanding of DNA repair by MGMT. [Cancer Res 2008;68(15):6171–80]
Long-term Dietary Cadmium Intake and Postmenopausal Endometrial Cancer Incidence: A Population-Based Prospective Cohort Study
Authors: Åkesson Agneta , Julin Bettina , Wolk Alicja 
Published: August 2008

Abstract
Environmental pollutants mimicking the effects of estrogen are suggested to contribute to the high incidence of hormone-related cancers, but supporting data are sparse. A potent estrogen-like activity of the pollutant cadmium, mediated via the estrogen receptor-α, has been shown in vivo. We prospectively examined the association between cadmium exposure and incidence of postmenopausal endometrial cancer. The Swedish Mammography Cohort is a population-based prospective cohort of 30,210 postmenopausal women free of cancer diagnose at baseline (1987) and who completed a food frequency questionnaire at baseline and in 1997. We estimated the dietary cadmium intake based on the questionnaire data and the cadmium content in all foods. During 16.0 years (484,274 person-years) of follow-up between the baseline and mid-2006, we ascertained 378 incident cases of endometrioid adenocarcinoma. The average estimated dietary cadmium intake was 15 μg/day (80% from cereals and vegetables). Cadmium intake was statistically significantly associated with increased risk of endometrial cancer in all women; the multivariate relative risk (RR) was 1.39 [95% confidence interval (CI), 1.04–1.86; Ptrend = 0.019], comparing highest tertile versus lowest. Among never-smoking women with body mass index (BMI) of &lt;27 kg/m2, the RR was 1.86 (95% CI, 1.13–3.08; Ptrend = 0.009). We observed a 2.9-fold increased risk (95% CI, 1.05–7.79) associated with long-term cadmium intake consistently above the median at both baseline 1987 and in 1997 in never-smoking women with low bioavailable estrogen (BMI of &lt;27 kg/m2 and nonusers of postmenopausal hormones). Our results support the hypothesis that cadmium may exert estrogenic effects and thereby increase the risk of hormone-related cancers. [Cancer Res 2008;68(15):6435–41]
MUC1 Oncoprotein Blocks Death Receptor–Mediated Apoptosis by Inhibiting Recruitment of Caspase-8
Authors: Agata Naoki , Ahmad Rehan , Kawano Takeshi , Raina Deepak , Kharbanda Surender , Kufe Donald 
Published: August 2008

Abstract
Stimulation of the death receptor superfamily induces the activation of caspase-8 and thereby the apoptotic response. The MUC1 oncoprotein is aberrantly overexpressed by diverse human malignancies and inhibits stress-induced apoptosis. The present results show that MUC1 blocks activation of caspase-8 and apoptosis in the response of malignant cells to tumor necrosis factor α, tumor necrosis factor–related apoptosis-inducing ligand, and Fas ligand. The results show that MUC1 associates constitutively with caspase-8. The MUC1 cytoplasmic domain (MUC1-CD) binds directly to the caspase-8 p18 fragment upstream to the catalytic Cys360 site. The results also show that MUC1-CD binds to Fas-associated death domain (FADD) at the death effector domain. In nonmalignant epithelial cells, MUC1 interacts with caspase-8 and FADD as an induced response to death receptor stimulation. The functional significance of these interactions is supported by the demonstration that MUC1 competes with caspase-8 for binding to FADD and blocks recruitment of caspase-8 to the death-inducing signaling complex. These findings indicate that MUC1 is of importance to the physiologic regulation of caspase-8 activity and that overexpression of MUC1, as found in human malignancies, could contribute to constitutive inhibition of death receptor signaling pathways. [Cancer Res 2008;68(15):6136–44]