bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of 53BP1 Causes PARP Inhibitor Resistance in Brca1-Mutated Mouse Mammary Tumors
Authors: Jaspers Janneke E. , Kersbergen Ariena , Boon Ute , Sol Wendy , van Deemter Liesbeth , Zander Serge A. , Drost Rinske , Wientjens Ellen , Ji Jiuping , Aly Amal , Doroshow James H. , Cranston Aaron , Martin Niall M.B. , Lau Alan , O'Connor Mark J. , Ganesan Shridar , Borst Piet , Jonkers Jos , Rottenberg Sven 
Published: October 2012

Abstract
Inhibition of PARP is a promising therapeutic strategy for homologous recombination–deficient tumors, such as BRCA1-associated cancers. We previously reported that BRCA1-deficient mouse mammary tumors may acquire resistance to the clinical PARP inhibitor (PARPi) olaparib through activation of the P-glycoprotein drug efflux transporter. Here, we show that tumor-specific genetic inactivation of P-glycoprotein increases the long-term response of BRCA1-deficient mouse mammary tumors to olaparib, but these tumors eventually developed PARPi resistance. In a fraction of cases, this resistance is caused by partial restoration of homologous recombination due to somatic loss of 53BP1. Importantly, PARPi resistance was minimized by long-term treatment with the novel PARP inhibitor AZD2461, which is a poor P-glycoprotein substrate. Together, our data suggest that restoration of homologous recombination is an important mechanism for PARPi resistance in BRCA1-deficient mammary tumors and that the risk of relapse of BRCA1-deficient tumors can be effectively minimized by using optimized PARP inhibitors.
Significance: In this study, we show that loss of 53BP1 causes resistance to PARP inhibition in mouse mammary tumors that are deficient in BRCA1. We hypothesize that low expression or absence of 53BP1 also reduces the response of patients with BRCA1-deficient tumors to PARP inhibitors. Cancer Discov; 3(1); 68–81. ©2012 AACR.
See related commentary by Fojo and Bates, p. 20
This article is highlighted in the In This Issue feature, p. 1
Oncogenic and Wild-type Ras Play Divergent Roles in the Regulation of Mitogen-Activated Protein Kinase Signaling
Authors: Young Amy , Lou David , McCormick Frank 
Published: October 2012

Abstract
H-Ras, K-Ras, and N-Ras regulate cellular growth and survival and are often activated by somatic mutation in human tumors. Although oncogenic lesions occur in a single Ras isoform within individual tumors, it is unclear whether the remaining wild-type isoforms play supporting roles in tumor growth. Here, we show that oncogenic and wild-type Ras isoforms play independent and nonredundant roles within the cell. Oncogenic Ras regulates basal effector pathway signaling, whereas wild-type Ras mediates signaling downstream of activated receptor tyrosine kinases (RTK). We show that both are necessary for exponential growth of Ras-mutant cell lines. Furthermore, we show that oncogenic Ras desensitizes signaling from EGF receptor (EGFR). Depletion of oncogenic Ras with siRNA oligonucleotides relieves this negative feedback, leading to the hyperactivation of EGFR and wild-type Ras signaling. Consistent with this model, combining oncogenic Ras depletion with EGFR inhibition potently increases cell death.
Significance: The results of this study highlight a novel role for wild-type Ras signaling in cancer cells harboring oncogenic RAS mutations. Furthermore, these findings reveal that therapeutically targeting oncogenic Ras signaling alone may be ineffective owing to feedback activation of RTKs, and suggest that blocking upstream RTKs in combination with downstream effector pathways may be beneficial in the treatment of Ras-mutant tumors. Cancer Discov; 3(1); 112–23. ©2012 AACR.
See related commentary by Hayes and Der, p. 24
This article is highlighted in the In This Issue feature, p. 1
Endothelial Lipase Activity Predicts High-Density Lipoprotein Catabolism in Hemodialysis
Authors: Miksztowicz Veronica , McCoy Mary G. , Schreier Laura , Cacciagiú Leonardo , Elbert Alicia , Gonzalez Ana Inés , Billheimer Jeffrey , Eacho Patrick , Rader Daniel J. , Berg Gabriela 
Published: October 2012

Objective—
A novel phospholipase assay was used to measure for the first time the behavior of endothelial and hepatic phospholipase activities in postheparin human plasma of hemodialyzed patients and its relationship with atherogenic and antiatherogenic lipoprotein levels.

Methods and Results—

Endothelial and hepatic phospholipase activity was assessed in a total SN1-specific phospholipase assay, using (1-decanoylthio-1-deoxy-2-decanoyl-sn-glycero-3-phosphoryl) ethylene glycol as the substrate. Hemodialyzed patients presented lower values of total and hepatic phospholipase activity than controls: 4.4 (1.9–9.0) versus 7.5 (3.6–18.0) and 2.6 (0.7–6.2) versus 6.6 (1.3–15.2) μmol of fatty acid released per milliliter of postheparin plasma per hour, respectively (
P
<0.001); however, endothelial lipase (EL) phospholipase activity was increased in patients: 1.7 (0.8–3.0) versus 1.1 (0.1–2.7) μmol of fatty acid released per milliliter of postheparin plasma per hour (
P
=0.008). EL was negatively associated with high-density lipoprotein (HDL)-cholesterol (
r
=–0.427;
P
=0.001), and apolipoprotein A-I levels, total phospholipase, and hepatic lipase activity were directly associated with low-density lipoprotein-cholesterol and apolipoprotein B. The association of EL and HDL-cholesterol remained significant when adjusting for waist circumference (β=–0.26;
P
=0.05), and the effect of hepatic lipase on low-density lipoprotein-cholesterol continued after adjusting for age (β=0.46;
P
= 0.001).

Conclusion—
Our results support the hypothesis that EL is the predominant enzyme responsible for lipolytic catabolism of HDLs in hemodialyzed patients and resolve the apparent paradox observed between low hepatic lipase activity and decreased HDL-cholesterol levels observed in these patients. In addition, the ability to assess total hepatic lipase and EL phospholipase activity in plasma will increase our knowledge of the mechanisms involved in controlling HDL levels and cardiovascular risk in hemodialyzed patients, as well as other populations with low levels of HDL-cholesterol.
Inflammatory Cytokines Promote Mesenchymal Transformation in Embryonic and Adult Valve Endothelial Cells
Authors: Mahler Gretchen J. , Farrar Emily J. , Butcher Jonathan T. 
Published: October 2012

Objective—
Inflammatory activation of valve endothelium is an early phase of aortic valve disease pathogenesis, but subsequent mechanisms are poorly understood. Adult valve endothelial cells retain the developmental ability to undergo endothelial-to-mesenchymal transformation (EndMT), but a biological role has not been established. Here, we test whether and how inflammatory cytokines (tumor necrosis factor-α and interleukin-6) regulate EndMT in embryonic and adult valve endothelium.

Methods and Results—
Using in vitro 3-dimensional collagen gel culture assays with primary cells, we determined that interleukin-6 and tumor necrosis factor-α induce EndMT and cell invasion in dose-dependent manners. Inflammatory-EndMT occurred through an Akt/nuclear factor-κB–dependent pathway in both adult and embryonic stages. In embryonic valves, inflammatory-EndMT required canonical transforming growth factor-β signaling through activin receptor-like kinases 2 and 5 to drive EndMT. In adult valve endothelium, however, inflammatory-induced EndMT still occurred when activin receptor-like kinases 2 and 5 signaling was blocked. Inflammatory receptor gene expression was significantly upregulated in vivo during embryonic valve maturation. Endothelial-derived mesenchymal cells expressing activated nuclear factor-κB were found distal to calcific lesions in diseased human aortic valves.

Conclusion—
Inflammatory cytokine–induced EndMT in valve endothelium is present in both embryonic and adult stages, acting through Akt/nuclear factor-κB, but differently using transforming growth factor-β signaling. Molecular signatures of valve EndMT may be important diagnostic and therapeutic targets in early valve disease.
Lipid Phosphate Phosphatase 3 Negatively Regulates Smooth Muscle Cell Phenotypic Modulation to Limit Intimal Hyperplasia
Authors: Panchatcharam Manikandan , Miriyala Sumitra , Salous Abdelghaffar , Wheeler Jessica , Dong Anping , Mueller Paul , Sunkara Manjula , Escalante-Alcalde Diana , Morris Andrew J. , Smyth Susan S. 
Published: October 2012

Objective—
The lipid phosphate phosphatase 3 (LPP3) degrades bioactive lysophospholipids, including lysophosphatidic acid and sphingosine-1-phosphate, and thereby terminates their signaling effects. Although emerging evidence links lysophosphatidic acid to atherosclerosis and vascular injury responses, little is known about the role of vascular LPP3. The goal of this study was to determine the role of LPP3 in the development of vascular neointima formation and smooth muscle cells (SMC) responses.

Methods and Results—
We report that LPP3 is expressed in vascular SMC after experimental arterial injury. Using gain- and loss-of-function approaches, we establish that a major function of LPP3 in isolated SMC cells is to attenuate proliferation (extracellular signal-regulated kinases) activity, Rho activation, and migration in response to serum and lysophosphatidic acid. These effects are at least partially a consequence of LPP3-catalyzed lysophosphatidic acid hydrolysis. Mice with selective inactivation of LPP3 in SMC display an exaggerated neointimal response to injury.

Conclusion—

Our observations suggest that LPP3 serves as an intrinsic negative regulator of SMC phenotypic modulation and inflammation after vascular injury, in part, by regulating lysophospholipid signaling. These findings may provide a mechanistic link to explain the association between a
PPAP2B
polymorphism and coronary artery disease risk.
Interobserver Agreement of ASPECT Score Distribution for Noncontrast CT, CT Angiography, and CT Perfusion in Acute Stroke
Authors: Finlayson Olga , John Verity , Yeung Robert , Dowlatshahi Dar , Howard Peter , Zhang Liying , Swartz Rick , Aviv Richard I. 
Published: October 2012

Background and Purpose—
The Alberta Stroke program early CT score (ASPECTS) is a semiquantative scale for estimating extent and distribution of early ischemic changes within the MCA territory in the acute stroke setting. Good interobserver agreement of total ASPECTS is demonstrated for noncontrast CT (NCCT) and other imaging modalities. Our purpose is to assess interobserver agreement for individual ASPECTS regions for different imaging modalities.

Methods—
One hundred and eighty-one consecutive patients presenting with acute stroke symptoms within 4.5 hours of onset were included. Four readers assigned total and individual ASPECTS for NCCT, CT angiography source images (CTA-SI), and CTP maps of cerebral blood volume (CTP-CBV). Interobserver agreement was assessed by measuring internal consistency and concordance of total and individual ASPECTS using Cronbach’s α and intraclass correlation coefficient, respectively.

Results—
Total ASPECTS demonstrated very good concordance and internal consistency for all 3 modalities. Intraclass correlation coefficient and Cronbach’s α were 0.834 and 0.859 for NCCT, 0.876 and 0.894 for CTA, and 0.903 and 0.911 for CTP-CBV, respectively. Performance for individual ASPECTS regions was inferior to total ASPECTS, but incremental improvement in interobserver reliability was demonstrated for NCCT, CTA-SI, and CTP-CBV, respectively. Highest concordance was shown for caudate, lentiform, and M1–M3, whereas performance for internal capsule and M4–M6 was poorer.

Conclusions—
CTP-CBV demonstrates the highest interobserver agreement for individual ASPECTS regions.
Baseline Smoking Status and the Long-Term Risk of Death or Nonfatal Vascular Event in People with Stroke
Authors: Kim Joosup , Gall Seana L. , Dewey Helen M. , Macdonell Richard A. L. , Sturm Jonathan W. , Thrift Amanda G. 
Published: October 2012

Background and Purpose—
Smoking may exacerbate the risk of death or further vascular events in those with stroke, but data are limited.

Methods—
1589 cases of first-ever and recurrent stroke were recruited between 1996 and 1999 from a defined geographical region in North East Melbourne. Both hospital and nonhospital cases were included. Over a 10-year period, all deaths, recurrent stroke events, and acute myocardial infarctions that were reported at follow-up interviews were validated using medical records. Cox proportional hazards regression was used to assess the association between baseline smoking status (never, ex, and current) and outcome (death, acute myocardial infarction, or recurrent stroke).

Results—

Patients who were current smokers (Hazard Ratio [HR], 1.30; 95% Confidence Interval [CI], 1.06–1.60;
P
=0.012) at the time of their stroke had poorer outcome when compared with those who had never smoked. Among those who survived the first 28 days of stroke, current smokers (HR, 1.42; 95% CI, 1.13–1.78;
P
<0.003) and ex-smokers (HR, 1.18; 95% CI, 1.01–1.39;
P
=0.039) at baseline had poorer outcome than those who had never smoked. Current smokers also had a greater risk of recurrent events than past smokers (HR, 1.23; 95% CI, 1.00–1.50;
P
=0.050).

Conclusions—
Patients who smoked at the time of their stroke or had smoked before their stroke had greater risk of death or recurrent vascular events when compared with patients who were never smokers. There are benefits of smoking cessation, with ex-smokers appearing to have a lesser risk of recurrent vascular events than current smokers.
Decadal Response of the Kuroshio Extension Jet to Rossby Waves: Observation and Thin-Jet Theory*
Authors: Sasaki Yoshi N. , Minobe Shoshiro , Schneider Niklas 
Published: October 2012

AbstractThis study examines interannual to decadal variability of the Kuroshio Extension (KE) jet using satellite altimeter observations from 1993 to 2010. The leading empirical orthogonal function (EOF) mode of sea level variability in the KE region represents the meridional shift of the KE jet, followed by its strength changes with a few month lag. This shift of the KE jet lags atmospheric fluctuations over the eastern North Pacific by about three years. Broad sea level anomalies (SLAs) emerge in the eastern North Pacific 3–4 years before the upstream KE jet shift, and propagate westward along the KE jet axis. In the course of the propagation, the meridional scale of the SLAs gradually narrows, and their amplitude increases. This westward propagation of SLAs with a speed of about 5 cm s−1 is attributed to the westward propagation of the meridional shift of the jet, consistent with the thin-jet theory, whose importance has been suggested by previous numerical studies. In addition, the westward-propagating signals tend to conserve their quasigeostrophic potential vorticity anomaly, which may explain the characteristic changes of SLAs during the propagation. After the westward-propagating signals of positive (negative) SLAs reach at the east coast of Japan, the upstream KE jet strengthens (weakens) associated with the strength changes of the northern and southern recirculation gyres. Interestingly, this strength change of the KE jet propagates eastward with a speed of about 6 cm s−1, suggesting an importance of advection by the current.
Multivariate analysis of countries’ government and health-care system influences on opioid availability for cancer pain relief and palliative care: More than a function of human development
Authors: Gilson Aaron M , Maurer Martha A , LeBaron Virginia T , Ryan Karen M , Cleary James F 
Published: October 2012

Background: Many international governmental and nongovernmental organizations regard unrelieved cancer pain as a significant global public health problem. Although opioids such as morphine are considered essential medicines in the provision of palliative care and for treating cancer pain, especially when the pain is severe, low- and middle-income countries often lack such medications. Aim: The primary aim of this study was to examine countries’ government and health-care system influences on opioid availability for cancer pain and palliative care, as a means to identify implications for improving appropriate access to prescription opioids. Design: A multivariate regression of 177 countries’ consumption of opioids (in milligrams/death from cancer and AIDS) contained country-level predictor variables related to public health, including Human Development Index, palliative care infrastructure, and health system resources and expenditures. Results: Results were highly explanatory (adjusted R2 = 82%) and Human Development Index was the most predictive variable when controlling for all other factors in the statistical model (B = 11.875, confidence interval = 10.216, 13.534, p < 0.0001). Conclusions: Study findings demonstrate that a limited number of predictor variables characterizing a country’s government and health-care system infrastructure can explain its opioid consumption level, with the greatest influence being very high Human Development Index. However, Human Development Index is not the most policy-relevant factor, and this finding should be reconciled against the reality that many countries with low or medium Human Development Index have succeeded in creating and sustaining a health-care system to strengthen cancer pain care and palliative care, including through the appropriate use of essential prescription opioids.
Similarities and differences between continuous sedation until death and euthanasia – professional caregivers’ attitudes and experiences: A focus group study
Authors: Anquinet Livia , Raus Kasper , Sterckx Sigrid , Smets Tinne , Deliens Luc , Rietjens Judith AC 
Published: October 2012

Background: According to various guidelines about continuous sedation until death, this practice can and should be clearly distinguished from euthanasia, which is legalized in Belgium. Aim: To explore professional caregivers’ perceptions of the similarities and differences between continuous sedation until death and euthanasia. Design: Qualitative data were gathered through focus groups. Questions pertained to participants’ perceptions of continuous sedation. The focus groups were recorded and transcribed verbatim. Analyses were conducted by a multidisciplinary research team using constant comparison analyses. Setting/Participants: We did four focus groups at Ghent University Hospital: two with physicians (n = 4 and n = 4) and two with nurses (n = 4 and n = 9). The participants could participate if they were ever involved in the use of continuous sedation until death. Results: Although the differences and similarities between continuous sedation until death and euthanasia were not specifically addressed in the questions addressed in the focus groups, it emerged as an important theme in the participants’ accounts. Many caregivers elaborated on the differences between both practices, particularly with regard to patients’ preferences and requests, decision-making and physicians’ intentions. However, some stated that the distinction between the two sometimes becomes blurred, especially when the sedating medication is increased disproportionally or when sedation is used for patients with a longer life expectancy. Conclusions: The differences and similarities between continuous sedation until death and euthanasia is an issue for several Flemish professional caregivers in their care for unbearably suffering patients at the end of life. Although guidelines strictly distinguish both practices, this may not always be the case in Flemish clinical practice.
Do Cartilage Repair Procedures Prevent Degenerative Meniscus Changes?: Longitudinal T1ρ and Morphological Evaluation With 3.0-T MRI
Authors: Jungmann Pia M. , Li Xiaojuan , Nardo Lorenzo , Subburaj Karupppasamy , Lin Wilson , Ma C. Benjamin , Majumdar Sharmila , Link Thomas M. 
Published: October 2012

Background: Cartilage repair (CR) procedures are widely accepted for treatment of isolated cartilage defects in the knee joint. However, it is not well known whether these procedures prevent degenerative joint disease. Hypothesis: Cartilage repair procedures prevent accelerated qualitative and quantitative progression of meniscus degeneration in individuals with focal cartilage defects. Study Design: Cohort study; Level of evidence, 2. Methods: Ninety-four subjects were studied. Cartilage repair procedures were performed on 34 patients (osteochondral transplantation, n = 16; microfracture, n = 18); 34 controls were matched. An additional 13 patients received CR and anterior cruciate ligament (ACL) reconstruction (CR&ACL), and 13 patients received only ACL reconstruction. Magnetic resonance imaging at 3.0-tesla with T1ρ mapping and sagittal fat-saturated intermediate-weighted fast spin echo (FSE) sequences was performed to quantitatively and qualitatively analyze menisci (Whole-Organ Magnetic Resonance Imaging Score [WORMS] assessment). Patients in the CR and CR&ACL groups were examined 4 months (n = 34; n = 13), 1 year (n = 21; n = 8), and 2 years (n = 9; n = 5) after CR. Control subjects were scanned at baseline and after 1 and 2 years, ACL patients after 1 and 2 years. Results: At baseline, global meniscus T1ρ values (mean ± SEM) were higher in individuals with CR (14.2 ± 0.5 ms; P = .004) and in individuals with CR&ACL (17.1 ± 0.9 ms; P < .001) when compared with controls (12.8 ± 0.6 ms). After 2 years, there was a statistical difference between T1ρ at the overlying meniscus above cartilage defects (16.4 ± 1.0 ms) and T1ρ of the subgroup of control knees without cartilage defects (12.1 ± 0.8 ms; P < .001) and a statistical trend to the CR group (13.3 ± 1.0 ms; P = .09). At baseline, 35% of subjects with CR showed morphological meniscus tears at the overlying meniscus; 10% of CR subjects showed an increase in the WORMS meniscus score within the first year, and none progressed in the second year. Control subjects with (without) cartilage defects showed meniscus tears in 30% (5%) at baseline; 38% (19%) increased within the first year, and 15% (10%) within the second year. Conclusion: This study demonstrated more severe meniscus degeneration after CR surgery compared with controls. However, progression of T1ρ values was not observed from 1 to 2 years after surgery. These results suggest that CR may prevent degenerative meniscus changes.